A water-soluble expanding column [6] of aromatics and its applications

Abstract

This invention discloses a water-soluble expanding column [6] aromatic hydrocarbon and its applications. This invention designs and synthesizes a water-soluble expanding column [6] aromatic hydrocarbon, which not only has a larger rigid cavity but also good water solubility. The expanding column [6] aromatic hydrocarbon PIM-3 of this invention can perfectly complex tetracarboxyporphyrin, inhibiting its aggregation in water and enhancing its photodynamic therapy effect.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a water-soluble extended column[6] of aromatic hydrocarbons and its applications. Background Technology

[0002] The rapid development of modern supramolecular chemistry has also significantly benefited from the design and preparation of new macrocycles with unique geometries and properties. Columnar aromatics are a relatively young class of existing macrocyclic hosts (crown ethers, cyclodextrins, cucurbiturates, and calixarenes), and have been a research hotspot internationally for the past decade. In practical preparation, the yield is very low when the columnar aromatics have more than six repeating units. How to increase the cavity size while maintaining the rigidity of the macrocycle is an important research topic.

[0003] Through a pre-modification method, this invention prepares water-soluble extended column[6] aromatics, which is a macrocyclic host with a larger cavity than column[6] aromatics and a size comparable to column[8] aromatics. While maintaining a similar cavity size, it has a rigid and non-foldable spatial structure, and is expected to be applied to the controlled loading and release of drugs. Summary of the Invention

[0004] One objective of this invention is to provide a water-soluble extended column [6] aromatic hydrocarbon, the structural formula of which is shown below:

[0005]

[0006] In one embodiment of the present invention, water-soluble extended column aromatics[6] are synthesized using the following route:

[0007]

[0008] Specifically:

[0009] Biphenyl dichlorobenzyl reacts with bromophenyl diethyl ether under AlCl3 catalysis to undergo a Friedel-Crafts alkylation reaction to generate a hemicyclic ring (PIM-1);

[0010] PIM-1 and paraformaldehyde were dissolved in dichloromethane and polymerized under the catalysis of boron trifluoride diethyl ether to generate extended macrocyclic ring (PIM-2);

[0011] The extended macrocyclic PIM-2 was dissolved in acetonitrile solvent and trimethylamine ethanol solution was added dropwise. After removing the solvent by rotary evaporation, water was added to dissolve the solid. After filtration, the filtrate was dried by rotary evaporation to obtain water-soluble extended column aromatics [6] (PIM-3).

[0012] The second objective of this invention is to provide the application of the above-mentioned water-soluble extended column[6] aromatic hydrocarbons in the preparation of tumor therapeutic drugs.

[0013] This invention designs and synthesizes a water-soluble extended column [6] aromatic hydrocarbon, which has two characteristics: first, it has a larger rigid cavity; second, it has good water solubility. At the same time, the synthesis process has been further optimized, that is, the monomer is pre-modified first, and bromo-p-phenylenediol diethyl ether is used as the starting material, which greatly simplifies the synthesis process of intermediate PIM-2.

[0014] The extended column[6] aromatic PIM-3 of the present invention can perfectly complex tetracarboxyporphyrin, inhibit its aggregation in water, and enhance its photodynamic therapy effect. Attached Figure Description

[0015] Figure 1 This is the hydrogen NMR spectrum of PIM-1.

[0016] Figure 2 This is the hydrogen NMR spectrum of PIM-2.

[0017] Figure 3 This is the hydrogen NMR spectrum of PIM-3.

[0018] Figure 4 The results of cytotoxicity tests were obtained before and after the water-soluble extended column[6] aromatic PIM-3 was complexed with tetracarboxyporphyrin (Py) under light and without illumination. Detailed Implementation

[0019] The preferred embodiments of the present invention will now be described in detail with reference to specific examples. It should be understood that the following examples are given for illustrative purposes only and are not intended to limit the scope of the invention. Those skilled in the art can make various modifications and substitutions to the present invention without departing from its spirit and essence.

[0020] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0021] Unless otherwise specified, all materials and reagents used in the following examples are commercially available.

[0022] The molecular structure of tetracarboxyporphyrin (Py) in this invention is shown below. Before use, it should be dissolved in ammonia and then evaporated to dryness.

[0023]

[0024] Example 1

[0025] This embodiment uses the following route to synthesize water-soluble extended column aromatics [6]:

[0026]

[0027] 1. Synthesis of hemicyclic PIM-1

[0028] In a 1000 mL round-bottom flask, 64.8 g (0.2 mol) of bromophenyl diethyl ether and 5.3 g (0.04 mol) of aluminum trichloride were dissolved in 400 mL of dichloromethane. Then, 5 g (0.02 mol) of biphenyl dichlorobenzyl (BCD) was dissolved in 100 mL of dichloromethane and added dropwise to the round-bottom flask via a constant-pressure dropping funnel. After the addition was complete, the reaction was allowed to proceed at room temperature for another 30 minutes, with TCL monitoring the reaction progress. After the reaction was complete, the reaction was quenched in a large amount of deionized water. The organic phase was then extracted, rotary evaporated, and separated by column chromatography with silica gel to obtain a white solid, PIM-1.

[0029] PIM-1: White solid, 37.5%, 1 H NMR (400MHz, CDCl3) δ:7.47(d,4H,ArH), δ:7.28(d,4H,ArH), δ:6.75(m,6H,ArH), δ:4.22(q,8H,OCH2), δ:4(s,4H,CH2), δ:3.59(m,8H,CH2).

[0030] 2. Synthesis of Ethyl Bromoextended Aromatic Hydrocarbon PIM-2

[0031] In a 500 mL round-bottom flask, PIM-1 (2 g, 2.4 mmol) and paraformaldehyde (0.22 g, 2.4 mmol) were dissolved in 250 mL of dichloromethane. Then, 1.5 mL of boron trifluoride diethyl ether was slowly added dropwise. The reaction was allowed to proceed for about one hour, and the reaction progress was monitored using a TCL (Transmission Coefficient of Motion). After the reaction was completed, saturated NaHCO3 was added to quench the reaction. The organic phase was extracted, silica gel was added, and the dried solid was obtained by rotary evaporation. The white solid PIM-2 was obtained by column chromatography.

[0032] PIM-2: White solid, 32%, 1 H NMR (400MHz, CDCl3) δ: 7.37 (d, 8H, ArH), δ: 7.21 (d, 8H, ArH), δ: 6.98 (s, 4H, ArH), δ: 6.67 (s, 4H, ArH), δ: 4.24(t,8H,OCH2),δ:4.19(t,8H,OCH2),δ:3.94(d,12H,CH2),δ:3.65(t,8H,CH2),δ:3.51(t,8H,CH2).

[0033] 3. Synthesis of macrocyclic novel water-soluble extended column[6] aromatic PIM-3

[0034] In a 100 mL round-bottom flask, PIM-2 (1.1 g, 0.76 mmol) was dissolved in 50 mL of acetonitrile, and then trimethylamine aqueous solution (AR, 30 wt.% in H2O, 6 g) was added and refluxed at 82 °C for 12 h. The solid was dried by a rotary vacuum evaporator, and then dissolved in 20 mL of water to remove impurities. The solution was then evaporated to dryness to obtain a novel water-soluble extended column [6] aromatic PIM-3.

[0035] PIM-3: White solid, 95% 1 H NMR(400MHz,D2O)δ:7.43(d,8H,ArH),δ:7.16(d,8H,ArH),δ:6.84(s,4H,ArH),δ:6.66(s,4H,ArH),δ:4 .22(d,16H,OCH2),δ:3.91(s,8H,CH2),δ:3.86(s,4H,CH2),δ:3.52(d,16H,CH2),δ:2.94(d,72H,CH3).

[0036] Example 2

[0037] PIM-3 is used to enhance the photodynamic therapy efficacy of tetracarboxyporphyrin (Py) for tumors.

[0038] Human cervical cancer cells (HeLa cells) were seeded into 96-well plates (1×10⁻⁶ cells per well). 4 Cells / well were incubated overnight at 37°C in a 5% CO2 incubator. Different concentrations of PIM-3, Py, and PIM-3@Py ([PIM-3] = [Py]) dispersions were added to the corresponding wells, and incubation continued for 4 hours. The cells were then subjected to a 660nm laser (100mW / cm²) for further treatment. 2 Cells were irradiated for 10 min as a control experiment and cultured at 37°C for 24 h. MTT reagent was added to each well, and the cells were cultured for another 4 h before the culture medium was removed. Absorbance was recorded using a microplate reader, and cytotoxicity was calculated.

[0039] like Figure 4 As shown, the nanomaterials formed by the host-guest interaction between PIM-3 and Py have a significantly enhanced killing effect on tumor cells.

Claims

1. Use of water-soluble expanded pillar[6]arene in the preparation of a preparation for enhancing the effect of tetra-carboxylic porphyrin tumor photodynamic therapy, the water-soluble expanded pillar[6]arene has the following formula: The application is that the nano material formed by the host-guest interaction between the water-soluble expanded pillar[6]arene and the tetra-carboxylic porphyrin is used for preparing a cervical cancer treatment drug. ； ​

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