Sulfated pillar aromatics, method for preparing same and use thereof

Abstract

Sulfated pillararenes and methods for preparing and using the same are provided. The pillararenes have a macrocyclic core having multiple aryl groups attached (e.g., covalently bonded) to adjacent methylene groups via para-substitution. The pillararenes have a hydrophobic cavity. The hydrophobic cavity can be used to chelate various materials or deliver chelated materials therein.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 62 / 982,460, filed on February 27, 2020, and U.S. Provisional Application No. 63 / 013,336, filed on April 21, 2020, the disclosures of which are incorporated herein by reference.

[0003] Statement Regarding Federally Funded Research

[0004] This invention was made with government support under Contract No. CHE-1404911 awarded by the National Science Foundation. The government has certain rights in this invention. Background Art

[0005] Several classes of molecular container compounds are known, including cyclodextrins, calixarenes, cyclophanes, pillararenes, and cucurbiturils. These molecular container compounds bind to their target molecules in solution and thereby modulate the properties of the target, including optical properties, solubility, odor, and even biological activity. Previous workers in the field of pillar[n]arenes have synthesized container molecules characterized by a hydrophobic cavity and carboxylic acid solubilizing groups and have shown that they bind with good affinity to cationic targets in water. The challenge in this field is how to create new molecular containers or modify existing ones so that they maintain good solubility in water while enhancing their binding affinity to their targets. Summary of the Invention

[0006] The present disclosure provides sulfated pillararene. The present disclosure also provides a method for preparing sulfated pillararene and its use.

[0007] In the present disclosure, it is demonstrated that, for example, positioning anion solubilizing groups (e.g., sulfate groups) at the edges of pillararenes' cavities significantly enhances their binding affinity for cationic targets in water and thereby increases their ability to act as chelating agents for various applications.

[0008] In one aspect, the present disclosure provides compounds. These compounds are sulfated pillararenes. Sulfated pillararenes comprise a macrocyclic core comprising a plurality of aryl groups, wherein adjacent aryl groups are covalently linked (e.g., bonded) via an alkyl linking group (e.g., a -CH2- group). The alkyl linking group is in the para position on the aryl group (e.g., a 1,4-phenyl bond). These bonds can be on different phenyl rings of the aryl group, and if the different phenyl rings overlap, they correspond to para bonds. In multiple examples, one or more or all of the adjacent aryl groups are not covalently linked (e.g., 1,3-phenyl bonds (wherein these bonds are on different phenyl rings or aryl groups, if the different phenyl rings overlap, these bonds do not correspond to meta bonds)) via an alkyl linking group at a meta position on the aryl group. Non-limiting examples of sulfated pillararenes are provided herein. Non-limiting examples of methods for preparing sulfated pillararenes are provided herein.

[0009] In one aspect, the present disclosure provides compositions comprising one or more sulfated pillararenes.Non-limiting examples of compositions are described herein.

[0010] The composition can include one or more sulfated pillararenes and one or more agents. In various examples, the agent comprises one or more positively charged nitrogen atoms (e.g., ammonium ions, primary ammonium ions, secondary ammonium ions, tertiary ammonium ions, quaternary ammonium ions, or combinations thereof, wherein the one or more non-hydrogen groups on the ammonium are selected from aliphatic groups, alkyl groups, aryl groups, and combinations thereof).

[0011] In one aspect, the present disclosure provides uses of sulfated pillararenes. Non-limiting examples of uses of sulfated pillararenes are provided herein.

[0012] Sulfated pillar arenes can be used to chelate various materials, which can be chemical compounds. In a number of non-limiting examples, one or more sulfated pillar arenes are used to chelate one or more neuromuscular blockers (such as, for example, rocuronium, tubocurarine, atracurium, (cis) atracurium besylate, mivacurium, gallamine, pancuronium, vecuronium, and rapacuronium, etc.); one or more anesthetics (such as, for example, N-methyl D-aspartate (NMDA) receptor antagonists (such as ketamine, etc.), short-acting anesthetics (such as etomidate, etc.), etc.); one or more pharmaceutical agents (such as, for example, drugs (such as anticoagulants, such as hexadimethrine, drugs of abuse (such as methamphetamine, cocaine, fentanyl, carfentanil, etc.), etc.); one or more pesticides (such as paraquat, diquat, organochlorines (such as DDT, aldrin, etc.), neonicotinoids (such as permethrin, etc.), organophosphates (such as malathion, glyphosate, etc.), pyrethroids, triazines (such as atrazine, etc.), etc.); one or more dyes (such as methylene blue, Nile red, etc.), etc. red), crystal violet, thioflavin T, thiazole orange, proflavin, acridine orange, methylene violet, azure A, neutral red, cyanine, direct orange 26, disperse dyes (e.g., disperse yellow 3, disperse blue 27, etc.), coumarin, Congo red, etc.); one or more malodorous compounds (such as, for example, low molecular weight thiols (e.g., C1-C4 thiols), low molecular weight amines (e.g., triethylamine, putrescein, cadaverine, etc.), etc.);or one or more chemical warfare agents (such as, for example, nitrogen mustard and sulfur mustard (e.g., bis(2-chloroethyl)ethylamine, bis(2-chloroethyl)methylamine, tris(2-chloroethyl)amine, bis(2-chloroethyl)sulfide, bis(2-chloroethylthioethyl)ether, etc.), nerve agents (such as, for example, those from the G, GV, and V series of nerve agents (e.g., tabun, sarin, soman, cyclosarin, 2-(dimethylamino)ethyl N,N-dimethylphosphoramidofluorate (GV), novichok agent, VE, VG, VM, VX, etc.), etc.), or a combination thereof.; BRIEF DESCRIPTION OF THE DRAWINGS

[0013] For a fuller understanding of the nature and objectives of the present disclosure, reference should be made to the following detailed description taken in conjunction with the accompanying drawings.

[0014] Figure 1 Examples of hosts (sulfated pillararenes) are shown.

[0015] Figure 2 Examples of cationic guests are shown.

[0016] Figure 3 Examples of drug abuse are shown.

[0017] Figure 4 Examples of neuromuscular blocking agents are shown.

[0018] Figure 5 Binding constants for complexes of exemplary hosts with cationic guests are shown.

[0019] Figure 6 Binding constants for complexes of exemplary hosts and drugs of abuse are shown.

[0020] Figure 7 Binding constants for complexes of exemplary hosts with neuromuscular blocking agents are shown.

[0021] Figure 8 Shows the recorded 1 H NMR spectra (500 MHz, RT, 20 mM phosphate-buffered D2O): a) P[6]AS, b) methamphetamine, c) an equimolar mixture of P[6]AS and methamphetamine (0.5 mM), and d) a 2:1 mixture of methamphetamine (1 mM) and P[6]AS (0.5 mM).

[0022] Figure 9 Shows the recorded 1H NMR spectra (500 MHz, RT, 20 mM phosphate-buffered D2O): a) P[6]AS, b) Motor 2, c) rocuronium, d) equimolar mixture of P[6]AS and rocuronium, e) equimolar mixture of Motor 2 and rocuronium, f) mixture of Motor 2 and rocuronium followed by the addition of P[6]AS, g) mixture of P[6]AS and rocuronium followed by the addition of Motor 2.

[0023] Figure 10 The crystal structure of P[6]AS is shown.

[0024] Figure 11 Shown are a) the structures of CB[n] and M2. b) the preparation of Column[n]MaxQ (P[5]AS-P[7]AS) and P[5]ACS, and the structure of WP[n]. Conditions: a) Py·SO3, pyridine, 90°C; b) propane sultone, NaOH, acetone, 8%.

[0025] Figure 12 Shown are the recorded values ​​for the following solutions: 1 H NMR spectra (600 MHz, D2O, 298 K): a) P[6]AS (1 mM), b) guest 25 (1 mM), c) mixture of P[6]AS (1 mM) and guest 25 (1 mM); d) mixture of P[6]AS (1 mM) and guest 25 (2 mM).

[0026] Figure 13 The X-ray crystal structures of P[6]AS and P[5]ACS are shown. a) Cross-eyed stereoview of a P[6]AS molecule in a unit cell. b) Views of the stacking of P[6]AS in the crystal along the z-axis and c) y-axis. d) Cross-eyed stereoview of a P[5]ACS molecule in a unit cell.

[0027] Figure 14 Shown are a) DP versus time plots from titration of a mixture of P[6]AS (100 μM) and 17 (500 μM) in a cell with 20 (1 mM) in a syringe. b) ΔH versus the molar ratio of P[6]AS to 20; the solid line represents the best fit of the data to a competitive binding model implemented in the PEAQ-ITC data analysis software, where K a =(1.20±0.06)×10 11 M -1 and ΔH = -17.1 ± 0.033 kcal mol -1 .

[0028] Figure 15Shows the recorded 1 H NMR spectra (600 MHz, D2O, RT): a) P[6]AS (1 mM), b) M2 (0.5 mM), c) rocuronium (0.5 mM), d) P[6]AS·rocuronium (0.5 mM), e) M2·rocuronium (0.5 mM), and f) the solution from fraction e after treatment with 1 equivalent of P[6]AS. Proton labels for M2, P[6]AS, and rocuronium are shown in Table 1. Figure 11 and Figure 4 Given in.

[0029] Figure 16 Shows the recorded data for P[5]ACS 1 H NMR spectrum (400 MHz, D2O, RT).

[0030] Figure 17 Shows the recorded data for P[5]ACS 13 C NMR spectroscopy (150 MHz, D2O, EtOH as internal reference, RT).

[0031] Figure 18 Shows the recorded values ​​for P[5]AS 1 H NMR spectrum (600 MHz, D2O, RT).

[0032] Figure 19 Shows the recorded values ​​for P[5]AS 13 C NMR spectroscopy (150 MHz, D2O, EtOH as internal reference, RT).

[0033] Figure 20 Shows the recorded values ​​for P[6]AS 1 H NMR spectrum (600 MHz, D2O, RT).

[0034] Figure 21 Shows the recorded values ​​for P[6]AS 13 C NMR spectroscopy (150 MHz, D2O and CD3OD 10:1, RT).

[0035] Figure 22 Shows the recorded values ​​for P[7]AS 1 H NMR spectrum (600 MHz, D2O, RT).

[0036] Figure 23 Shows the recorded values ​​for P[7]AS 13 C NMR spectrum (150 MHz, D2O, dioxane as external reference, RT).

[0037] Figure 24 Shows the recorded 1 H NMR spectra (600 MHz, RT, 20 mM phosphate-buffered D2O): a) P[5]ACS, b) 17, c) an equimolar mixture of P[5]ACS and 17 (1 mM), and d) a 2:1 mixture of 17 (2 mM) and P[5]ACS (1 mM).

[0038] Figure 25 Shows the recorded 1 H NMR spectra (600 MHz, RT, 20 mM phosphate-buffered D2O): a) P[5]ACS, b) 21, c) an equimolar mixture of P[5]ACS and 21 (1 mM), and d) a 2:1 mixture of 21 (2 mM) and P[5]ACS (1 mM).

[0039] Figure 26 Shows the recorded 1 H NMR spectra (600 MHz, RT, 20 mM phosphate-buffered D2O): a) P[5]AS, b) 23, c) an equimolar mixture of P[5]AS and 23 (1 mM), and d) a 2:1 mixture of 23 (2 mM) and P[5]AS (1 mM).

[0040] Figure 27 Shows the recorded 1 H NMR spectra (600 MHz, RT, 20 mM phosphate-buffered D2O): a) P[5]AS, b) 21, c) an equimolar mixture of P[5]AS and 21 (1 mM), and d) a 2:1 mixture of 21 (2 mM) and P[5]AS (1 mM).

[0041] Figure 28 Shows the recorded 1 H NMR spectra (600 MHz, RT, 20 mM phosphate-buffered D2O): a) P[5]AS, b) 22, c) an equimolar mixture of P[5]AS and 22 (1 mM) and d) a 2:1 mixture of 22 (2 mM) and P[5]AS (1 mM), e) a 3:1 mixture of 22 (3 mM) and P[5]AS (1 mM), and f) a 4:1 mixture of 22 (4 mM) and P[5]AS (1 mM).

[0042] Figure 29 Shows the recorded 1H NMR spectra (600 MHz, RT, 20 mM phosphate-buffered D2O): a) P[5]AS, b) 12, c) an equimolar mixture of P[5]AS and 12 (1 mM), and d) a 2:1 mixture of 12 (2 mM) and P[5]AS (1 mM), e) a 3:1 mixture of 12 (3 mM) and P[5]AS (1 mM), and f) a 4:1 mixture of 12 (4 mM) and P[5]AS (1 mM).

[0043] Figure 30 Shows the recorded 1 H NMR spectra (600 MHz, RT, 20 mM phosphate-buffered D2O): a) P[5]AS, b) 25, c) an equimolar mixture of P[5]AS and 25 (0.5 mM), d) a 2:1 mixture of 25 (1 mM) and P[5]AS (0.5 mM), e) a 3:1 mixture of 25 (1.5 mM) and P[5]AS (0.5 mM), and f) a 4:1 mixture of 25 (2 mM) and P[5]AS (0.5 mM).

[0044] Figure 31 Shows the recorded 1 H NMR spectra (600 MHz, RT, 20 mM phosphate-buffered D2O): a) P[5]AS, b) 26, c) an equimolar mixture of P[5]AS and 26 (0.5 mM), d) a 2:1 mixture of 26 (1 mM) and P[5]AS (0.5 mM), and e) a 3:1 mixture of 26 (1.5 mM) and P[5]AS (0.5 mM).

[0045] Figure 32 Shows the recorded 1 H NMR spectra (600 MHz, RT, 20 mM phosphate-buffered D2O): a) P[6]AS, b) 23, c) an equimolar mixture of P[6]AS and 23 (1 mM), and d) a 2:1 mixture of 23 (2 mM) and P[6]AS (1 mM).

[0046] Figure 33 Shows the recorded 1 H NMR spectra (600 MHz, RT, 20 mM phosphate-buffered D2O): a) P[6]AS, b) 17, c) an equimolar mixture of P[6]AS and 17 (1 mM), and d) a 2:1 mixture of 17 (2 mM) and P[6]AS (1 mM).

[0047] Figure 34 Shows the recorded 1H NMR spectra (600 MHz, RT, 20 mM phosphate-buffered D2O): a) P[6]AS, b) 24, c) an equimolar mixture of P[6]AS and 24 (1 mM), and d) a 2:1 mixture of 24 (2 mM) and P[6]AS (1 mM).

[0048] Figure 35 Shows the recorded 1 H NMR spectra (600 MHz, RT, 20 mM phosphate-buffered D2O): a) P[6]AS, b) 11, c) an equimolar mixture of P[6]AS and 11 (1 mM), and d) a 2:1 mixture of 11 (2 mM) and P[6]AS (1 mM).

[0049] Figure 36 Shows the recorded 1 H NMR spectra (600 MHz, RT, 20 mM phosphate-buffered D2O): a) P[6]AS, b) 12, c) an equimolar mixture of P[6]AS and 12 (1 mM), and d) a 2:1 mixture of 12 (2 mM) and P[6]AS (1 mM).

[0050] Figure 37 Shows the recorded 1 H NMR spectra (600 MHz, RT, 20 mM phosphate-buffered D2O): a) P[6]AS, b) 21, c) an equimolar mixture of P[6]AS and 21 (1 mM), and d) a 2:1 mixture of 21 (2 mM) and P[6]AS (1 mM).

[0051] Figure 38 Shows the recorded 1 H NMR spectra (600 MHz, RT, 20 mM phosphate-buffered D2O): a) P[6]AS, b) 22, c) an equimolar mixture of P[6]AS and 22 (1 mM), and d) a 2:1 mixture of 22 (2 mM) and P[6]AS (1 mM).

[0052] Figure 39 Shows the recorded 1 H NMR spectra (600 MHz, RT, 20 mM phosphate-buffered D2O): a) P[6]AS, b) 26, c) an equimolar mixture of P[6]AS and 26 (0.5 mM), and d) a 2:1 mixture of 26 (1 mM) and P[6]AS (0.5 mM).

[0053] Figure 40 Shows the recorded1 H NMR spectra (600 MHz, RT, 20 mM phosphate-buffered D 2 O): a) P[7]AS, b) 11, c) an equimolar mixture of P[7]AS and 11 (0.5 mM), and d) a 2:1 mixture of 11 (1 mM) and P[7]AS (0.5 mM).

[0054] Figure 41 Shows the recorded 1 H NMR spectra (600 MHz, RT, 20 mM phosphate-buffered D2O): a) P[7]AS, b) 17, c) an equimolar mixture of P[7]AS and 17 (0.5 mM), and d) a 2:1 mixture of 17 (1 mM) and P[7]AS (0.5 mM).

[0055] Figure 42 Shows the recorded 1 H NMR spectra (600 MHz, RT, 20 mM phosphate-buffered D2O): a) P[7]AS, b) 23, c) an equimolar mixture of P[7]AS and 23 (0.5 mM), and d) a 2:1 mixture of 23 (1 mM) and P[7]AS (0.5 mM).

[0056] Figure 43 Shows the recorded 1 H NMR spectra (600 MHz, RT, 20 mM phosphate-buffered D2O): a) P[7]AS, b) 21, c) an equimolar mixture of P[7]AS and 21 (0.5 mM), and d) a 2:1 mixture of 21 (1 mM) and P[7]AS (0.5 mM).

[0057] Figure 44 Shows the recorded 1 H NMR spectra (600 MHz, RT, 20 mM phosphate-buffered D2O): a) P[7]AS, b) 22, c) an equimolar mixture of P[7]AS and 22 (0.5 mM), and d) a 2:1 mixture of 22 (1 mM) and P[7]AS (0.5 mM).

[0058] Figure 45 Shows the recorded 1 H NMR spectra (600 MHz, RT, 20 mM phosphate-buffered D2O): a) P[5]AS, b) acetylcholine, c) an equimolar mixture of P[5]AS and acetylcholine (0.5 mM), and d) a 2:1 mixture of acetylcholine (1 mM) and P[5]AS (0.5 mM).

[0059] Figure 46 Shows the recorded 1 H NMR spectra (600 MHz, RT, 20 mM phosphate-buffered D2O): a) P[5]AS, b) rocuronium, c) an equimolar mixture of P[5]AS and rocuronium (0.5 mM), d) a 2:1 mixture of rocuronium (1 mM) and P[5]AS (0.5 mM), and e) a 3:1 mixture of rocuronium (1.5 mM) and P[5]AS (0.5 mM).

[0060] Figure 47 Shows the recorded 1 H NMR spectra (600 MHz, RT, 20 mM phosphate-buffered D2O): a) P[5]AS, b) vecuronium, c) an equimolar mixture of P[5]AS and vecuronium (0.5 mM), d) a 2:1 mixture of vecuronium (1 mM) and P[5]AS (0.5 mM), and e) a 3:1 mixture of vecuronium (1.5 mM) and P[5]AS (0.5 mM).

[0061] Figure 48 Shows the recorded 1 H NMR spectra (600 MHz, RT, 20 mM phosphate-buffered D2O): a) P[5]AS, b) pancuronium, c) an equimolar mixture of P[5]AS and pancuronium (0.5 mM), d) a 2:1 mixture of pancuronium (1 mM) and P[5]AS (0.5 mM), and e) a 3:1 mixture of pancuronium (1.5 mM) and P[5]AS (0.5 mM).

[0062] Figure 49 Shows the recorded 1 H NMR spectra (600 MHz, RT, 20 mM phosphate-buffered D2O): a) P[6]AS, b) vecuronium, c) an equimolar mixture of P[6]AS and vecuronium (0.5 mM), and d) a 2:1 mixture of vecuronium (1 mM) and P[6]AS (0.5 mM).

[0063] Figure 50 Shows the recorded 1 H NMR spectra (600 MHz, RT, 20 mM phosphate-buffered D2O): a) P[6]AS, b) acetylcholine, c) an equimolar mixture of P[6]AS and acetylcholine (0.5 mM), and d) a 2:1 mixture of acetylcholine (1 mM) and P[6]AS (0.5 mM).

[0064] Figure 51 Shows the recorded 1 H NMR spectra (600 MHz, RT, 20 mM phosphate-buffered D2O): a) P[6]AS, b) rocuronium, c) an equimolar mixture of P[6]AS and rocuronium (0.5 mM), and d) a 2:1 mixture of rocuronium (1 mM) and P[6]AS (0.5 mM).

[0065] Figure 52 Shows the recorded 1 H NMR spectra (600 MHz, RT, 20 mM phosphate-buffered D2O): a) P[6]AS, b) pancuronium, c) an equimolar mixture of P[6]AS and pancuronium (0.5 mM), and d) a 2:1 mixture of pancuronium (1 mM) and P[6]AS (0.5 mM).

[0066] Figure 53 Shows the recorded 1 H NMR spectra (600 MHz, RT, 20 mM phosphate-buffered D2O): a) P[7]AS, b) vecuronium, c) an equimolar mixture of P[7]AS and vecuronium (0.5 mM), and d) a 2:1 mixture of vecuronium (1 mM) and P[7]AS (0.5 mM).

[0067] Figure 54 Shows the recorded 1 H NMR spectra (600 MHz, RT, 20 mM phosphate-buffered D2O): a) P[7]AS, b) rocuronium, c) an equimolar mixture of P[7]AS and rocuronium (0.5 mM), and d) a 2:1 mixture of rocuronium (1 mM) and P[7]AS (0.5 mM).

[0068] Figure 55 Shows the recorded 1 H NMR spectra (600 MHz, RT, 20 mM phosphate-buffered D2O): a) P[7]AS, b) pancuronium, c) an equimolar mixture of P[7]AS and pancuronium (0.5 mM), and d) a 2:1 mixture of pancuronium (1 mM) and P[7]AS (0.5 mM).

[0069] Figure 56 Shows the recorded 1H NMR spectra (600 MHz, RT, 20 mM phosphate-buffered D2O): a) P[7]AS, b) cisatracurium, c) 1:4 mixture of cisatracurium (0.125 mM) and P[7]AS (0.5 mM), d) 1:2 mixture of cisatracurium (0.25 mM) and P[7]AS (0.5 mM), e) equimolar mixture of P[7]AS and cisatracurium (0.5 mM).

[0070] Figure 57 The recorded values ​​for dilutions of the bulk P[5]AS (20.0-0.1 mM) are shown. 1 H NMR spectroscopy (600 MHz, D2O, 298 K). The host P[5]AS is weakly self-associated in water, as evidenced by upfield chemical shift changes in the aromatic region at 7.33-7.40 ppm protons.

[0071] Figure 58 A plot of the chemical shift of P[5]AS versus [P[5]AS] is shown. The solid line represents the best nonlinear fit of the data to a 2-sheet self-association model, where K a =19.7M -1 .

[0072] Figure 59 The data recorded for dilutions of P[6]AS (20.0-0.1 mM) are shown. 1 H NMR spectroscopy (600 MHz, D2O, 298 K). The host P[6]AS is weakly self-associated in water, as evidenced by upfield chemical shift changes in the aromatic region at 7.34-7.38 ppm protons.

[0073] Figure 60 A plot of the chemical shift of P[6]AS relative to [P[6]AS] is shown. The solid line represents the best nonlinear fit of the data to a 2-sheet self-association model, where K a =16.2M -1 .

[0074] Figure 61 Shown for Rim-P[5]AS record 1 H NMR spectrum (400 MHz, D2O).

[0075] Figure 62 Shown for Rim-P[5]AS record 13 C NMR spectroscopy (150 MHz, D2O, EtOH as internal reference).

[0076] Figure 63HepG2 toxicology assays are shown. AK (A, C) and MTS assays (B, D) were performed after cells had been incubated with the indicated containers for 24 h. UT = untreated control; Stx = staurosporine.

[0077] Figure 64 HEK293 toxicology assays are shown. AK (A, C) and MTS assays (B, D) were performed after cells had been incubated with the indicated containers for 24 h. UT = untreated control; Stx = staurosporine.

[0078] Figure 65 Figure 2 shows the MTD study for P[6]AS. Female Swiss Webster mice (n=5 per group) were administered different concentrations of P[6]AS or phosphate-buffered saline (PBS) via the tail vein on days 0 and 2 (indicated by *). The normalized mean weight change for each study group is indicated. Error bars represent SEM.

[0079] Figure 66 Figure 2 shows the in vivo reversal of methamphetamine-induced hyperlocomotion by P[6]AS. The mean hyperlocomotion counts of male Swiss Webster mice (n=8; mean body weight (g) ± SD: 39 ± 2.203) were plotted as a function of treatment. The treatment sequence was counterbalanced over several days, and mice received only one treatment per day. On six consecutive days of testing, mice received a single treatment of PBS (PBS; 0.01 M; 0.2 mL, infused), P[6]AS alone (P[6]AS; 4 mM; 0.178 mL, infused), methamphetamine alone (METH; 0.5 mg / kg; 0.022 mL, infused), a premixed solution of P[6]AS and methamphetamine (premix; ~7:1 P[6]AS:Meth; 0.178 mL P[6]AS + 0.022 mL Meth, infused), P[6]AS followed by methamphetamine 30 s later (block; 0.178 mL P[6]AS, 0.022 mL Meth, infused), and methamphetamine followed by P[6]AS 30 s later (reversal; 0.022 mL Meth, 0.178 mL P[6]AS, infused). Bars represent mean locomotor activity counts. Error bars represent standard error of the mean (SEM). Points represent counts per mouse (n=8). P-values ​​presented are for significant (p<0.05) Tukey-corrected post hoc comparisons only.

[0080] Figure 67Shown is the excitatory autonomic activity effect of reversing the body that observes after 5 minutes delay between the processing of methamphetamine and P[6]AS use.At the 7th day and the 8th day, mice (n=8) accept methamphetamine and then be the 0.01M PBS infusion (REV-C that uses after 5 minutes; 0.022mL Meth, 0.2mL PBS, infusion), or accept methamphetamine and then be the P[6]AS (REV-5 that uses in offset mode after 5 minutes; 0.022mL Meth, 0.178mL P[6]AS, infusion).After being exposed to methamphetamine, use P[6]AS in 5 minutes and reduce excitatory autonomic activity (paired t-check, t (7)=2.757, p=0.0282).Bar represents average autonomic activity count.Error bar represents the standard error (SEM) of mean value.Point represents the counting of every mice (n=8).

[0081] Figure 68 The chemical structures of MDMA, mephedrone, heroin, and methamphetamine are shown.

[0082] Figure 69 Shown are a) DP versus time from titration of the molecular container P[6]AS (100 μM) and 1,3-propanediammonium chloride (150 μM) in a cell using MDMA (1.00 mM) in a syringe in 20 mM NaH2PO4 buffer (pH 7.4); b) ΔH versus molar ratio. The solid line represents the best nonlinear fit of the data to the competitive binding model (K a =(3.92±0.20)×10 7 M -1 , ΔH=-13.3±0.1kcal / mol, -TΔS=2.95kcal / mol).

[0083] Figure 70 Shown are a) DP versus time from titration of the molecular container P[6]AS (10 μM) in a cell with mephedrone (100 μM) in 20 mM NaH2PO4 buffer (pH 7.4) from a syringe; b) ΔH versus molar ratio. The solid line represents the best nonlinear fit of the data to a 1:1 binding model (Ka = (1.91 ± 0.19) × 10 7 M -1 , ΔH=-12.6±0.11kcal / mol, -TΔS=2.68kcal / mol).

[0084] Figure 71Shown are a) DP versus time from titration of the molecular container P[6]AS (10 μM) in a cell with heroin (100 μM) in 20 mM NaH2PO4 buffer (pH 7.4) from a syringe; b) ΔH versus molar ratio. The solid line represents the best nonlinear fit of the data to a 1:1 binding model (K a =(5.78±0.02)×10 5 M -1 , ΔH=-11.9±0.11kcal / mol, -TΔS=4.01kcal / mol).

[0085] Figure 72 Shown are a) DP versus time from a titration of molecular containers P[6]AS (100 μM) and 17 (500 μM) with rocuronium (1.00 mM) in 20 mM NaH2PO4 buffer (pH 7.4); b) ΔH versus molar ratio. The solid line represents the best nonlinear fit of the data to the competitive binding model (K a =(6.33±0.08)×10 11 M -1 , ΔH=-24.9±0.177kcal / mol, -TΔS=8.79kcal / mol).

[0086] Figure 73 Shown are a) DP versus time from a titration of molecular containers P[6]AS (100 μM) and 17 (500 μM) with vecuronium (1.00 mM) in 20 mM NaH2PO4 buffer (pH 7.4); b) ΔH versus molar ratio. The solid line represents the best nonlinear fit of the data to the competitive binding model (K a =(1.00±0.34)×10 12 M -1 , ΔH=-18.5±0.095kcal / mol, -TΔS=2.10kcal / mol).

[0087] Figure 74 Shown are a) DP versus time from a titration of molecular containers P[6]AS (100 μM) and 17 (150 μM) with pancuronium (1.00 mM) in 20 mM NaH2PO4 buffer (pH 7.4); b) ΔH versus molar ratio. The solid line represents the best nonlinear fit of the data to the competitive binding model (K a =(7.35±1.23)×10 10 M -1, ΔH=-16.5±0.216kcal / mol, -TΔS=1.63kcal / mol).

[0088] Figure 75 Shown are a) DP versus time for a molecular container P[7]AS (10 μM) titrated with cisatracurium (0.05 mM) in 20 mM NaH2PO4 buffer (pH 7.4); b) ΔH versus molar ratio. The solid line represents the best nonlinear fit (K) of the data to a 1:1 binding model with n=0.5. a =(1.52±0.12)×10 7 M -1 , ΔH=-35.0±0.396kcal / mol, -TΔS=25.2kcal / mol).

[0089] Figure 76 Shown are a) DP versus time from a titration of molecular container P[6]AS (100 μM) and propane-1,3-diammonium (150 μM) with methamphetamine (1.00 mM) in 20 mM NaH2PO4 buffer (pH 7.4); b) ΔH versus molar ratio. The solid line represents the best nonlinear fit of the data to the competitive binding model (K a =(9.90±0.39)×10 6 M -1 , ΔH=-10.4±0.040kcal / mol, -TΔS=0.833kcal / mol).

[0090] Figure 77 Shown are a) DP versus time from a titration of molecular container P[6]AS (100 μM) and propane-1,3-diammonium (1.00 mM) with fentanyl (1.00 mM) in 20 mM NaH2PO4 buffer (pH 7.4); b) ΔH versus molar ratio. The solid line represents the best nonlinear fit of the data to the competitive binding model (K a =(1.02±0.03)×10 8 M -1 , ΔH=-15.0±0.052kcal / mol, -TΔS=4.02kcal / mol).

[0091] Figure 78 Shown are a) DP versus time from molecular container P[6]AS (100 μM) titrated with cocaine (1.00 mM) in 20 mM NaH2PO4 buffer (pH 7.4); b) ΔH versus molar ratio. The solid line represents the best nonlinear fit of the data to a 1:1 binding model (Ka =(1.92±0.06)×10 6 M -1 , ΔH=-15.6±0.047kcal / mol, -TΔS=7.07kcal / mol).

[0092] Figure 79 Shown are a) DP versus time from molecular container P[6]AS (100 μM) titrated with ketamine (1.00 mM) in 20 mM NaH2PO4 buffer (pH 7.4); b) ΔH versus molar ratio. The solid line represents the best nonlinear fit of the data to a 1:1 binding model (K a =(1.52±0.25)×10 5 M -1 , ΔH=-22.0±1.02kcal / mol, -TΔS=14.9kcal / mol).

[0093] Figure 80 Shown are a) DP versus time from a titration of the molecular container P[6]AS (100 μM) and propane-1,3-diammonium (150 μM) with phencyclidine (1.00 mM) in 20 mM NaH2PO4 buffer (pH 7.4); b) ΔH versus molar ratio. The solid line represents the best nonlinear fit of the data to the competitive binding model (K a =(5.85±0.47)×10 7 M -1 , ΔH=-12.4±0.076kcal / mol, -TΔS=1.84kcal / mol).

[0094] Figure 81 Shown are a) DP versus time from molecular container P[6]AS (100 μM) titrated with morphine (1.00 mM) in 20 mM NaH2PO4 buffer (pH 7.4); b) ΔH versus molar ratio. The solid line represents the best nonlinear fit of the data to a 1:1 binding model (K a =(1.36±0.07)×10 6 M -1 , ΔH=-12.9±0.073kcal / mol, -TΔS=4.49kcal / mol).

[0095] Figure 82Shown are a) DP versus time from molecular container P[6]AS (100 μM) titrated with hydromorphone (1.00 mM) in 20 mM NaH2PO4 buffer (pH 7.4); b) ΔH versus molar ratio. The solid line represents the best nonlinear fit of the data to a 1:1 binding model (K a =(1.31±0.04)×10 6 M -1 , ΔH=-11.9±0.042kcal / mol, -TΔS=3.55kcal / mol).

[0096] Figure 83 Shown are a) DP versus time from molecular container P[6]AS (100 μM) titrated with oxycodone (1.00 mM) in 20 mM NaH2PO4 buffer (pH 7.4); b) ΔH versus molar ratio. The solid line represents the best nonlinear fit of the data to a 1:1 binding model (K a =(9.52±0.36)×10 4 M -1 , ΔH=-8.62±0.097kcal / mol, -TΔS=1.83kcal / mol). DETAILED DESCRIPTION

[0097] Although the claimed subject matter will be described in terms of certain examples, other examples, including examples that do not provide all of the benefits and features set forth herein, are also within the scope of this disclosure. Various structural, logical, and process step changes may be made without departing from the scope of this disclosure.

[0098] The range of values ​​disclosed herein is a range of values. These ranges specify lower and upper limits. Unless otherwise indicated, these ranges include lower limits, upper limits, and all values ​​between the lower and upper limits, including but not limited to all values ​​to the minimum value (whether lower or upper limit).

[0099] As used herein, unless otherwise indicated, the term "group" refers to a chemical entity that is monovalent (i.e., has one end that can covalently bond to other chemical species), divalent, or multivalent (i.e., has two or more ends that can covalently bond to other chemical species). The term "group" also includes free radicals (e.g., monovalent and multivalent, such as, for example, divalent, trivalent, etc. free radicals). Illustrative examples of groups include:

[0100]

[0101] As used herein, unless otherwise indicated, the term "aryl group" refers to a C5 to C 18(including all integer carbon numbers and carbon number ranges therebetween) aromatic or partially aromatic carbocyclic groups (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 、C 12 、C 13 、C 14 、C 15 、C 16 、C 17 and C 18 ). Aryl group may also be referred to as aromatic group. Aryl group may include polyaryl groups, such as for example fused ring or biaryl group. Aryl group may be unsubstituted or substituted by one or more substituents. The example of substituent includes but is not limited to various substituents, such as for example halogen (-F, -Cl, -Br and -I), azido group, aliphatic group (such as alkyl group, alkenyl group, alkynyl group etc.), aryl group, hydroxyl group, alkoxide group (alkoxide group), carboxylate group, carboxylic acid group, ether group, ester group, amide group, thioether group, thioester group etc., and their combination. Substituent may be or further include sulfonate group or sulfate group. The example of aryl group includes but is not limited to phenyl group, biaryl group (such as biphenyl group etc.) and fused ring group (such as naphthyl group, anthracene group, pyrenyl group etc.), and they may be unsubstituted or substituted.

[0102] As used herein, unless otherwise indicated, the term "heteroaryl group" refers to a C1 to C2-containing aromatic ring. 18 Monocyclic, polycyclic or bicyclic groups (e.g., aryl groups), wherein one or both aromatic rings contain at least one heteroatom (e.g., nitrogen, oxygen, sulfur, etc.) in the aromatic rings, including all integer carbon numbers and carbon number ranges therebetween (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 、C 12 、C 13 、C 14 、C 15 、C 16 、C 17 and C 18). The heteroaryl group can be substituted or unsubstituted. The example of the heteroaryl group includes but is not limited to benzofuranyl group, thienyl (thienyl) group, furyl group, pyridyl group, pyrimidinyl group, oxazolyl group, quinolyl (quinolyl) group, thiophenyl (thiophenyl) group, isoquinolyl group, indolyl group, triazinyl group, triazolyl group, isothiazolyl group, isoxazolyl group, imidazolyl group, benzothiazolyl group, pyrazinyl group, pyrimidinyl group, thiazolyl group and thiadiazolyl group etc. The example of substituent includes but is not limited to halogen (-F, -Cl, -Br and -I), aliphatic group (for example, alkyl group, alkenyl group, alkynyl group etc.), aryl group, alkoxide group, amine group, carboxylate group, carboxylic acid, ether group, alcohol group, alkynyl group (for example, ethynyl group etc.) etc., and their combination.

[0103] As used herein, unless otherwise indicated, the term "aliphatic" refers to a branched or unbranched hydrocarbon group optionally containing one or more degrees of unsaturation. Unsaturation can come from, but is not limited to, cyclic aliphatic groups. For example, an aliphatic group / moiety is C1 to C 40 Aliphatic groups, including all integer carbon numbers and ranges therebetween (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 、C 12 、C 13 、C 14 、C 15 、C 16 、C 17 、C 18 、C 19 、C 20 、C 21 、C 22 、C 23 、C 24 、C 25 、C 26 、C 27 、C 28 、C 29 、C 30 、C 31 、C 32 、C 33 、C 34 、C 35 、C 36 、C 37 、C 38 、C 39 and C 40). Aliphatic groups include, but are not limited to, alkyl groups, alkenyl groups, and alkynyl groups. Aliphatic groups may be unsubstituted or substituted with one or more substituents. Examples of substituents include, but are not limited to, various substituents, such as, for example, halogen (-F, -Cl, -Br, and -I), azido groups, aliphatic groups (e.g., alkyl groups, alkenyl groups, alkynyl groups, etc.), aryl groups, hydroxyl groups, alkoxide groups, carboxylate groups, carboxylic acid groups, ether groups, ester groups, amide groups, thioether groups, thioester groups, and combinations thereof.

[0104] As used herein, unless otherwise indicated, the term "alkyl group" refers to a branched or unbranched saturated hydrocarbon group. Examples of alkyl groups include, but are not limited to, methyl groups, ethyl groups, n-propyl groups and isopropyl groups, n-butyl groups, isobutyl groups, sec-butyl groups and tert-butyl groups. For example, an alkyl group can be C1 to C 12 , which includes all integer carbon numbers and carbon number ranges therebetween (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 and C 12 ). The alkyl group may be unsubstituted or substituted with one or more substituents. Examples of substituents include, but are not limited to, various substituents such as, for example, halogen (-F, -Cl, -Br, and -I), an azido group, an aliphatic group (e.g., an alkyl group, an alkene group, an alkynyl group, etc.), an aryl group, a hydroxyl group, an alkoxide group (-OR, wherein R is an alkyl group), a carboxylate group, a carboxylic acid group, an ether group, an ester group, an amide group, a thioether group, a thioester group, etc., and combinations thereof.

[0105] The present disclosure provides sulfated pillararene. The present disclosure also provides a method for preparing sulfated pillararene and its use.

[0106] In the present disclosure, it has been shown that, for example, positioning anion solubilizing groups at the edges of pillararenes' cavities significantly enhances their binding affinity for cationic targets in water and thereby increases their ability to act as chelating agents for a wide variety of applications.

[0107] In one aspect, the present disclosure provides a compound. The compound is a sulfated pillararene. The sulfated pillararene comprises a macrocyclic core comprising a plurality of aryl groups, wherein adjacent aryl groups are covalently linked (e.g., bonded) via an alkyl linking group (e.g., a -CH2- group). The alkyl linking group is in the para position on the aryl group (e.g., a 1,4-phenyl bond). The bond can be on different phenyl rings of the aryl group, and if the different phenyl rings overlap, it corresponds to a para bond. In multiple examples, one or more or all of the adjacent aryl groups are not covalently linked (e.g., a 1,3-phenyl bond (in the case where the bond is located on different phenyl rings or aryl groups, if the different phenyl rings overlap, these bonds do not correspond to meta bonds)) via an alkyl linking group at the meta position on the aryl group. Non-limiting examples of sulfated pillararenes are provided herein. Non-limiting examples of methods for preparing sulfated pillararenes are provided herein.

[0108] In several examples, sulfated pillararenes have the following structure:

[0109]

[0110] wherein Ar is an aryl group attached (e.g., covalently bonded) to an adjacent methylene group (e.g., a 1,4-phenyl group) with para substitution, which may be part of a larger aryl group; and each R is independently selected from -OS(O)2O - M + (where M + Yes + , K + , Ca 2+ Mg 2+ 、Zn 2+ 、H4N + 、Et3NH + 、Me4N + 、(HOCH2CH2)3NH + , or cationic forms of ethylenediamine, piperazine, or tris(hydroxymethyl)aminomethane (TRIS)), -OS(O)2OH, non-sulfate anionic groups (such as, for example, sulfonate (and corresponding acid) groups (e.g., -O(CH2) m S(O)2O - M + (where M + Yes + , K + , Ca 2+ Mg 2+ 、Zn 2+ 、H4N + 、Et3NH + 、Me4N + 、(HOCH2CH2)3NH+ , or the cationic form of ethylenediamine, piperazine, or tris(hydroxymethyl)aminomethane (TRIS)) / -O(CH2) m S(O)2OH, where m is 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, 8), -C6H5S(O)2OH, etc., and such groups where the terminal O is removed), carbonate (and corresponding acid) groups (e.g., -O(CH2) m C(O)O - M + (where M + Yes + , K + , Ca 2+ Mg 2+ 、Zn 2 + 、H4N + 、Et3NH + 、Me4N + 、(HOCH2CH2)3NH + , or the cationic form of ethylenediamine, piperazine, or tris(hydroxymethyl)aminomethane (TRIS)) / -O(CH2) m C(O)OH, wherein n is 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, 8), etc., such as, for example, -OCH2CO2 - M + / -OCH2CO2H groups, etc. and such groups in which the terminal O is removed), phosphonate (and corresponding acid) groups (e.g., -O(CH2) m P(O)(OH)2 - M + (where M + Yes + , K + , Ca 2+ Mg 2+ 、Zn 2+ 、H4N + 、Et3NH + 、Me4N + 、(HOCH2CH2)3NH + , or the cationic form of ethylenediamine, piperazine, or tris(hydroxymethyl)aminomethane (TRIS)) / -O(CH2) mP(O)(OH)2, wherein m is 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, 8), etc., such as, for example, -O(CH2)2P(O)(OH)2, etc., and such groups in which the terminal O is removed), a phosphate group -OP(O)(OH)2, etc.), a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted aliphatic group, an O-alkyl group (including an alkyl group), an azide group, -H, a substituted or unsubstituted alkyl group, a halogen (e.g., -Br, -F, -I, -Cl), an amide group, a cyano group, a substituted or unsubstituted sulfur-containing aliphatic group (e.g., -S-alkyl and polysulfide, etc.), a nitro group, an amino group, a substituted or unsubstituted nitrogen-containing aliphatic groups (e.g., polyamines, aliphatic groups containing secondary and / or tertiary amines, etc.), substituted or unsubstituted polyethylene glycol groups, polyether groups, O-aryl groups (e.g., aryloxy groups), ester groups, carbamate groups, imine groups, aldehyde groups, -SO3H groups, -SO3Na groups, -OSO2F groups, -OSO2CF3 groups, -OSO2OR"' groups (wherein R"' is a substituted or unsubstituted aryl group or a substituted or unsubstituted alkyl group), etc., and combinations thereof; x is 0, 1, 2 or 3; and y is independently 0, 1, 2, 3 or 4 at each occurrence, provided that at least one y is 1 and at least one R group is -OS(O)2O - M + (where M + Yes + , K + ) or -OS(O)2OH, or a salt, partial salt, hydrate, polymorph, stereoisomer, conformer or mixture thereof. One or more R groups can be located at any position on the aryl group. In the case of an aryl group having multiple R groups, a single R group can be at any combination of the positions of the aryl groups. In various examples, all aryl groups contain R groups that are independently -OS(O)2O - M + (where M + Yes + , K + , Ca 2+ Mg 2+ 、Zn 2+ 、H4N + 、Et3NH + 、Me4N + 、(HOCH2CH2)3NH + , or cationic forms of ethylenediamine, piperazine, and tris(hydroxymethyl)aminomethane (TRIS)) or -OS(O)2OH. In various examples, at least one aryl group does not contain an R group that is -OS(O)2O -M + (where M + Yes + , K + , Ca 2+ Mg 2+ 、Zn 2+ 、H4N + 、Et3NH + 、Me4N + 、(HOCH2CH2)3NH + , or a cationic form of ethylenediamine, piperazine, or tris(hydroxymethyl)aminomethane (TRIS)) or -OS(O)OH. In various embodiments, the aryl group can be further substituted with various substituents such as, for example, -H, an alkyl group, an aliphatic group, a polyethylene glycol group, or the like, or a combination thereof.

[0111] In certain embodiments, M + Yes + , K + , Ca 2+ Mg 2+ 、Zn 2+ 、H4N + 、Et3NH + 、Me4N + 、(HOCH2CH2)3NH + , or cationic forms of ethylenediamine, piperazine, or tris(hydroxymethyl)aminomethane (TRIS).

[0112] In certain embodiments, M + Yes + , K + and H4N + In certain embodiments, M + Yes + .

[0113] Sulfated pillar aromatics can comprise various aryl groups.Aryl groups can be all identical or at least two differences in the aryl groups.The limiting examples of aryl groups are independently selected from phenyl group, condensed ring group (for example, naphthyl group, anthracenyl group, phenanthrenyl group, tetraphenyl group, pentacene group etc.), biaryl group (for example, biphenyl group etc.), terphenyl group etc., and their combination when occurring at every turn.For avoidance of doubt, unless otherwise indicated, when phenyl group was not a part for larger aryl group, it was C h group.Phenyl group can be referred to as phenylene group.

[0114] Adjacent aryl groups can be connected by various bonds. These bonds are para-linked phenyl group bonds. In many examples, at least some or all of these bonds are 1,4-phenyl group bonds. Non-limiting examples of para-linked phenyl group bonds include:

[0115]

[0116]

[0117] and combinations thereof. These are illustrative examples. Other para-linked phenyl group bonds are within the scope of this disclosure. In several examples, the bond is not a meta bond.

[0118] The aryl group may comprise one or more phenyl groups. In a number of non-limiting examples, at least two, at least three, or at least four, or all of the one or more phenyl groups in the one or more aryl groups of the cyclic core of the compound have at least one or at least two R groups independently selected from -OS(O)2O - M + (where M + Yes + , K + , Ca 2+ Mg 2+ 、Zn 2+ 、H4N + 、Et3NH + 、Me4N + 、(HOCH2CH2)3NH + , or a cationic form of ethylenediamine, piperazine or tris(hydroxymethyl)aminomethane (TRIS)) and -OS(O)2OH. All aryl groups (one or more or all of which may be phenyl groups) may contain a sulfate group -OS(O)2O - M + (where M + Yes + , K + , Ca 2+ Mg 2+ 、Zn 2+ 、H4N + 、Et3NH + 、Me4N + 、(HOCH2CH2)3NH + , or a cationic form of ethylenediamine, piperazine, or tris(hydroxymethyl)aminomethane (TRIS)) or -OS(O)2OH. In various examples, at least one aryl group (which may be a phenyl group) does not contain a sulfate group (e.g., -OS(O)2O - M + (where M +Yes + , K + , Ca 2+ Mg 2+ 、Zn 2+ 、H4N + 、Et3NH + 、Me4N + 、(HOCH2CH2)3NH + , or a cationic form of ethylenediamine, piperazine, or tris(hydroxymethyl)aminomethane (TRIS)) or -OS(O)2OH).

[0119] In several examples, sulfated pillararenes have the following structure:

[0120]

[0121]

[0122] In various examples, each R is -OS(O)2O - M + (where M + Yes + , K + , Ca 2+ Mg 2+ 、Zn 2+ 、H4N + 、Et3NH + 、Me4N + 、(HOCH2CH2)3NH + , or a cationic form of ethylenediamine, piperazine, or tris(hydroxymethyl)aminomethane (TRIS)) and -OS(O)2OH.

[0123] In several examples, sulfated pillararenes have the following structure:

[0124]

[0125] In various examples, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32 of the R groups are independently -OS(O)2O - M + Group (wherein M + Yes + , K + , Ca 2+ Mg 2+ 、Zn 2+ 、H4N + 、Et3NH +、Me4N + 、(HOCH2CH2)3NH + , or a cationic form of ethylenediamine, piperazine or tris(hydroxymethyl)aminomethane (TRIS)) or a -OS(O)2OH group.

[0126] In one aspect, the present disclosure provides compositions comprising one or more sulfated pillararenes.Non-limiting examples of compositions are described herein.

[0127] The composition can include one or more sulfated pillararenes and one or more agents. In various examples, the agent comprises one or more positively charged nitrogen atoms (e.g., ammonium ions, primary ammonium ions, secondary ammonium ions, tertiary ammonium ions, quaternary ammonium ions, or combinations thereof, wherein the one or more non-hydrogen groups on the ammonium are selected from aliphatic groups, alkyl groups, aryl groups, and combinations thereof).

[0128] The composition may comprise one or more sulfated pillararenes, one or more pharmaceutical carriers, and optionally one or more pharmaceutical agents. The compositions described herein may have one or more pharmaceutically acceptable carriers. Suitable pharmaceutically acceptable carriers are known in the art. Some non-limiting examples of pharmaceutically acceptable carriers can be found in the following literature: Remington: The Science and Practice of Pharmacy (2005), 21st Edition, Philadelphia, PA. Lippincott Williams & Wilkin. In many examples, the pharmaceutical carrier is pure water or a buffer, such as PBS buffer.

[0129] Any suitable technology can be utilized, at any time point before using the composition, to prepare a composition comprising one or more sulfated pillar aromatics (which can form a guest-host complex) in combination with one or more medicaments. Compound-agent complexes can be formed, for example, by mixing the compound and the medicament in a suitable solvent. It is desirable that the compound and the medicament be soluble in a solvent so that the compound and the medicament form a non-covalent complex. Any suitable solvent can be used. In some examples, the solvent is an aqueous solution, which includes but is not necessarily limited to water and various buffer solutions (e.g., PBS buffer, etc.). Non-aqueous solvents (e.g., MeOH, EtOH and other organic solvents, and combinations thereof) can also be used, which are then removed, and if desired, the composition can be redissolved in an aqueous solution for use. Generally speaking, a solution of one or more compounds can be provided with a known concentration, the example of which includes but is not limited to 0.1 to 90 mM (including end values ​​and including all integers therebetween to ten decimal places), and the medicament desired to enhance solubility is added to the solution. One or more medicaments can be provided, for example, in solid form. The combination can be oscillated or stirred for a period of time and the amount of the dissolved medicament monitored. If all of the added agent goes into solution, more agent can be added until some detectable portion thereof remains undissolved (e.g., solid). The soluble compound-agent complex can then be separated and analyzed by any suitable technique, such as by recovering a centrifuged fraction and analyzing it by NMR to determine the concentration of the agent in solution. In various examples, the compound is provided in a composition comprising the drug in a ratio of at least 1 to 1 (e.g., a ratio of pillararene to drug) that is related to the compound-agent stoichiometry. In various examples, the ratio of pillararene (e.g., pillararene sulfate) to drug is 100:1 to 1:5, including all ratio values ​​and ranges therebetween (e.g., 100:1, 5:1, 1:2, 1:3, 1:4, or 1:5).

[0130] Composition can be prepared at the patient's bedside or prepared by drug manufacturer.In the latter case, composition can be provided in any suitable container (such as for example sealed sterile vial, ampoule etc.), and can be further packaged to include the instruction document (its combination can be called test kit) used for pharmacists, doctors, other health care providers etc. Composition can be provided in liquid form, or with lyophilized or powder form (if necessary, it can be reconstructed when ready to use) provide.Especially, composition can be provided with any suitable delivery form or solvent combination (its example includes but is not limited to liquid, caplet, capsule, tablet, inhalant or aerosol etc.).Delivery device can comprise the component that promotes medicament to release in specific time period and / or interval, and can comprise the composition that enhances drug delivery, such as nanoparticle, microsphere or liposome preparation, various these are known in the art and are commercially available.In addition, every kind of composition as herein described can comprise one or more medicaments.

[0131] The compositions of the present disclosure may comprise more than one agent. Likewise, compositions may comprise different host-guest complexes. For example, a first composition comprising one or more sulfated pillararenes and a first agent may be prepared separately from a composition comprising the same compound and a second agent, and such formulations may be mixed to provide a dual (or more) means of achieving a desired prophylaxis or treatment in an individual. Additionally, compositions may be prepared using mixed formulations of any of the sulfated pillararenes compounds disclosed herein.

[0132] The solid substrate can comprise one or more sulfated pillar arenes disposed on (e.g., chemically bonded to) at least a portion of the surface of the substrate. At least a portion or all of the sulfated pillar arenes can be chemically bonded to at least a portion of the surface by covalent bonds, non-covalent bonds, or combinations thereof. Methods for conjugating sulfated pillar arenes to solid surfaces are known in the art. In various examples, the sulfated pillar arenes are conjugated to the surface by covalent and / or non-covalent bond forming reactions (including but not limited to amide bond formation, azide alkyne cycloaddition, gold thiol interactions, silanol condensation, and the like, and combinations thereof).

[0133] The solid substrate can include (or be) various materials. In a number of non-limiting examples, the solid substrate includes or is silica (such as, for example, silica particles), polymer beads, polymer resins (such as, for example, polystyrene, polyNIPAM, polyacrylic acid, metal nanoparticles (such as gold nanoparticles, silver nanoparticles, magnetic nanoparticles), metals (such as, for example, gold, etc.), or combinations thereof.

[0134] In one aspect, the present disclosure provides uses of sulfated pillararenes. Non-limiting examples of uses of sulfated pillararenes are provided herein, for example, as described in the Representations and Examples.

[0135] Sulfated pillar arenes can be used to chelate various materials, which can be chemical compounds. In a number of non-limiting examples, one or more sulfated pillar arenes are used to chelate one or more neuromuscular blockers (such as, for example, rocuronium bromide, tubocurarine, atracurium, (cis) atracurium besylate, mevecurium, galamin, pancuronium bromide, vecuronium bromide and lapacurium, etc.); one or more anesthetics (such as, for example, N-methyl D-aspartate (NMDA) receptor antagonists (such as ketamine, etc.), short-acting anesthetics (such as etomidate, etc.), etc.); one or more pharmaceutical agents (such as, for example, drugs ( For example, anticoagulants such as, for example, hexamethylenetetramine, drugs of abuse such as methamphetamine, cocaine, fentanyl, carfentanyl, PCP, MDMA, heroin, etc.); one or more pesticides such as, for example, paraquat, diquat, organochlorines such as DDT, aldrin, etc., neonicotinoids such as permethrin, etc., organophosphates such as malathion, glyphosate, etc., pyrethroids, triazines such as atrazine, etc.; one or more dyes such as, for example, methylene blue, Nile red, crystalline Violet, Thioflavin T, Thiazole Orange, Proflavin, Acridine Orange, Methylene Violet, Azure A, Neutral Red, Cyanine, Direct Orange 26, Disperse Dyes (e.g., Disperse Yellow 3, Disperse Blue 27, etc.), Coumarin, Congo Red, etc.); one or more malodorous compounds (such as, for example, low molecular weight mercaptans (e.g., C1-C4 mercaptans), low molecular weight amines (e.g., triethylamine, putrescine, cadaverine, etc.), etc.); or one or more chemical warfare agents (such as, for example, nitrogen mustards and sulfur mustards (e.g., bis(2-chloroethyl)ethylamine, bis(2-chloroethyl)methylamine, tri( Nerve agents (e.g., bis(2-chloroethyl)amine, bis(2-chloroethyl)sulfide, bis(2-chloroethylthioethyl)ether, etc.), nerve agents (such as, for example, those from the G, GV, and V series of nerve agents (e.g., tabun, sarin, soman, cyclosarin, 2-(dimethylamino)ethyl N,N-dimethylphosphoramidofluorate (GV), Novichok, VE, VG, VM, VX, etc.), etc.); one or more hallucinogens (e.g., ergolines, lysergic acid diethylamide (LSD), psilocybin, tryptamines, dimethyltryptamine (DMT), phenethylamines, mescaline, ayahuasca, dextromethorphan, etc.);One or more toxins (e.g., dioxins, perfluoroalkyl sulfonates (PFAS), perfluorooctanoic acid (PFOA), decabromodiphenyl ether (DECA), heavy metals (e.g., mercury), muscarine, tyramine, strychnine, tetrodotoxin, saxitoxin, etc., cholesterol, deoxycholic acid, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, phenylalanine, tyrosine, arginine, histamine); one or more metabolites (e.g., toxic metabolites such as, for example, N-methyl-4-phenylpyridine, spermine, spermidine, N-nitroso compounds such as 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone); or combinations thereof.

[0136] The material that can be a chemical compound can include one or more cationic groups. In various examples, the material that can be a chemical compound includes one or more positively charged nitrogen atoms (e.g., ammonium ions, primary ammonium ions, secondary ammonium ions, tertiary ammonium ions, quaternary ammonium ions, or combinations thereof, wherein the one or more non-hydrogen groups on the ammonium are selected from aliphatic groups, alkyl groups, aryl groups, and combinations thereof).

[0137] In several examples, a method for sequestering one or more neuromuscular blockers, one or more anesthetics, one or more pharmaceuticals, one or more pesticides, one or more dyes, one or more malodorous compounds, one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or a combination thereof, includes contacting one or more neuromuscular blockers, one or more anesthetics, one or more pharmaceuticals, one or more pesticides, one or more dyes, one or more malodorous compounds, one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or a combination thereof with one or more sulfated pillararenes and / or one or more compositions, wherein the one or more neuromuscular blockers, one or more anesthetics, one or more pharmaceuticals, one or more pesticides, one or more dyes, one or more malodorous compounds, one or more chemical warfare agents, or a combination thereof are sequestered by the one or more sulfated pillararenes and / or one or more compositions.

[0138] One or more neuromuscular blockers, one or more anesthetics, one or more pharmaceuticals, one or more pesticides, one or more dyes, one or more malodorous compounds, one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or a combination thereof can be present in an aqueous sample, a solid sample (such as, for example, a soil sample), a gaseous sample, etc. The aqueous sample can be obtained (e.g., via extraction or other methods for separating one or more neuromuscular blockers, one or more anesthetics, one or more pharmaceuticals, one or more pesticides, one or more dyes, one or more malodorous compounds, one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or a combination thereof from a solid sample). The aqueous sample can be a wastewater sample (e.g., a municipal wastewater sample, an industrial wastewater sample, etc.), an industrial water sample (e.g., water used to manufacture commercial products such as, for example, reagents, solvents, etc.), a municipal water sample, etc.

[0139] Composition can include one or more pharmaceutically active agents. In multiple non-limiting examples, at least a portion (or all) of one or more compounds has one or more pharmaceutically active agents arranged in the cavity of one or more compounds. It is not intended to be bound by any particular theory, it is believed that complex (which can be referred to as guest-host complex) is formed by, for example, one or more interactions (for example, one or more non-covalent interactions formed therebetween, such as, for example, one or more non-covalent bonds) between compound (which can be referred to as host) and one or more neuromuscular blockers, one or more anesthetics, one or more medicaments (which can be one or more medicaments with undesirable (for example, low) water solubility), one or more pesticides, one or more dyes, one or more malodorous compounds, one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites or a combination thereof (which can be referred to as one or more guests). Therefore, guest-host complex can be considered as an organized chemical entity produced by the association (for example, by non-covalent intermolecular forces) of one or more medicaments (one or more guests) and host that are kept together.

[0140] The composition can include various pharmaceutically active agents. Non-limiting examples of pharmaceutical agents include drugs. One or more pharmaceutically active agents can have different water solubilities. The pharmaceutically active agent can have hydrophobic, hydrophilic, or amphiphilic properties.

[0141] The complex can be removed from an aqueous sample, a solid sample, a gaseous sample, etc. In various examples, one or more neuromuscular blockers, one or more anesthetics, one or more pharmaceutical agents, one or more pesticides, one or more dyes, one or more malodorous compounds, one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or a combination thereof are removed from an aqueous sample, a solid sample, a gaseous sample, etc. using a solid surface having one or more sulfated pillar aromatics disposed thereon.

[0142] Sulfated pillararenes can be used to sequester various materials in an individual. In various non-limiting examples, one or more neuromuscular blockers, one or more anesthetics, one or more pharmaceutical agents, one or more pesticides, one or more dyes, one or more malodorous compounds, one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or a combination thereof are present in the individual, and contacting comprises administering the one or more compounds and / or one or more compositions to the individual.

[0143] The sulfated pillararenes can be used to reverse drug-induced neuromuscular blockade and / or anesthesia and / or the effects of one or more drugs, which may be drugs of abuse, in a subject.

[0144] In multiple non-limiting examples, methods for reversing the effects of drug-induced neuromuscular blockade and / or anesthesia and / or one or more medicaments (e.g., one or more drugs of abuse) in or on an individual comprise administering one or more sulfated pillar aromatics and / or one or more compositions to an individual in need of reversing neuromuscular blockade and / or reversing anesthesia and / or reversing the effects of one or more medicaments (e.g., one or more drugs of abuse). An individual may need to reverse drug-induced neuromuscular blockade. An individual may need to reverse anesthesia. An individual may need to reverse drug-induced neuromuscular blockade and anesthesia. An individual may need to reverse the effects of one or more medicaments, such as, for example, one or more drugs (which may be one or more drugs of abuse). An individual may have been exposed to one or more drugs of abuse (e.g., carfentanil, etc.) in a terrorist attack.

[0145] Sulfated pillararenes can be used as containers for dissolving chemical compounds. Improving the solubility of compounds in, for example, aqueous solutions is desirable for studying pharmaceutical compounds and for improving drug bioavailability for purposes such as therapeutic and / or preventive purposes. For example, sulfated pillararenes are used to enhance the stability of drugs in water, in a solid state, or both (e.g., to reduce degradation, increase shelf life, etc.).

[0146] In certain examples, sulfated pillararenes can be used to salvage promising drug candidates with undesirable solubility and bioavailability, thereby mitigating losses in the drug development process for anticancer agents and agents intended to treat other diseases. Containers can be used to target drug delivery to specific cell types, such as tumor cells, to increase the effectiveness of existing drugs, reduce one or more of their toxic side effects, or both.

[0147] In various examples, the compositions comprise one or more sulfated pillararenes and one or more pharmaceutical agents. Such compositions can be provided as pharmaceutical formulations as described herein.

[0148] It is important to emphasize that there are no particular limitations on the one or more agents that may be included in the composition comprising one or more sulfated pillararenes and one or more agents. In some instances, the one or more agents combined with the one or more sulfated pillararenes are poorly water-soluble one or more agents. In certain other instances, the one or more agents combined with the one or more sulfated pillararenes are water-soluble one or more agents.

[0149] If desired, the solubility of any particular agent can be determined using any of a variety of techniques well known to those skilled in the art. If desired, the solubility can be determined at any pH (e.g., physiological pH) and / or at any desired temperature. Suitable temperatures include, but are not necessarily limited to, 4°C to 70°C (inclusive), and including all integer °C values ​​therebetween.

[0150] With respect to poorly soluble or low solubility agents suitable for use in the present disclosure, in various instances such agents are considered to be those having a solubility in water or aqueous buffer of less than 100 μM.

[0151] In a number of other examples, poorly soluble pharmaceutical agents are considered to include compounds that are Biopharmaceutics Classification System (BCS) Class 2 or Class 4 drugs. The BCS is well known to those skilled in the art and is based on the water solubility of drugs reported in readily available references, and for orally administered drugs, it includes correlation with human intestinal membrane permeability (see, e.g., Takagi et al., (2006) Molecular Pharmaceutics, Vol. 3, No. 6, pp. 631-643). Thus, a skilled person can readily identify a drug as a member of BCS Class 2 or Class 4 based on published literature, or can test a drug with an unknown BCS or other solubility value to determine whether it has properties consistent with any of these classifications, or is otherwise suitable for use in the present disclosure. In one example, solubility is determined according to the parameters listed in this matrix:

[0152] Solubility Parts of solvent required for 1 part of solute Solubility range (mg / mL) Very soluble <1 ≥1000 Soluble 1 to 10 100-1000 Soluble 10 to 30 33-100 Slightly soluble 30 to 100 10-33 slightly soluble 100 to 1000 1-10 Very slightly soluble 1,000 to 10,000 0.1-1 Practically insoluble ≥10000 <0.1

[0153] Thus, for the purposes of this disclosure, a poorly soluble agent that can be combined with one or more sulfated pillararenes can be any agent that falls into the categories of sparingly soluble, slightly soluble, very slightly soluble, and practically insoluble in a matrix such as described above.

[0154] Again, it should be emphasized that there is no limitation on the agents that can be combined with one or more sulfated pillararenes, other than those characterized as having low solubility in aqueous solution. In this regard, at least one utilization of the present disclosure is the combination of one or more of a wide variety of different agents with one or more sulfated pillararenes, and as a result of combining these compounds with the one or more agents, the solubility of the one or more agents is increased. In various examples, the types of agents suitable for solubilization include, but are not limited to, mitotic inhibitors (e.g., paclitaxel, a mitotic inhibitor used in cancer chemotherapy, etc.); nitrogen mustard alkylating agents (e.g., melphalan, sold under the trade name Alkeran for chemotherapy, etc.); benzimidazoles (e.g., albendazole, sold as Albenza, Eskazole, Zentel, and Andazol, used to treat a variety of helminth infections, etc.); antagonists of estrogen receptors in breast tissue used to treat breast cancer (e.g., tamoxifen, etc.); Ifen), which is an estrogen receptor antagonist when metabolized to its active form of hydroxytamoxifen, etc.); antihistamines (e.g., cinnarizine, sold as Stugeron and Stunarone, used to control the symptoms of motion sickness, etc.); thienopyridine antiplatelet agents (e.g., clopidogrel, sold as Plavix, used to inhibit blood clots in coronary artery disease and other diseases, etc.); and antiarrhythmics (e.g., amiodarone, used to treat tachyarrhythmias, etc.). Other agents not explicitly listed here are also included within the scope of the present disclosure. Some examples of such agents include, but are not limited to, adjuvants for enhancing immune responses, analgesics, detectable labeling agents for diagnostic imaging, etc. Any combination of these exemplary agents may be used. Sulfated pillar arenes can be combined with and improve the solubility of agents that are members of distinct classes of compounds characterized by completely different chemical structures and biological activities.

[0155] The compositions of the present disclosure can be administered to any person or non-human animal in need of treatment or prevention of one or more conditions for which the medicament is intended to provide a preventive or therapeutic benefit. Thus, an individual can be diagnosed with, suspected of having, or at risk of developing any of a variety of conditions (desirably reducing their severity). Non-limiting examples of such conditions include cancer, including solid tumors, blood cancers (e.g., leukemias, lymphomas, myelomas, etc.). Specific examples of cancer include, but are not limited to, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, pseudomyxoma peritonei, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, head and neck cancer, sweat gland carcinoma, sebaceous gland carcinoma, and fibrosarcoma. carcinoma), papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatomica, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinomacarcinoma), Wilns' tumor, cervical cancer, testicular tumor, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, lymphoma, multiple myeloma, thymoma, Waldenstrom's macroglobulinemia, heavy chain disease, etc.

[0156] In addition to various malignancies, the compounds of the present disclosure are also suitable for providing benefit for cardiovascular-related disorders, examples of which include, but are not limited to, angina pectoris, arrhythmias, atherosclerosis, cardiomyopathy, congestive heart failure, coronary artery disease, carotid artery disease, endocarditis, coronary thrombosis, myocardial infarction, hypertension, hypercholesterolemia / hyperlipidemia, mitral valve prolapse, peripheral arterial disease, stroke, thrombosis, embolism, other forms of ischemic injury, and the like.

[0157] In addition, the compositions of the present disclosure can be used in connection with the treatment of a wide variety of infectious diseases. A wide variety of agents intended for the treatment and / or inhibition of infectious diseases caused by, for example, bacteria, protozoa, helminths, fungal sources, viral sources, etc., can be aided by the use of the compositions of the present disclosure.

[0158] Various methods known to those skilled in the art can be used to introduce the compounds and / or compositions of the present disclosure into individuals. These methods include, but are not limited to, intravenous, intramuscular, intracranial, intrathecal, intradermal, subcutaneous, oral routes, etc., and combinations thereof. The composition comprising the dosage of the compound and the medicament will necessarily depend on the needs of the individual to whom the composition is to be administered. These factors include, but are not necessarily limited to, body weight, age, sex, medical history, and the nature and stage of the disease for which treatment or preventive effect is desired. The composition can be used in combination with any other conventional treatment modality designed to improve the disease for which treatment or preventive effect is desired, the non-limiting examples of which include surgical intervention and radiotherapy. The composition can be administered once, or in a series of administrations at different intervals determined using a person of ordinary skill in the art, and the benefits of the present disclosure are provided.

[0159] The methods of the present disclosure can be used on a variety of subjects. In various examples, the subject is a human or a non-human mammal. Examples of non-human mammals include, but are not limited to, farm animals such as, for example, cattle, pigs, sheep, and the like, as well as pets or sports animals such as, for example, horses, dogs, cats, and the like. Other non-limiting examples of subjects include, but are not limited to, rabbits, rats, mice, and the like.

[0160] The steps of the methods described in the multiple examples disclosed herein are sufficient to implement the methods of the present disclosure. Thus, in one example, the method is essentially composed of a combination of the steps of the methods disclosed herein. In another example, the method is composed of such steps.

[0161] In one aspect, the present disclosure provides an article of manufacture comprising a compound of the present disclosure.

[0162] The article can be a manufactured article. Non-limiting examples of articles include wipes impregnated with one or more compounds of the present disclosure. For example, such wipes are used to clean surfaces from any material that can be chelated by the compound (e.g., the pillararenes of the present disclosure). For example, the wipes are used to clean surfaces that have been or were previously exposed to toxins, drugs of abuse, etc., or combinations thereof.

[0163] The following statements illustrate various embodiments of the present disclosure.

[0164] Statement 1. A compound having the following structure:

[0165]

[0166] wherein Ar is an aryl group, wherein adjacent aryl groups are linked via para-linked phenyl group linkages (e.g., one or more 1,4-phenyl group linkages) (e.g., the aryl groups are linked to adjacent methylene groups with para substitution), which may be part of a larger aryl group; and each R is independently selected from -OS(O)2O - M + (where M + Yes + , K + , Ca 2+ Mg 2+ 、Zn 2+ 、H4N + 、Et3NH + 、Me4N + 、(HOCH2CH2)3NH + , or cationic forms of ethylenediamine, piperazine, or tris(hydroxymethyl)aminomethane (TRIS)), and -OS(O)2OH, non-sulfate anionic groups (such as, for example, sulfonate (and corresponding acid) groups (e.g., -O(CH2) m S(O)2O - M + (where M + Yes + , K + , Ca 2+ Mg 2+ 、Zn 2+ 、H4N + 、Et3NH + 、Me4N + 、(HOCH2CH2)3NH + , or the cationic form of ethylenediamine, piperazine, or tris(hydroxymethyl)aminomethane (TRIS)) / -O(CH2) m S(O)2OH, where n is 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, 8), -C6H5S(O)2OH, etc., and such groups with the terminal O removed), carboxylate (and corresponding acid) groups (e.g., -O(CH2) m C(O)O - M + (where M + Yes + , K + , Ca 2+ Mg 2+ 、Zn 2+ 、H4N + 、Et3NH + 、Me4N + 、(HOCH2CH2)3NH +, or the cationic form of ethylenediamine, piperazine, or tris(hydroxymethyl)aminomethane (TRIS)) / -O(CH2) m C(O)OH, wherein m is 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, 8), etc., such as, for example, -OCH2CO2 - M + / -OCH2CO2H groups, etc., and such groups in which the terminal O is removed), phosphate (and corresponding acid) groups (e.g., -O(CH2) m P(O)(OH)2 - M + (where M + Yes + , K + , Ca 2+ Mg 2+ 、Zn 2+ 、H4N + 、Et3NH + 、Me4N + 、(HOCH2CH2)3NH + , or the cationic form of ethylenediamine, piperazine, or tris(hydroxymethyl)aminomethane (TRIS)) / -O(CH2) m P(O)(OH)2, wherein m is 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, 8), etc., such as, for example, -O(CH2)2P(O)(OH)2, etc., and such groups in which the terminal O is removed), a phosphate group -OP(O)(OH)2, etc.), a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted aliphatic group, an O-alkyl group (including an alkyl group), a polyether group (e.g., a polyethylene glycol (PEG) group), an azide group, -H, a substituted or unsubstituted alkyl group, a halogen (e.g., -Br, -F, -I, -Cl), an amide group, a cyano group, a substituted or unsubstituted sulfur-containing aliphatic group (e.g., -S-alkyl and polythioether, etc.), a nitro group groups, amino groups, substituted or unsubstituted nitrogen-containing aliphatic groups (e.g., polyamines, aliphatic groups containing secondary and / or tertiary amines, etc.), substituted or unsubstituted polyethylene glycol groups, polyether groups, O-aryl groups (e.g., aryloxy groups), ester groups, carbamate groups, imine groups, aldehyde groups, -SO3H groups, -SO3Na groups, -OSO2F groups, -OSO2CF3 groups, -OSO2OR"' groups (wherein R"' is a substituted or unsubstituted aryl group or a substituted or unsubstituted alkyl group), etc., and combinations thereof; x is 0, 1, 2 or 3; and y is independently 0, 1, 2, 3 or 4 at each occurrence, provided that at least one y is 1 and at least one R group is -OS(O)2O - M + (where M+ Yes + , K + , Ca 2+ Mg 2+ 、Zn 2+ 、H4N + 、Et3NH + 、Me4N + 、(HOCH2CH2)3NH + , or a cationic form of ethylenediamine, piperazine, or tris(hydroxymethyl)aminomethane (TRIS)) or -OS(O)2OH, or a salt, partial salt, hydrate, polymorph, stereoisomer, conformer, or mixture thereof. The one or more R groups may be at any one or more positions on the aryl group. In the case of an aryl group with multiple R groups, each R group may be at any combination of positions on the aryl group. In various embodiments, the aryl group may be further substituted with various substituents.

[0167] Statement 2. A compound according to Statement 1, wherein the aryl group at each occurrence is independently selected from a phenyl group, a fused ring group (e.g., a naphthyl group, an anthracenyl group, a phenanthrenyl group, a tetraphenyl group, a pentacene group, etc.), a biaryl group (e.g., a biphenyl group, etc.), a terphenyl group, etc.

[0168] Statement 3. A compound according to Statement 1 or 2, wherein at least two, at least three, or at least four, or all of the one or more phenyl groups of the one or more aryl groups comprised by the cyclic core of the compound have at least one or at least two independently selected from -OS(O)2O - M + and -OS(O)2OH as R groups.

[0169] Statement 4. A compound according to Statement 3, wherein the compound has the structure:

[0170]

[0171] In various examples, each R is -OS(O)2O - M + and -OS(O)2OH.

[0172] Statement 5. A compound according to any one of the preceding statements, wherein all aryl groups comprise independently -OS(O)2O - M + Or the R group of -OS(O)2OH.

[0173] Statement 6. A compound according to any one of Statements 1 to 3, wherein at least one aryl group does not comprise -OS(O)2O - M+ Or the R group of -OS(O)2OH.

[0174] Statement 7. A compound according to Statement 1, wherein the compound has the structure:

[0175]

[0176] Statement 8. A compound according to Statement 7, wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 or 32 of the R groups are independently -OS(O)2O - M + group or -OS(O)2OH group.

[0177] Statement 9. A compound according to Statement 7 or 8, wherein each phenyl group contained in the cyclic core of the compound has at least one or at least two independently selected from -OS(O)2O - M + and -OS(O)2OH as R groups.

[0178] Statement 10. A compound according to any one of Statements 7-9, wherein at least one phenyl group does not comprise -OS(O)2O - M + Or the R group of -OS(O)2OH.

[0179] Statement 11. A composition comprising one or more compounds according to any one of the preceding statements.

[0180] Statement 12. The composition according to Statement 11, further comprising a pharmaceutical carrier.

[0181] Statement 13. The composition of Statement 11, wherein the one or more compounds are disposed (eg, chemically bonded) to at least a portion of the solid substrate.

[0182] Statement 14. The composition of statement 13, wherein the solid substrate comprises (or is) silica (such as, for example, silica particles), polymer beads, polymer resins (such as, for example, polystyrene, polyNIPAM, polyacrylic acid), metal nanoparticles (such as, for example, gold nanoparticles, silver nanoparticles, magnetic nanoparticles), metals (such as, for example, gold, etc.), etc., or combinations thereof.

[0183] Statement 15. A composition according to any one of Statements 11-14, wherein at least a portion (or all) of the one or more compounds has one or more pharmaceutically active agents disposed in a cavity of (e.g., non-covalently coordinated to) the one or more compounds.

[0184] Statement 16. A method for sequestering the following substances: one or more neuromuscular blockers (such as, for example, rocuronium, tubocurarine, atracurium, (cis) atracurium besylate, mevecurium, galamin, pancuronium, vecuronium, and lapacurium, etc.); one or more anesthetics (such as, for example, N-methyl D-aspartate (NMDA) receptor antagonists (e.g., ketamine, etc.), short-acting anesthetics (e.g., etomidate, etc.), etc.); one or more pharmaceutical agents (such as, for example, drugs (e.g., anticoagulants, such as, for example, hexamethylenetetramine, etc.), drugs of abuse (e.g., methamphetamine, cocaine, fentanyl, carfentanil, PCP, MDMA, heroin, etc.), etc.); one or more pesticides (such as, for example, paraquat, dimethoate, etc.); one or more malodorous compounds (such as, for example, low molecular weight mercaptans (e.g., C1-C4 mercaptans), low molecular weight amines (e.g., triethylamine, putrescine, cadaverine, etc.), etc.); or one or more chemical warfare agents (such as, for example, nitrogen mustard and sulfur mustard (e.g., such as bis(2-chloroethyl)ethylamine, bis(2-chloroethyl)methylamine, tris(2-chloroethyl)amine, bis(2-chloroethyl)sulfide, bis(2-chloroethylthioethyl)ether, etc.), nerve agents (such as, for example, those from the G, GV, and V series of nerve agents (e.g., tabun, sarin, soman, cyclosarin, 2-(dimethylamino)ethyl N,N-dimethylphosphoramidofluorate (GV), Novichok, VE, VG, VM, VX, etc.), etc.); one or more hallucinogens (e.g., ergot alkaloids, lysergic acid diethylamide (LSD), psilocybin, tryptamine, dimethyltryptamine (DMT), phenylethylamine, mescaline, ayahuasca, dextromethorphan, etc.); one or more toxins (e.g., dioxins, perfluoroalkyl sulfonates (PF AS), perfluorooctanoic acid (PFOA), decabromodiphenyl ether (DECA), heavy metals (e.g., mercury), muscarine, tyramine, strychnine, tetrodotoxin, saxitoxin, etc., cholesterol, deoxycholic acid, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, phenylalanine, tyrosine, arginine, histamine); one or more metabolites (e.g., toxic metabolites, such as, for example, N-methyl-4-phenylpyridine, spermine, spermidine, N-nitroso compounds such as 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone); etc., or a combination thereof, which is chelated by one or more compounds according to any one of Statements 1 to 10 and / or one or more compositions according to any one of Statements 11 to 14.

[0185] Statement 17. A method according to statement 16, wherein one or more neuromuscular blockers, one or more anesthetics, one or more pharmaceutical agents, one or more pesticides, one or more dyes, one or more malodorous compounds, one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or a combination thereof are present in an aqueous sample, in a solid sample (such as, for example, a soil sample), in a gaseous sample, on a solid surface, etc.

[0186] Statement 18. The method of statement 17, wherein the aqueous sample is a wastewater sample (e.g., a municipal wastewater sample, an industrial wastewater sample, etc.), an industrial water sample (e.g., water used to manufacture commercial products such as reagents, solvents, etc.), a municipal water sample, etc.

[0187] Statement 19. A method according to any one of Statements 16-18, wherein the complex is formed by one or more compounds and one or more neuromuscular blockers, one or more anesthetics, one or more pharmaceutical agents, one or more pesticides, one or more dyes, one or more malodorous compounds, one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or a combination thereof (e.g., one or more interactions therebetween (e.g., one or more non-covalent bonds formed therebetween)).

[0188] Statement 20. The method according to any one of Statements 16-19, wherein the complex is removed from an aqueous sample, a solid sample, a gaseous sample, or the like.

[0189] Statement 21. The method of statement 16, wherein the one or more neuromuscular blockers, one or more anesthetics, one or more pharmaceutical agents, one or more pesticides, one or more dyes, one or more malodorous compounds, one or more chemical warfare agents, one or more hallucinogens, one or more toxins, one or more metabolites, or a combination thereof are present in and / or on the individual, and contacting comprises administering to the individual the one or more compounds and / or the one or more compositions.

[0190] Statement 22. The method of Statement 21, wherein the subject is a human or a non-human mammal.

[0191] Statement 23. A method for reversing drug-induced neuromuscular blockade and / or anesthesia and / or the effects of one or more agents (e.g., one or more drugs of abuse) in an individual, comprising administering to an individual in need of reversal of neuromuscular blockade and / or reversal of anesthesia and / or reversal of the effects of one or more agents (e.g., one or more drugs of abuse) one or more compounds according to any one of Statements 1-10 and / or one or more compositions according to any one of Statements 11-14.

[0192] Statement 24. The method of statement 23, wherein the subject is in need of reversal of drug-induced neuromuscular blockade.

[0193] Statement 25. The method of statement 23, wherein the subject is in need of reversal of anesthesia.

[0194] Statement 26. The method of statement 23, wherein the individual is in need of reversal of drug-induced neuromuscular blockade and anesthesia.

[0195] Statement 27. The method of statement 23, wherein the subject is in need of reversal of the effects of one or more agents, the one or more agents being selected from the group consisting of one or more drugs of abuse, one or more pesticides, one or more chemical warfare agents, one or more nerve agents, one or more hallucinogens, one or more toxins, and / or one or more metabolites. In one example, the subject is exposed to one or more drugs of abuse (e.g., carfentanil, etc.), one or more pesticides, one or more chemical warfare agents, one or more nerve agents, one or more hallucinogens, one or more toxins, one or more metabolites (as in a terrorist attack), and combinations thereof.

[0196] Statement 28. The method of any one of Statements 23-27, wherein the individual in need thereof is a human.

[0197] Statement 29. The method according to any one of Statements 23-27, wherein the individual in need thereof is a non-human mammal.

[0198] Statement 30. A method for preventing and / or treating a condition in an individual, comprising administering to an individual in need of prevention and / or treatment one or more compounds according to any one of Statements 1-10 and one or more agents, wherein the one or more compounds and the one or more agents are present as a complex (or a composition comprising one or more of said complexes, which may be a pharmaceutical composition), wherein following administration, treatment and / or prevention of the condition in the individual is effected.

[0199] Statement 31. The method of statement 30, wherein one or more of the one or more agents has a solubility in the aqueous solvent of less than 100 μM.

[0200] Statement 32. A compound according to any one of Statements 1-10, a composition according to any one of Statements 11-15, or a method according to any one of Statements 16-31, wherein M + Yes + , K + 、H4N + 、Et3NH + 、Me4N + 、(HOCH2CH2)3NH + .

[0201] Statement 33. A compound according to any one of Statements 1-10, a composition according to any one of Statements 11-15, or a method according to any one of Statements 16-31, wherein M + Yes + .

[0202] The following examples are provided to illustrate the present disclosure. They are not intended to be limiting in any way.

[0203] Example 1

[0204] This example provides a description of compounds of the disclosure, methods of making the compounds, characterization of the compounds, and uses of the compositions.

[0205] General Experimental Details. Starting materials were purchased from commercial suppliers and used without further purification or prepared by literature procedures. Melting points were measured in open capillaries on a Meltemp apparatus and are uncorrected. IR spectra were recorded on a JASCO FT / IR 4100 spectrometer and expressed in cm. -1 Report. 1 H NMR spectra were measured on a Bruker instrument. 1 H operates at 400 or 600 MHz and for 13 C was operated at 100 MHz. Mass spectra were performed using a JEOL AccuTOF electrospray instrument (ESI). ITC data were collected on a Malvern Microcal PEAQ-ITC instrument.

[0206] Synthesis procedures and characterization data.

[0207] Subject P[5]AS.

[0208]

[0209] The first two compounds (2 and 3) were synthesized by utilizing a method adapted from methods known in the art. The procedure for the final step was: to a mixture of compound 3 (0.200 g, 0.328 mmol) and pyridine sulfur trioxide complex (1.050 g, 6.56 mmol) was added anhydrous pyridine (10 mL). The resulting mixture was stirred at 90 ° C for 24 hours under N2. The reaction mixture was cooled to room temperature. The product precipitated from the solution and was collected by filtration. The solid was slurried in water (5 mL) and the pH was adjusted to 8.4 by slowly adding saturated NaHCO3 aqueous solution. After adding EtOH (35 mL), the crude product was collected by centrifugation at 7000 rpm×7 min. The precipitate was suspended in ethanol (20 mL×2), sonicated for 30 minutes, and the solid was collected by centrifugation. The crude solid was redissolved in a minimum amount of water (2 ml) and used G25 resin (30 mm × 200 mm) was purified by size exclusion chromatography and eluted with water. The pure product was collected as the front fractions. After drying under high vacuum, compound P[5]AS was obtained as a white solid (0.374 g, 0.229 mmol, 70% yield). Mp>310 ° C (decomposed). IR (ATR, cm -1 ): 3490w, 1630m, 1497m, 1399m, 1234s, 1116s, 1042s, 995m, 941m, 858m, 806m. 1 H NMR (600MHz, D2O): 7.31 (s, 10H), 4.00 (s, 10H). 13 C NMR (150 MHz, D2O, EtOH as internal reference): 147.4, 134.1, 125.6, 30.8. MS (ESI): m / z 791.78179 ([M-2Na] 2- ), the theoretical value is 791.79597.

[0210] Main body P[5]ACS.

[0211]

[0212] A solution of P[5]A (0.200 g, 0.28 mmol) in NaOH (10 wt %, 2 mL) was treated dropwise with a solution of propane sultone (0.687 g, 5.63 mmol) in acetone (4 mL). The solution was stirred at room temperature for 5 days (d), then EtOH (25 mL) was added to the mixture to give the crude product as a precipitate. The precipitate was obtained by filtration, and the solid was dissolved in H2O (0.5 mL) and then reprecipitated by adding EtOH (5 mL) to give P[5]ACS as a light yellow solid (45 mg, 0.022 mmol, 8%). Mp>300 °C (decomposed). IR (ATR, cm -1 ): 3452w, 2936w, 1725m, 1625m, 1479m, 1471m, 1406m, 1181s, 1035s, 951w, 798m, 756m. 1 H NMR (400MHz, D2O): 6.76 (s, 10H), 3.90 (m, 10H), 3.86 (s, 10H), 3.68 (m, 10H), 3.05 (m, 20H), 2.08 (m, 20H). 13 C NMR (150 MHz, D2O, EtOH as internal reference): δ 150.9, 129.8, 116.7, 68.5, 49.1, 31.1, 25.5. HR-MS (ESI): m / z 1002.03215 ([M-2Na] 2- ), the theoretical value is 1002.03072.

[0213] Subject P[6]AS.

[0214]

[0215] The first two compounds (7 and 8) were synthesized using methods adapted from those known in the art. The procedure for the final step was: to a mixture of compound 8 (0.200 g, 0.27 mmol) and pyridine sulfur trioxide complex (1.090 g, 6.83 mmol) was added anhydrous pyridine (10 mL). The resulting mixture was stirred at 70 ° C for 24 hours under N2. The reaction mixture was cooled to room temperature. The product precipitated from the solution and was collected by filtration. The solid was slurried in water (5 mL) and the pH was adjusted to 8.4 by slowly adding saturated NaHCO3 aqueous solution. After adding EtOH (35 mL), the crude product was collected by centrifugation 7000 rpm×7 min. The precipitate was suspended in ethanol (20 mL×2), sonicated for 30 minutes, and the solid was collected by centrifugation. The crude solid was redissolved in a minimum amount of water (2 ml) and used G25 resin (30 mm × 200 mm) was purified by size exclusion chromatography and eluted with water. The pure product was collected as the front fraction. After drying under high vacuum, compound P[6]AS was obtained as a white solid (0.352 g, 0.18 mmol, 66% yield). Mp>290 ° C (decomposed). IR (ATR, cm -1 ): 3509w, 1712m, 1630m, 1498m, 1364m, 1237m, 1113s, 1045s, 995m, 942m, 861m, 813m. 1 H NMR (600MHz, D2O): 7.35 (s, 12H), 4.11 (s, 12H). 13 C NMR (150 MHz, D2O and CD3OD 10:1): δ 148.1, 133.6, 125.6, 31.5. MS (ESI): m / z 954.7593 ([M-2Na] 2- ), the theoretical value is 954.7537.

[0216] Subject P[6]A8S.

[0217]

[0218] The first three compounds were synthesized by utilizing methods adapted from those known in the art. The procedure for the last step was: to a mixture of compound octahydroxypillar[6]arene (0.100 g, 0.15 mmol) and pyridine sulfur trioxide complex (0.479 g, 3 mmol) was added anhydrous pyridine (5 mL). The resulting mixture was stirred at 70°C for 24 hours under N2. The reaction mixture was cooled to room temperature. The product precipitated from the solution and was collected by filtration. The solid was slurried in water (4 mL) and the pH was adjusted to 8.4 by slowly adding saturated aqueous Na2CO3. After adding EtOH (10 mL), the crude product was collected by centrifugation at 7000 rpm×7 min. The precipitate was suspended in ethanol (10 mL×2), sonicated for 30 minutes, and the solid was collected by centrifugation. The crude solid was redissolved in a minimum amount of water (0.5 ml) and used G25 resin (30 mm × 200 mm) was purified by size exclusion chromatography and eluted with water. The pure product was collected as the front fraction. After drying under high vacuum, compound P[6]A8S(10) was obtained as a white solid (0.075 g, 0.051 mmol, 33% yield). Mp>285 ° C (decomposed). IR (ATR, cm -1): 3491w, 1630m, 1440s, 1234s, 1078m, 1043s, 941m, 878m, 800m, 667m. 1 H NMR (600MHz, D2O): 7.39 (s, 4H), 7.25 (s, 4H), 7.04 (s, 8H), 4.07 (s, 4H), 3.99 (s, 8H). 13 C NMR (150 MHz, D2O, EtOH as internal reference): δ 147.7, 147.6, 138.7, 134.2, 133.2, 129.2, 125.3, 125.1, 35.7, 31.1. MS (ESI): m / z 718.88334 ([M-2Na] 2- ), the theoretical value is 718.88632.

[0219] Subject P[7]AS.

[0220]

[0221] The first two compounds were synthesized by using methods adapted from those known in the art. The procedure used for the last step was: to compound (HO) 14 Anhydrous pyridine (3 mL) was added to a mixture of column [7] aromatic hydrocarbon (0.020 g, 0.023 mmol) and pyridine sulfur trioxide complex (0.375 g, 2.34 mmol). The resulting mixture was stirred at 70 ° C for 24 hours under N2. The reaction mixture was cooled to room temperature. The product precipitated from the solution and was collected by filtration. The solid was slurried in water (1 mL) and the pH was adjusted to 8.4 by slowly adding saturated Na2CO3 aqueous solution. After adding EtOH (10 mL), the crude product was collected by centrifugation 7000 rpm×7 min. The precipitate was suspended in ethanol (10 mL×2), sonicated for 30 minutes, and the solid was collected by centrifugation. The crude solid was redissolved in a minimum amount of water (0.5 ml) and used G25 resin (30 mm × 200 mm) was purified by size exclusion chromatography and eluted with water. The pure product was collected as the front fraction. After drying under high vacuum, compound P[7]AS was obtained as a white solid (0.025 g, 0.011 mmol, 46% yield). Mp>290 ° C (decomposed). IR (ATR, cm -1 ): 3494w, 1624m, 1444s, 1244m, 1102s, 1049s, 995m, 875m, 807m, 614s. 1 H NMR (600MHz, D2O): 7.29 (s, 14H), 4.14 (s, 14H).13 C NMR (150 MHz, D2O, dioxane as external reference): δ 147.6, 132.8, 124.7, 30.8. MS (ESI): m / z 547.36023 ([M-4Na] 4- ), the theoretical value is 547.36080.

[0222] Rim-P[5]AS.

[0223]

[0224] The starting material 2-(benzyloxy)-5-methoxybenzyl alcohol was synthesized based on methods known in the art. Pentahydroxy post [5] arene compounds were synthesized by utilizing methods known in the art. Anhydrous pyridine (10 mL) was added to a mixture of pentahydroxy post [5] arene (0.200 g, 0.328 mmol) and pyridine sulfur trioxide complex (1.050 g, 6.56 mmol). The resulting mixture was stirred at 70 ° C for 24 hours under N2. The reaction mixture was cooled to room temperature. The product precipitated from the solution and collected by filtration. The solid was slurried in water (5 mL) and the pH was adjusted to 9 by slowly adding saturated NaHCO3 aqueous solution. EtOH (EtOH / H2O v / v=2:1) ​​was added to produce a precipitate, which was removed by centrifugation (7000 rpm×10 min). The filtrate was collected as a crude product and redissolved in a minimum amount of water (2 mL) and used Purification was performed by size exclusion chromatography on G25 resin (5 cm x 50 cm) using water as the eluent. The front fractions eluted from the column contained the pure product. After drying under high vacuum, Rim-P[5]AS was obtained as a white solid (0.374 g, 0.229 mmol, 67% yield, content: ~92%) by using sodium 2-bromoethanesulfonate as 1 H NMR internal standard determination). Mp>300°C (decomposed). 1 H NMR (400MHz, D2O): 7.21 (s, 5H), 6.56 (s, 5H), 3.90 (s, 10H), 3.24 (s, 15H). 13 C NMR (150 MHz, D2O, EtOH as internal reference): 155.3, 143.2, 134.5, 129.6, 124.7, 114.9, 56.7, 30.6.

[0225] Solubility determination.

[0226] Determination of the solubility of P[5]AS in water. Compound P[5]AS was added in excess to 0.5 mL of deuterium oxide. The suspension was magnetically stirred at room temperature overnight and then centrifuged twice (4500 rpm) for 10 minutes each. The supernatant (50 μL) and sodium 3-(trimethylsilyl) propionate-2,2,3,3-d4 (TMSP) (10 mM, 50 μL in D2O) were added to 0.4 mL of deuterium solvent. The concentration of P[5]AS was determined using 1 H NMR measurements and calculations were performed using sodium 3-(trimethylsilyl)propionate-2,2,3,3-d4 (TMSP) as an internal reference.

[0227] Determination of the solubility of P[6]AS in water. Compound P[6]AS was added in excess to 0.5 mL of deuterium oxide. The suspension was magnetically stirred at room temperature overnight and then centrifuged twice (4500 rpm) for 10 minutes each. The supernatant (50 μL) and sodium 3-(trimethylsilyl) propionate-2,2,3,3-d4 (TMSP) (10 mM, 50 μL in D2O) were added to 0.4 mL of deuterated solvent. The concentration of P[6]AS was determined using 1 H NMR measurements and calculations were performed using sodium 3-(trimethylsilyl)propionate-2,2,3,3-d4 (TMSP) as an internal reference.

[0228] Isothermal titration calorimetry (ITC) was used to determine the K between various hosts and cationic guests or drugs of abuse or neuromuscular blockers. a All ITC experiments were performed in a 200 μL working volume of the sample cell of the PEAQ ITC instrument. We used syringes with a 40 μL capacity. In each case, the host solution and the guest solution were prepared in 20 mM NaH2PO4 buffer (pH 7.4). The sample cell was filled to capacity (200 μL) with the host solution and the guest solution was titrated with (first injection = 0.4 μL, subsequent 18 injections = 2 μL). The binding data were fitted using a 1:1 binding model in the MicroCal PEAQ-ITC analysis software. In which K a When the α is too large to be determined by direct titration, a competitive ITC titration is performed, in which the K a The competing guest with ΔH is included in the ITC cell along with the host, which is then tested for its K a The object is titrated.

[0229] WP5, WP6 and the following compounds are compounds used in comparative examples:

[0230]

[0231]

[0232] The selected drugs and the subject 1 H NMR spectroscopy. Figure 8 Shows the drug (methamphetamine) and the subject (P[6]AS) 1 An example of HNMR spectroscopy.

[0233] Competitive binding 1 H NMR spectroscopy. Figure 9 P[6]AS was shown to bind to rocuronium more strongly than a previously known compound (Motor 2, which is also known as Calabadion 2).

[0234] The crystal structure P[6]AS was also determined. Figure 10 and Figure 13 The crystal structure of P[6]AS is shown.

[0235] Table 1. Crystallographic data and structure refinement of P[6]AS.

[0236] Crystal C 45.44 H 24 Na 12 O 65.65 S 12 empirical formula

[0237]

[0238]

[0239] Table 2. Fractional atomic coordinates and equivalent isotropic displacement parameters of P[6]AS Ueq is defined as 1 / 3 of the trace of the orthogonalized UIJ tensor.

[0240]

[0241]

[0242] Table 3. Anisotropic displacement parameters of P[6]AS The anisotropic displacement factor exponent takes the following form: -2π 2 [h 2 a* 2 U 11 +2hka*b*U 12 +…].

[0243]

[0244]

[0245] Fig. 4. P[6]ASS SOIL.

[0246]

[0247]

[0248] 1 1+YX,1-X,+Z! 2 1-Y,+XY,+Z! 3 1-Y+X,1-Y,1 / 2-Z! 4 +X,+XY,1 / 2+Z! 5 2-X,1-Y,1-Z! 6 1-X,1-Y,1-Z! 7 2-X,1-X+Y,1 / 2-Z! 8 1+YX,+Y,1 / 2+Z! 9 1-Y,1+XY,+Z! 10 +Y,+X,1 / 2-Z! 11 -X,-Y,1-Z; 12 -Y+X,+X,1-Z! 13 +Y,-X+Y,1-Z

[0249] Fig. 5. P[6]ASS FIGURE.

[0250]

[0251]

[0252] 1 1+YX,1-X,+Z! 2 1-Y,+XY,+Z! 3 1-Y+X,1-Y,1 / 2-Z! 4 +X,+XY,1 / 2+Z! 5 2-X,1-Y,1-Z! 6 1-X,1-Y,1-Z! 7 2-X,1-X+Y,1 / 2-Z! 8 1+YX,+Y,1 / 2+Z! 9 1-Y,1+XY,+Z! 10 +Y,+X,1 / 2-Z! 11 +X,+XY,-1 / 2+Z! 12 1+YX,+Y,-1 / 2+Z! 13 -Y+X,1-Y,1 / 2-Z! 14 -X,-Y,1-Z; 15 -Y+X,+X,1-Z!16 +Y, -X+Y, 1-Z; 17 +YX, 1-X, +Z

[0253] Table 6. Torsion angles of P[6]AS.

[0254]

[0255]

[0256] 1 1-Y, +XY, +Z; 2 2-X, 1-Y, 1-Z; 3 2-X, 1-X+Y, 1 / 2-Z; 4 +Y, +X, 1 / 2-Z; 5 +X, +XY, -1 / 2+Z; 6 1+YX, +Y, -1 / 2+Z; 7 -Y+X, 1-Y, 1 / 2-Z; 8 1-X, 1-Y, 1-Z; 9 1+YX, 1-X, +Z; 10 1+YX,+Y,1 / 2+Z; 11 1-Y, 1+XY, +Z; 12 1+X, 1+Y, +Z; 13 -Y+X, +X, 1-Z; 14 -X, -Y, 1-Z; 15 +Y, -X+Y, 1-Z; 16 +YX, 1-X, +Z; 17 +YX, -X, +Z; 18 -Y, +XY, +Z

[0257] Table 7. Hydrogen atomic coordinates and isotropic displacement parameters of P[6]AS

[0258] atom Z y z U(eq) H3 1.002(2) 0.569(2) 0.2874(14) 0.039(9) H4 0.937(2) 0.703(2) 0.1741(14) 0.026(7) H6 0.691(2) 0.532(2) 0.3338(14) 0.032(8) H7 0.590(2) 0.588(2) 0.2112(14) 0.035(8)

[0259] Table 8. Atom occupancy of P[6]AS.

[0260] atom Occupancy rate atom Occupancy rate atom Occupancy rate Na3 0.6667 O1 0.887(5) O2 0.887(5) O3 0.887(5) S1 0.887(5) O4 0.887(5) O1A 0.113(5) O2A 0.113(5) O3A 0.113(5) S1A 0.113(5) O4A 0.113(5) O5 0.58(3) S2 0.58(3) O6 0.58(3) O7 0.58(3) O8 0.58(3) O5A 0.42(3) S2A 0.42(3) O6A 0.42(3) O7A 0.42(3) O8A 0.42(3) O1B 0.85 C2B 0.285(13) O3B 0.308(7) C4B 0.15 O1C 0.808(11) O2C 0.317(10) O3C 0.306(10) O1D 0.353(9) C2D 0.412(17)

[0261] Experiment. A suitable P[6]AS single crystal was selected and measured on a Bruker Smart Apex2 diffractometer. This crystal corresponds to C 45.44 H 24 Na 12 O 65.65 S 12The crystal was held at 150(2)K during data collection. The integrated intensity was correct for absorption using the multiscan method using SADABS software. The minimum and maximum transmissions obtained were 0.634 and 0.959, respectively. The structure was solved using the ShelXT-2014 (Sheldrick, 2015a) program and refined using the ShelXL-2015 (Sheldrick, 2015c) program and least squares minimization using the ShelX software package. The number of constraints used = 387.

[0262] Crystal structure determination. 45.44 H 24 Na 12 O 65.65 S 12 (M=2280.86g / mol) crystal data: trigonal, empty

[0263] Intergroup P-3c1 (no.165), Z=2, T=150(2)K, μ(MoKα)=0.519mm -1 , D calc =1.881g / cm 3 , 23483 reflections (4°≤2Θ≤53.178°) were measured, 2810 unique (R int =0.0602, R sig =0.0410) (for all calculations). The final R1 was 0.0448 (I>2σ(I)) and wR2 was 0.1097 (for all data).

[0264] Refinement details. H atoms (except those in disordered solvents) were located from difference Fourier maps and freely refined (including Uiso). Water and ethanol solvents are severely disordered and modeled with partially occupied O and C atoms.

[0265] Example 2

[0266] This example provides the synthesis, X-ray crystal structure, and molecular recognition properties of the pillar[n]arene derivative P[6]AS (occasionally referred to herein as pillar[6]MaxQ), as well as the analogs P[5]AS and P[7]AS for guest 11-28. This example demonstrates the ultratight binding affinity of P[5]AS and P[6]AS for quaternary (di)ammonium ions, which supports their use in non-covalent bioconjugation in vitro and in vivo for imaging and delivery applications, and as chelators in vivo.

[0267] In more detail, those skilled in the art will recognize that progress in the construction of supramolecular systems for biological applications (e.g., imaging and drug delivery) and chemical applications (e.g., sensing, catalysis, separation) relies heavily on the availability of a library of building blocks that can be readily integrated into more complex and functional systems. Molecular containers—whether prepared by covalent bond-forming reactions or by self-assembly processes—occupy a central area of ​​this field. Some of the most popular molecular containers include cyclodextrins, calix[n]arenes, crown ethers, cyclophanes, coordination cages, molecular clamps and tweezers, cucurbit[n]urils (CB[n]), and H-bonded capsules. Within this group, the CB[n] family ( Figure 11 a) have proven to be particularly useful because they form tight CB[n]·guest complexes in a selective and stimuli-responsive manner, which allows them to be used to create sensing ensembles, supramolecular polymers, molecular machines, for bioconjugation, as non-covalent locking systems, and for drug solubilization and delivery. Given the high binding affinity of acyclic CB[n] for its optimal guests, acyclic CB[n] (e.g., M2, Figure 11 a) As in vivo chelators for neuromuscular blockers and drugs of abuse. Recently, pillar[n]arenes ( Figure 11 The synthesis and molecular recognition properties of pillar[n]arenes, such as WP[5] and WP[6], in both organic and aqueous solutions have been extensively studied and their chemical and biological applications have been well reviewed. Pillar[n]arenes represent a sweet spot for the study of molecular recognition in water, as they typically exhibit K values ​​in the μM range. d values ​​and are more readily functionalized than CB[n]. Thus, this example provides a description of the preparation of column[n]arene sulfates (also known as column[n]MaxQ), which have an extremely high binding affinity (K) for quaternary diammonium ions in aqueous solution. d in the pM range), which makes them particularly well-suited as in vivo chelating agents.

[0268] Considering the creation of new ultra-tight binding hosts based on pillar[n]arene leads us to consider the relevant structural features of CB[n] ( Figure 11a). The ultra-tight binding characteristics of CB[n] have been traced back to their highly electrostatically negative urea C=O entrances and the number and energy of water molecules released within the host cavity upon binding (e.g., non-classical hydrophobic effect). Due to their double CH2-linkers, CB[n] do not have free rotors, cannot undergo self-complexation, and are therefore highly pre-organized hosts. The present disclosure relates to replicating these structural features in the pillar[n] aromatic family through rational molecular design. Although anionic water-soluble pillar aromatics (e.g., WP[5] and WP[6]) are known, they contain a CH2-linker between the aromatic ring and the anionic functional group (e.g., carboxylate, sulfonate, phosphonate). The present disclosure includes removing the CH2-linker and replacing it with a highly acidic sulfate functional group to provide a higher negative charge density around the opening of the cavity. At the same time, the addition of two sulfate groups per phenylene group is envisioned to electrostatically minimize the known possibility of phenylene groups tilting into their own cavities.

[0269] Figure 11 The synthesis of P[5]AS-P[7]AS is shown. The parent hydroxylated pillar arenes (P[5]AP[7]A) were prepared according to literature procedures. Subsequently, P[5]AP[7]A was reacted individually with pyridine·SO3 in pyridine at 90°C to afford P[5]AS-P[7]AS in 70%, 66% and 46% yields, respectively. To gain insight into the role of the CH2-linker, P[5]ACS was prepared as a control compound in low yield (8%) by reacting P[5]A with propane sultone and NaOH in acetone. Finally, the known hosts WP[5] and WP[6] were prepared as additional comparators by methods known in the art. All new compounds were prepared by 1 H and 13 The structure of the phenylene group was characterized by C NMR, IR, and high-resolution electrospray ionization mass spectrometry. It is known that pillar[6]arenes can exist in five different conformations due to rotation around the phenylene unit. Figure 12 a shows the recorded P[6]AS in D2O at room temperature. 1 H NMR, which consists of two relatively sharp singlets. This suggests that P[6]AS is either locked in the depicted C6-symmetric structure or that the phenylene units rotate rapidly on the chemical shift time scale. Based on host-guest experiments, it can be inferred that OSO3 - The rotation of the radical through the ring of the P[6]AS pillararene is rapid.

[0270] The intrinsic water solubility of the two most effective hosts (P[5]AS: 100 mM; P[6]AS: 20 mM; see below) was determined by 1The H NMR resonances were measured by integrating the methyl resonances of sodium 3-(trimethylsilyl)propionate-2,2,3,3-d4 at a known concentration as an internal standard. 1 Dilution experiments monitored by H NMR spectroscopy were performed to quantify their intermolecular self-association. Using a standard 2-fold self-association model, P[5]AS and P[6]AS were recorded as the molecules used to calculate K s The spectra of the function of the concentration of the values ​​(P[5]AS: 20-0.1 mM; P[6]AS: 20-0.1 mM). These K s The values ​​ensured that the host remained monomeric at the mM concentrations used in the NMR and ITC experiments described below in this example. Crystals of both P[6]AS and P[5]ACS were obtained, and their structures as solved by X-ray diffraction measurements ( Figure 13 , CCDC 1996177 and CCDC 1996179). Figure 13 d shows the structure of one molecule of P[5]ACS in a crystal. As is commonly seen in pillararene crystal structures, the phenylene rings are oriented approximately perpendicular to the average plane of the macrocycle, and the substituents serve to deepen the cavity. The S···S distance between the sulfonates attached to the individual phenylene rings is within the range. Figure 13 a shows the structure of a single molecule of P[6]AS in a crystal. Unlike P[5]ACS, P[6]AS adopts an unusual conformation in which alternating phenylene units are slightly tilted into cavities on opposite faces of the macrocycle in a geometry reminiscent of cyclotriveratrylene. The tilt of the phenylene units from the vertical was measured to be 35-38 degrees. Interestingly, OSO3 - The groups do not lie in the average plane of the phenylene unit, but are alternately displayed above and below this plane. This tilt and alternation results in 12 OSO3 - The groups are placed roughly on a side of And the height is Therefore, P[6]AS is located in a small volume (the volume of CPK molecules of P[6]AS). It has a relatively high charge density of -12. + The effect of the counterion on the observed conformation of P[6]AS is unclear. P[6]AS molecules are packed into a hexagonal array in the xy-plane, e.g. Figure 13 As shown in b; OSO3 - The subunits coordinate Na +ions are extensively bridged. These hexagonally packed P[6]AS sheets are aligned with each other along the z-axis, so that the P[6]AS unit defines a tube ( Figure 13 c) The accumulation of P[5]ACS also showed that the Na + A network of ions holds the stacked sheets together.

[0271] Figure 12 a shows two singlets of P[6]AS alone and a single set of sharp resonances of the P[6]AS·25 complex ( Figure 12 c) The significant upfield shift observed for the resonance of guest 25 confirms its inclusion in the cavity of P[6]AS. At a 1:2 P[6]AS:25 ratio, the resonance of guest 25 shifts back towards that of free 25, indicating that guest exchange occurs rapidly on the chemical shift timescale. Figure 2-4 Similar studies have been conducted on different combinations of hosts and guests, and in many cases the situation is more complicated. For example, in many cases, after mixing with one equivalent of guest, the aromatic H-atom (H a ) broadens or splits into many different sharp resonances. Of course, it is well known that pillar[n]arenes have several different lower symmetry conformations (n ​​= 5: 4 conformers; n = 6: 5 conformers), which would be expected to produce broadened or additional resonances, as observed in a guest-dependent manner. For the host P[6]AS and P[7]AS, upfield shifts of the guest resonances were observed upon binding, indicating cavity binding of the hydrophobic portion of the guest. For P[5]AS, the narrower guests (e.g., 21 and 23) bound within the cavity, as indicated by the upfield shifts in the chemical shifts, but the broader guests (e.g., 12 and 25) showed NMe3 + groups rather than their hydrophobic parts, which indicates that the + ITC measurements (see below) indicated that 12 and 25 bound to P[5]AS with a host:guest stoichiometry of 1:2.

[0272] Initially, through 1 H NMR spectroscopy was used to study the effect of the new host on the guest 11-28 ( Figure 2 Compounds 11–28 were selected because they have different numbers of charged groups (one or two), lengths of hydrophobic residues, widths of hydrophobic residues, and degrees of ammonium ion substitution (1°, 2°, 3°, 4°) for evaluating the preference of new entities. Figure 12 The recorded values ​​for P[6]AS, 25 and 1:1 and 1:2 mixtures of P[6]AS and 25 are shown. 1H NMR spectroscopy is a particularly well-resolved example. Next, the strength of the binding interactions between various hosts and guests is quantified. Given 1 To investigate the complexity and tight binding observed in the H NMR spectra (see below), we used isothermal titration calorimetry (ITC). For most complexes, we performed direct titration of the host in the cell with the guest in a syringe. Figure 5-7 Thermodynamic parameters determined by these direct ITC titrations are shown, and representative experimental data are shown in Figures 69-83 Direct titration is not suitable for K a Value exceeds 4×10 7 M -1 In these cases, we used competition ITC experiments in which a mixture of host and excess weaker binding guest in the cell was titrated with the stronger binding guest in the syringe. In these ITC competition experiments, the ΔH and K values ​​of the weaker host·guest complexes were calculated. a Values ​​were determined independently and used as input for competitive ITC titrations. Figure 14 a shows the titration of a mixture of P[6]AS and weaker bound guest 17 in the cell using the stronger bound guest 20 in the syringe. Figure 14 b) Fitting to a competitive binding model allowed extraction of thermodynamic parameters (K a =(1.20±0.06)×10 11 M -1 ; ΔH = -17.1 ± 0.033 kcal mol -1 ). Figure 5-7 Results of competitive ITC titrations of more compact host·guest complexes are reported.

[0273] Figure 5-7 The extensive data set presented in allows for a comprehensive discussion of the binding preferences of the new hosts compared to the previously known WP[5] and WP[6]. All complexes are driven by favorable ΔH values, suggesting that these complexes benefit from non-classical hydrophobic effects as planned. First, it is noted that the binding of P[5]ACS with its (CH2)3-linker to the alkyldiammonium ions 16-20 is ≈10 weaker than that observed for WP[5]. 1 -10 2 times, which may be the result of these linkers partially blocking the host cavity or reacting with the anion SO3 -The result of longer linkers of the groups is that the electrostatic interactions are reduced. In addition, P[5]ACS and WP[5] show little selectivity in binding based on the degree of methylation of the diammonium ion (e.g., 1°: 17, 2°: 18; 3°: 19; 4°: 20). In contrast, P[5]AS is a superior host for diammonium ions than WP[5] (e.g., 17: 41-fold; 18: 390-fold; 19: 7300-fold; 20: 88000-fold). P[5]AS shows increasing binding affinity as the degree of methylation of the guest N atom increases. Therefore, this class of hosts is called column[n]MaxQ to indicate their generally excellent binding affinity and selectivity for quaternary ammonium ions. Comparison of the binding affinity of P[5]AS for quaternary diammonium ions of different lengths (e.g., 15, 16, 20) shows that the binding of C4-diammonium ions is 317-458 times weaker than that of the C5- and C6-analogs, likely due to the interaction of N···N with - O3S···SO3 - The better matching of the distance and the increased hydrophobicity of the C6-hydrophobic residues. It is very interesting that P[5]AS has a better effect on the performance of the monoquaternary guest 13 (4.41×10 8 M -1 ) and double quarter guest 20 (9.90×10 11 M -1 ) revealed the importance of electrostatic interactions in the recognition process. All of these narrow guests formed 1:1 P[5]AS·guest complexes. In contrast, ITC results revealed that broader guests (e.g., 12, 25, 27, cis, roc, vec, pan) were unable to form inclusion complexes with P[5]AS, but instead formed 1:2 P[5]AS:guest complexes at the entrance. ITC titrations of P[5]AS with this subset of guests fit well with a 1:1 binding model where N=2, and thus Figure 5-7 K reported in a Value has M -1 unit, and involves each of two independent binding events. + K a Value (P[5]AS·26; K a =3.11×10 4 M -1 ) revealed that each quaternary ammonium head group made a significant contribution to the observed ultrahigh affinity of P[5]AS for (di)quaternary ammonium ions (e.g., 20).

[0274] Figure 5-7 The binding constants (K) of various hosts and guests 11-28 are shown. a , M -1 ) and thermodynamic parameters (ΔH, kcalmol-1 ), neuromuscular blocking agents are shown in Figure 4 and drug abuse is shown in Figure 3 and Figure 68 Conditions: H₂O, 20 mM NaH₂PO₄ buffer, pH 7.4, 298 K. - Not measured. nb = No heat change detected by ITC. a Measured by direct ITC titration with [host] ≥ 10 μM. b Measured by competitive ITC titration with 13. c Measured by competitive ITC titration with 14. d Measured by competitive ITC titration with 16. e Measured by competitive ITC titration with 17. f Measured by competitive ITC titration with 21. g Measured by competitive ITC titration with 24. h Measured by competitive ITC titration with 27. i Measured by competitive ITC titration with 28. j 1:2 host:guest complex. k 2:1 host:guest complex.

[0275] A relevant comparison can be made between the host WP[6] and P[6]AS, which exhibited 1:1 host:guest complexation for all guests used in this study. For example, P[6]AS was an excellent host for 20 of the 23 guests studied, with the exception of the inclusion of 1° ammonium ions 24 and 27. Similar to P[5]AS, P[6]AS was selected based on guest length (e.g., 14 vs. 28 vs. 17; 15 vs. 16 vs. 20) and on the degree of methylation of the diammonium ion (e.g., 17 vs. 20; K a =1.43×10 9 Relative to 1.20×10 11 M -1 ) is highly selective. Interestingly, P[6]AS is highly selective for Me4N + (26, K a =2.32×10 6 M -1 ) has a binding affinity 75 times stronger than that of P[5]AS, which suggests that P[6]AS should be considered as a potent host for quaternary ammonium ions. In fact, P[6]AS has a high K d Values ​​range from single-digit μM to 1 pM, placing P[6]AS alongside CB[n] as one of the highest affinity synthetic host-guest systems in water, despite the significant difference in the balance of driving forces for complexation (e.g., electrostatic versus hydrophobic effects). Figure 5-7 The binding affinity of P[7]AS for a group of guests (11-28) is shown. In this case, a comparison with the water-soluble pillararene analog (WP[7]) cannot be made because it is not available. However, see Figure 5-7It was revealed that P[7]AS is a significantly less efficient acceptor than P[6]AS for guest groups other than the primary ammonium ion 24. Although the reasons for the relatively poor performance of P[7]AS have not been determined, without intending to be bound by any particular theory, it is speculated that the reasons may be similar to those for the CB[n] host family, where the size of the electrostatically negative entrance and the energetics and number of bound water in the host cavity play an important role.

[0276] Given the demonstrated preference of P[5]AS and P[6]AS for quaternary diammonium ions, the client group was expanded to include the clinically important neuromuscular blockers roc, vec, pan, and cis as well as acetylcholine (ACh). Macrocyclic receptors (e.g., manufactured by Merck as Bridion TM The commercially available γ-cyclodextrin derivative sugammadex, acyclic CB[n]-type receptor M2 and WP[6]) have previously been used as in vivo chelators for NMBAs. Therefore, the binding affinities of P[5]AS-P[7]AS, WP[5] and WP[6] for NMBAs were measured ( Figure 7 Most strikingly, P[6]AS was found to bind more tightly to roc, vec, and pan than to WP[6] or sugammadex. 4 -10 5 times, while maintaining a very good discrimination level for acetylcholine (10 3 -10 4 times), acetylcholine is also present in the neuromuscular junction. In fact, the affinity of P[6]AS for roc, vec and pan is the same as that of the previously reported main M2 (K a :M2·roc=3.4×10 9 M -1 ; M2·vec=1.6×10 9 M -1 ; M2·pan=5.3×10 8 M -1 ) is >100 times higher than that of M2. The subject M2 has been shown to successfully reverse the biological effects of ROC, VEC and CIS in rats in vivo. To further confirm the superior binding affinity of P[6]AS to M2 for ROC, a 1 Head-to-head testing monitored by H NMR spectroscopy. Figure 15 ae shows the recorded values ​​for uncomplexed P[6]AS, M2 and roc, and for P[6]AS·roc complex and M2·roc complex. 1 H NMR. For the M2·roc complex, for enantiomerically pure complexes, there is H a* and H b*Splitting into a total of 8 resonances and downfield shifts. For both complexes, the presence of an axial steroidal Me-group (H p and H q ), which allows monitoring the composition of the mixture of these two competing host·guest complexes. Figure 15 f shows the recorded values ​​when a solution of M2·roc (0.5 mM) was treated with 1 equivalent of P[6]AS. 1 H NMR spectroscopy. The loss of the M2·roc resonance and the appearance of the P[6]AS·roc resonance further confirm the superior affinity of P[6]AS in the context of neuromuscular blockers. Previously, due to the lower binding affinity (K a =4.8×10 6 M -1 ) was caused by M2, which was only observed at higher doses (≥40 mg kg -1 ) in rats to achieve the in vivo reversal of the effects of cis. The experiment found that P[7]AS and cis form a (P[7]AS)2·cis complex, in which the benzylisoquinolinium end groups are each complexed by the P[7]AS main body. The ITC data of (P[7]AS)2·cis can be fitted to the N 位点 =2 and K a =1.52×10 7 M -1 Therefore, P[7]AS has the potential to be converted into a reversal agent in vivo for cis.

[0277] In summary, this example describes the synthesis of P[5]AS-P[7]AS, the X-ray crystal structures of P[5]ACS and P[6]AS, and their molecular recognition properties for (di)ammonium ions in aqueous solution. P[n]AS packs 2n negative charges into a small volume near the entrance of the receptor, which increases the electrostatic contribution to the binding free energy. It was found that the binding affinity of P[5]AS and P[6]AS for (di)quaternary (di)ammonium ions is significantly higher than that of WP[5] and WP[6]. Therefore, the proposed family name is column[n]MaxQ. The picomolar affinity of P[6]AS for roc and vec greatly exceeds that of the acyclic CB[n]-type receptors M2 and BRIDION, which are used in clinical practice. TM The ultratight binding (e.g., picomolar K) exhibited by P[5]AS and P[6]AS is shown in Table 1. d) place them alongside CB[n] as some of the most potent synthetic receptors in water. The ultratight binding of P[5]AS and P[6]AS suggests that sulfated pillararenes and their functionalized derivatives may be used as non-covalent linkers for bioconjugation, for (bio)chemical separations, for theranostics, and for chelation and remediation in chemical and biological systems.

[0278] Isothermal titration calorimetry (ITC) was used to determine the K a . All ITC experiments were performed in a 200 μL working volume of the sample cell of the PEAQ ITC instrument. A 40 μL capacity injection syringe was used. In each case, the host solution and the guest solution were prepared in 20 mM NaH2PO4 buffer (pH 7.4). The sample cell was filled to capacity (200 μL) with the host solution and the guest solution was titrated (first injection = 0.4 μL, subsequent 18 injections = 2 μL). Binding data were fitted using a 1:1 binding model or a competitive binding model in the MicroCal PEAQ-ITC analysis software.

[0279] Example 3

[0280] This example provides the in vivo effects of P[6]AS on reversing methamphetamine-induced hyperlocomotion in a relevant mouse model. This example also provides results from in vivo toxicology studies of P[5]AS and P[6]AS.

[0281] Cytotoxicity data of P[5]AS and P[6]AS. To test the cytotoxicity and cell survival of the above compounds, we used two different assays: MTS (CellTiter 96AQueous ) assay and AK ( which measures cell death by releasing the cytosolic enzyme adenylate kinase into the supernatant. The MTS and AK assays were performed using a 400 nm RT-PCR bioassay kit (BioAssay Kit). Both assays were performed using two different cell lines. HEK293 and Hep G2 cells are frequently used in drug toxicity studies. HEK293 (human kidney cell line) is used to evaluate the effects of drugs on the renal system, while Hep G2 (human liver cell line) is used to assess the response of liver cells in which drugs are metabolized. MTS and AK assays for both cell lines were performed after incubation for 24 h with compounds at concentrations of 0.01 mM, 0.03 mM, 0.1 mM, 0.3 mM, and 1 mM. Eight technical replicates were assigned for untreated cells, and four technical replicates were assigned for cells treated with each compound and staurosporine (a cell apoptosis inducer).

[0282] The collected absorbance and relative luminescence data were normalized to percent cell survival (MTS) and percent cell death (AK) using equations 1 and 2:

[0283] 1) Cell survival % = (Abs sample / average Abs UT) × 100

[0284] 2) Cell death % = (RLU sample / average RLU distilled water) × 100

[0285] Toxicity studies on the hepatocyte cell line HepG2 using MTS and AK assays showed that P[5]AS exhibited low cytotoxicity up to 1 mM concentration and high cell tolerance up to 0.3 mM concentration ( Figure 63 A, B). P[6]AS showed low cytotoxicity up to 1 mM concentration and high cell tolerance up to 0.1 mM concentration to human HepG2 cells ( Figure 63 C, D).

[0286] Similar toxicity studies on human kidney (HEK293) cells showed that P[5]AS exhibited low cytotoxicity up to 1 mM concentration and high cell tolerance up to 0.1 mM concentration ( Figure 64 A, B). P[6]AS exhibited low cytotoxicity up to 1 mM concentration and high cell tolerance up to 0.03 mM concentration ( Figure 64 CD).

[0287] In vivo maximum tolerated dose study (MTD). Animal studies (IACUC#R-JAN-17-25) were conducted at the University of Maryland, Microbiology Building under the supervision of Dr. Volker Briken. A total of 20 female Swiss Webster mice were used in this study. Three different concentrations of P[6]AS (11.31 mM, 7.54 mM, 3.77 mM) were used. A PBS control group was also included. Each concentration group and control group contained 5 mice. Mice received the compound in 0.150 ml of PBS via tail vein injection, with a 48-hour interval between injections. The weight and health of the mice were monitored for 2 weeks after the last injection. Behavioral summary: The 11.31 mM dose group showed dose-dependent side effects in the form of freeze up and some breathing difficulties. The 11.31 mM dose group returned to baseline behavior (behavior observed using the PBS control) ≈ 2-3 hours after injection. The lowest dose group, 3.77 mM, showed no overall side effects and behaviors comparable to those of the PBS control group.

[0288] MTD study of P[6]AS. Female Swiss Webster mice (n=5 per group) were administered various concentrations of P[6]AS or phosphate-buffered saline (PBS) via the tail vein on days 0 and 2 (indicated by *). The normalized mean body weight change for each study group is indicated. Error bars represent SEM.

[0289] Reversal of methamphetamine-induced excitatory autonomic activity by P[6]AS in vivo

[0290] Animals. Eight male Swiss Webster (CFW) mice were obtained from Charles River Laboratories, weighing ~30 g upon arrival. Mice were individually housed in a temperature and humidity controlled room on a 12 h light / dark schedule with lights on at 6:00 a.m. Eastern Time (EST). During the duration of both experiments, mice had free access to food and water. All behavioral testing was performed between 6:30 a.m. and 2:00 p.m. EST, and all experimental procedures were approved by the University of Maryland Animal Care and Use Committee and in accordance with the guidelines established by the National Research Council.

[0291] Surgical procedure. Mice were anesthetized by intraperitoneal (IP) injection of ketamine (100 mg / kg) / xylazine (10 mg / kg) (n=8) and implanted with a jugular vein catheter with a head-mounted port. All surgical procedures were performed using aseptic technique, with body temperature monitored and maintained throughout the operation. The catheter was placed in the right jugular vein, with the port leading subcutaneously to the top of the skull. The port (5MM Up Pedestal; P1 Technologies) was fixed to the skull with a combination of super glue (Loctite) and dental cement. Immediately after surgery, mice received an injection of Rimadyl (5 mg / kg) and 0.4 mL warm sterile saline. Mice were treated with Rimadyl (5 mg / kg) for two days after surgery and were given at least 5 days to recover before recovery training. The catheter was flushed with 0.1 mL sterile saline solution containing gentamicin (0.33 mg / mL) and 0.1 mL sterile saline solution containing heparin (20 IU / mL) every day to reduce coagulation and keep the catheter open. Catheter patency was assessed daily starting on the first day after surgery until the end of testing. Any mouse whose catheter showed significant reflux on the majority of days was excluded from analysis.

[0292] Behavioral testing. Mice were trained using a standard self-shaping task as previously described. All behavioral procedures were conducted in a Med Associates testing chamber equipped with a food cup, a retractable lever, and four floor-mounted infrared (IR) beams. Timestamps were generated when the head entered the food cup, the lever was deflected downward, or the floor beam was broken, and recorded by a behavioral computer.

[0293] Mice were given one day of diet box training consisting of random delivery of thirty 20 mg sucrose pellets (Bioserv) at a variable interval of 30 ± 15 to habituate the mice to the box and pellet delivery. To minimize the effects of novelty-induced feeding inhibition, mice were given five to six 20 mg sucrose pellets in their respective home cages for 2-3 days before the start of training.

[0294] After diet box training, mice began a Pavlovian training phase, which included presenting a lever (CS) for 8 seconds, followed by immediate delivery of a sucrose pellet and retraction of the lever. The CS was presented at random intervals of 90 ± 30 seconds. Each Pavlovian phase included 30 trials. Pavlovian training lasted 4 days before surgery. After surgery and recovery, mice underwent another 8 days of Pavlovian training while being exposed to various treatments.

[0295] Experimental Design. The efficacy of P[6]AS was evaluated using a semi-counterbalanced design in which all mice received each possible experimental treatment. The objectives of the experiment were: (1) to verify that methamphetamine binding via P[6]AS is not impaired in vivo, (2) to verify that P[6]AS does not alter locomotor behavior, and (3) to confirm that P[6]AS can sequester methamphetamine in vivo. On the first day, mice underwent a refresher session without treatment, regardless of the experimental setting. Over the next six sessions, mice received one of six possible treatments: 0.01 M PBS (0.2 mL, infused), P[6]AS alone (4 mM; 0.178 mL, infused), methamphetamine alone (0.5 mg / kg; 0.022 mL, infused), a premixed solution of P[6]AS and methamphetamine (premix; ~7:1 P[6]AS:Meth; 0.178 mL P[6]AS+0.022 mL Meth, infused), P[6]AS followed by methamphetamine administered 30 s later (0.178 mL P[6]AS, 0.022 mL Meth, infused), and methamphetamine followed by P[6]AS administered 30 s later (0.022 mL Meth, 0.178 mL P[6]AS, infused). Mice received only one infusion per day. The methamphetamine dose was chosen based on previously published values ​​at which reliable excitatory autonomic activity was observed in mice. This was done to select the minimum dose that reliably induced excitatory autonomic activity.

[0296] After completing the first six stages, mice completed the behavioral test of other two days.On the 7th day, half mice (n=4) accepted P[6]AS, followed by the methamphetamine (0.178mL P[6]AS, 0.022mL Meth, infusion) that used after 5 minutes, then the methamphetamine infusion that used on the 8th day of test, followed by the P[6]AS (0.022mLMeth, 0.178mL P[6]AS, infusion) that used after 5 minutes.The other half mice (n=4) accepted identical but reversed treatment of order on the 7th day and the 8th day.

[0297] For each experiment, total locomotor activity counts (i.e., the total number of beam breaks) were obtained for each mouse throughout each training period. For each experiment, locomotor activity counts were then analyzed during the treatment period using a one-way repeated measures ANOVA (paired post hoc t-test with Tukey's correction) in Graphpad Prism (version 9.0.0).

[0298] After 5 minutes of delay between the treatment utilizing methamphetamine and P[6]AS to use, observe the body reversal of the excitatory autonomic activity effect that methamphetamine brings out.At the 7th day and the 8th day, mouse (n=8) accepts methamphetamine, then is the infusion 0.01M PBS (REV-C) that uses after 5 minutes; 0.022mL Meth, 0.2mL PBS infusion), perhaps receives methamphetamine, then is the P[6]AS (REV-5) that uses in offset mode after 5 minutes; 0.022mL Meth, 0.178mL P[6]AS, infusion).After being exposed to methamphetamine 5 minutes, use P[6]AS and reduce excitatory autonomic activity (paired t-check, t (7)=2.757, p=0.0282).Bar represents average autonomic activity count.Error bar represents the standard error (SEM) of mean value.Point represents the counting for every mouse (n=8).

[0299] Will recognize from the above that this embodiment provides the analysis of the effect of P[6]AS aspect chelating methamphetamine in vivo.Eight male Swiss Webster (CFW) mice are trained according to the Pavlovian automatic shaping task described previously, and obtain locomotor activity value and carry out corresponding analysis.In order to set up the excitatory locomotor activity that methamphetamine brings out and check the effect of P[6]AS, first mice are carried out single infusion PBS (0.01M), only P[6]AS, only methamphetamine, the premixed solution of P[6]AS and methamphetamine, P[6]AS is then followed by the methamphetamine after 30s to use or methamphetamine is followed by using P[6]AS (in offset mode) after 30s to treat. Figure 66 Depicted the result of this experiment by drawing the voluntary activity count along with treatment change.Mixed effects analysis discloses the significant main effect (F (5,35) = 7.116, p = 0.0001) of treatment, wherein the comparison afterwards of Tukey correction demonstrates the significant increase (p's < 0.05) utilizing the processing of methamphetamine relative to all other treatments in voluntary activity count.Crucially, there is no difference in the voluntary activity aspect of the comparison for reversal (i.e. first meth, then P [6] AS after 30 seconds), this shows that P [6] AS itself does not have a negative impact on voluntary activity behavior, and the successive use of P [6] AS reduces the excitatory voluntary activity that methamphetamine brings out to control level.

[0300] Although the results of this first analysis indicate the potential efficacy of P[6]AS in chelating methamphetamine and inducing behavioral changes, it is possible that the 30-second interval between methamphetamine administration and P[6]AS administration in the reversal condition was too short to be behaviorally relevant. To address this issue, subsequent experiments were performed in which mice (n=8) were administered methamphetamine followed by 0.01M PBS 5 minutes later (REV-C) or methamphetamine followed by P[6]AS 5 minutes later (REV-5) on days 7 and 8 of the test before completing the self-shaping task in a counterbalanced manner. Figure 67 Locomotor activity counts as a function of REV-C or REV-5 treatment are plotted. A significant reduction in locomotor activity was observed under REV-5 relative to REV-C (paired t-test, t(7)=2.757, p=0.0282). Although not directly comparable from an experimental design perspective, it is important to note that on days 1-6, locomotor activity levels under REV-5 were very close to those observed under control conditions, while locomotor activity counts under REV-C appeared close to those observed when methamphetamine alone was used. Overall, these findings suggest that P[6]AS is able to chelate methamphetamine in vivo and reverse methamphetamine-induced excitatory locomotor activity, with little to no effect on the animals' own locomotor behavior.

[0301] Example 4

[0302] The following examples show ITC data for various drugs in combination with the subjects of the present disclosure.

[0303] Table 9. K values ​​for MDMA, mephedrone, and heroin a .

[0304]

[0305]

[0306] a Measured by competitive ITC titration of the host (0.1 mM) and 1,3-propanediammonium chloride (0.15 mM) in a cell using a guest (1 mM) in a syringe. b Directly measured by ITC titration of the host (100 μM) in a cell using a guest (100 μM) in a syringe. c Directly measured by ITC titration of the host (0.1 mM) in a cell using a guest (1 mM) in a syringe.

[0307] Figures 69-71 ITC data for P[6]AS and MDMA, mephedrone, and heroin are shown.

[0308] Although the present disclosure has been described with respect to one or more specific embodiments, it should be understood that other embodiments of the present disclosure may be formed without departing from the scope of the present disclosure.

Claims

1. A compound having the following structure: in Each R is independently selected from: -OS(O)2O - M + , where M + Yes + , K + 、H4N + 、Et3NH + 、Me4N + 、(HOCH2CH2)3NH + , or a salt, partial salt or mixture thereof.

2. The compound according to claim 1, wherein M + Yes + .

3. A compound having the following structure: Where R is SO3Na, or a salt, partial salt or mixture thereof.

4. A composition comprising one or more compounds according to claim 1 or 3. The composition according to claim 4 , further comprising a pharmaceutical carrier.

6. The composition of claim 4, wherein the one or more compounds are disposed on at least a portion of a solid substrate.

7. The composition of claim 6, wherein the solid substrate comprises silica, polymer beads, polymer resin, metal nanoparticles, metal, or a combination thereof.

8. The composition of claim 4, wherein at least a portion or all of the one or more compounds have one or more pharmaceutically active agents disposed within a cavity of the one or more compounds.

9. Use of the compound according to claim 1 or 3 in the preparation of a medicament for chelating one or more neuromuscular blockers, one or more anesthetics, one or more pharmaceutical agents or a combination thereof. wherein the one or more neuromuscular blockers are selected from rocuronium, atracurium, cisatracurium, pancuronium and vecuronium, wherein the one or more anesthetic agents is ketamine, wherein the one or more pharmaceutical agents are selected from one or more drugs of abuse, wherein the one or more drugs of abuse are selected from methamphetamine, cocaine, fentanyl, MDMA, heroin, mephedrone, morphine, hydromorphone, oxycodone, and phencyclidine.

10. The use of claim 9, wherein the one or more neuromuscular blockers, the one or more anesthetics, the one or more pharmaceutical agents, or a combination thereof are present in an aqueous sample, in a solid sample, in a gaseous sample, or on a solid surface.

11. The use according to claim 10, wherein the aqueous sample is a wastewater sample, an industrial water sample or a municipal water sample.

12. The use according to claim 9, wherein the compound is complexed with the one or more neuromuscular blockers, the one or more anesthetics, the one or more pharmaceutical agents, or a combination thereof.

13. The use according to claim 12, wherein the complex is removed from an aqueous sample, a solid sample or a gaseous sample.

14. The use of claim 9, wherein the one or more neuromuscular blocking agents, the one or more anesthetic agents, the one or more pharmaceutical agents, or a combination thereof are present in and / or on the individual.

15. The use according to claim 14, wherein the subject is a human or a non-human mammal.

16. Use of a compound according to claim 1 or 3 in the preparation of a medicament for reversing drug-induced neuromuscular blockade and / or anesthesia and / or the effects of one or more pharmaceutical agents in a subject in need thereof, wherein the neuromuscular blockade is induced by rocuronium, atracurium, cisatracurium, pancuronium, and vecuronium, wherein the anesthesia is induced by ketamine, wherein the one or more pharmaceutical agents are selected from drugs of abuse, wherein the drugs of abuse are selected from methamphetamine, cocaine, fentanyl, MDMA, heroin, mephedrone, morphine, hydromorphone, oxycodone, and phencyclidine.

17. The use according to claim 16, wherein the subject is in need of reversal of drug-induced neuromuscular blockade.

18. The use according to claim 16, wherein the subject requires reversal of anesthesia.

19. The use of claim 16, wherein the subject is in need of reversal of drug-induced neuromuscular blockade and anesthesia.

20. The use of claim 16, wherein the subject is in need of reversal of the effects of one or more pharmaceutical agents.

21. The use according to claim 16, wherein the individual in need thereof is a human.

22. The use according to claim 16, wherein the individual in need thereof is a non-human mammal.

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