Process for the preparation of phenylboronic acid-based zwitterionic surfactants and their use for the synthesis of pH-responsive dimer molecules

Abstract

The application discloses a phenylboronic acid-based zwitterionic surfactant and a preparation method and application thereof, wherein the phenylboronic acid group of the phenylboronic acid-based zwitterionic surfactant includes two isomers, i.e. m BDC n AB or p BDC n AB, and alkyl chain lengths are C 10 alkyl, C 12 alkyl and C 14 alkyl, and a total of six surfactants are abbreviated as BDC n AB. BDC n AB is mixed with dodecyl-dimethyl-1,2-dihydroxypropyl ammonium chloride to prepare a mixed micelle, and an asymmetric spacer group with a dynamic covalent bond combined by a borate ester bond is generated in situ under mild conditions of normal temperature and neutral pH, thereby obtaining a pH-responsive dimer surfactant, and the dimer surfactant has a pH response interval consistent with a drug release condition for treating cancer in a human body, and can be used for preparing a drug-loaded micelle for treating cancer in the human body.

Description

Technical Field

[0001] This invention belongs to the field of novel surfactant structure design, synthesis and application technology, specifically relating to the preparation method and application of a novel phenylboronic acid-based zwitterionic surfactant and a dynamic covalent asymmetric spacer dimer surfactant. Background Technology

[0002] Betaine amphoteric surfactants are a class of biosurfactants with low biotoxicity, weak skin irritation, and strong surface activity. Common types are sulfonic acid and carboxylic acid amphoteric surfactants, which have wide applications in the medical, food, cosmetic, and chemical industries. This invention designs and synthesizes a class of phenylboronic acid-based ammonium base amphoteric surfactants. Within a certain pH range, the head group exhibits amphoteric characteristics with the coexistence of quaternary ammonium cations and borate anions, demonstrating the amphoteric properties of betaine surfactants. The introduction of aromatic borate groups endows the surfactant with special functions. Firstly, the borate anion has the ability to form borate esters with vicinal diol molecules. Secondly, both boric acid and borate esters are weak acids, depending on the pH. a The pK value of aromatic boric acid exhibits pH-responsive functionality, exhibiting the properties of surfactant monomers and their aggregates. a The value is closely related to the properties of the directly attached aromatic group and its derived groups. Due to the diversity of derived groups, pK is determined. a The adjustability of the pH value further determines the adjustability of the pH response. Unlike general aromatic boric acid molecules (such as phenylboronic acid), surfactants with aromatic boric acid head groups also possess other unique properties, including a high density of boric acid groups on the surface of the aggregates, diversity of aggregate morphologies, and pH response of the aggregate morphology. This inevitably provides new expansion space for the broad application fields of surfactants. Summary of the Invention

[0003] The technical problem solved by this invention is to provide a novel phenylboronic acid-based zwitterionic surfactant and its preparation method. The novel phenylboronic acid-based zwitterionic surfactant prepared by this method can be used to synthesize asymmetric spacer dimer surfactants with dynamically covalently covalent borate bonds in mixed micelles under mild conditions of room temperature and neutral pH. The asymmetric spacer dimer surfactant has a pH response range that matches the release conditions of cancer drugs in the human body and can be used to further prepare drug-loaded micelles for cancer treatment in the human body.

[0004] To solve the above-mentioned technical problems, the present invention adopts the following technical solution: a phenylboronic acid-based zwitterionic surfactant, characterized in that: the phenylboronic acid group of the phenylboronic acid-based zwitterionic surfactant includes two isomers, para- and meta-, namely m-BDC. n AB or p-BDC nAB, with alkyl chain lengths of C and C respectively. 10 Alkyl, C 12 Alkyl or C 14 Alkyl groups, a total of 6 surfactants, abbreviated as BDC n AB, its general structural formula is:

[0005]

[0006] Where n = 10, 12 or 14.

[0007] Further specified, in aqueous solution, it reacts with monomeric surfactants (pK) a =8.0) Comparison, p-BDC n pK of AB micelles a It increased to 8.6 ± 0.2, while m-BDC n pK of AB micelles a The pK value decreased to 7.4 ± 0.2, indicating hydrogen bond interactions. a The mechanism of change is beneficial for regulating the charge properties of the micelle surface through pH, ​​when pH < pK. a Under the conditions of cationic form and pH > pK a It is a zwitterionic type, and the pH is at pK. a Nearby are micelles containing a mixture of two types of surfactants.

[0008] Further specifying, p-BDC n AB has a higher value than m-BDC n The critical micelle concentration (CMC) of AB reflects the effect of the boric acid hydroxyl orientation on the intermolecular hydrogen bond interaction between the two isomers; the CMC decreases with the increase of alkyl chain length, reflecting the effect of hydrophobicity; the high density of boric acid groups on the micelle surface pointing towards the aqueous phase is conducive to the interaction with water-soluble ortho-hydroxyl molecules (such as sugar molecules), and can also form dimer surfactants in situ with dihydroxyl-containing surfactants in mixed surfactant micelles.

[0009] The specific synthetic route of the phenylboronic acid-based zwitterionic surfactant described in this invention is as follows:

[0010] .

[0011] The application of the phenylboronic acid-based zwitterionic surfactant of this invention in the preparation of dynamically covalently covalently borate-linked asymmetric spacer dimer surfactants is characterized by the following specific process: The phenylboronic acid-based zwitterionic surfactant BDC... nMixed micelles were prepared by mixing AB with dodecyl-dimethyl-1,2-dihydroxypropylammonium chloride (DMHAC), and a dynamic covalently bonded asymmetric spacer dimer surfactant with borate ester bond was generated in situ under mild conditions of room temperature and neutral pH.

[0012] Furthermore, the dynamic covalently bonded asymmetric spacer dimer surfactant has a pH response range that matches the release conditions of cancer-treating drugs in the human body, and can be used to prepare drug-loaded micelles for cancer treatment in the human body.

[0013] This invention designs and provides a series of methods for synthesizing betaine zwitterionic surfactants based on phenylboronic acid. The monomer molecules and aggregates have responsive functions in a narrow pH range and can be esterified with vicinal diol molecules at physiological pH and generate asymmetric pH-responsive dimer surfactants in situ within micelles.

[0014] This invention, currently unreported, offers the following advantages and benefits compared to conventional mixed surfactants: It synthesizes a six-phenylboronic acid-based betaine zwitterionic surfactant. By leveraging the electron-withdrawing effect of the positive charge of the quaternary ammonium salt in the molecular structure, the acid dissociation constant of boric acid is reduced to near neutral pH. The critical micelle concentration of the surfactant was characterized. Utilizing the principle of boronic acid reacting with vicinal diol molecules to form boronic esters in an aqueous system, at neutral pH, the synthesized boronic acid-based betaine surfactant is mixed with the vicinal dihydroxy-containing cationic surfactant DMHAC to form mixed micelles. Esterification occurs in situ within the micelles, generating a pH-responsive dimer surfactant with asymmetric spacer groups linked by boronic ester bonds. The pK of the boronic ester bonds in this dimer molecule... a It is slightly acidic, pH-responsive, and stable at physiological pH levels, which matches the pH conditions for the release of cancer-treating drugs in the human body. The structure and composition of the mixed micelles offer broad design flexibility, and the high density of boric acid groups on the micelle surface enhances the sensitivity to interactions with diol groups. Compared to non-surface-active phenylboronic acid systems, these properties offer significant potential for expansion in pH-related sensing devices or probe applications. Attached Figure Description

[0015] Figure 1 shows (A) the absorbance of 0.1 mM p-BDDeAB (monomer) at 271 nm versus pH; and (B) the fluorescence intensity of 14 mM p-BDDeAB (micelles) at 299 nm versus pH. The solvent was 100 mM phosphate solution. The solid line in the figure is the Boltzmann simulation curve, obtained from the extreme value of the first derivative to pK. a .

[0016] Figure 2 The Nile Red fluorescence intensity (λ) in 20 mM PBS at pH 8.0.max = 638 nm) as a function of p-BDDAB concentration.

[0017] Figure 3 The graph shows the intrinsic fluorescence intensity of BDDAB as a function of pH in a mixed micelle solution of DMHAC and BDDAB. The composition of the mixed solution is C. DMHAC =14mM, C BDDAB =1.4mM, C PBS =20mM, fluorescence wavelength λ= 300nm.

[0018] Figure 4 shows the conductivity of DMHAC and (A) p-BDDAB and (B) m-BDDAB mixed solutions in PBS at pH 7.1 as a function of total concentration. The composition of the mixed solutions is C. DMHAC : C BDDAB =10:1. Detailed Implementation

[0019] The following examples further illustrate the above-described content of the present invention, but it should not be construed as limiting the scope of the subject matter of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention.

[0020] Example

[0021] This invention proposes BDC with a phenylboronic acid head group. nThe synthesis technique of AB (structure shown below), and the specific steps for characterizing its structure and purity are as follows: Taking m-BDDAB (n=12) as an example, N,N-dimethyldodecaneamine and m-benzylbromophenylboronic acid are used as raw materials and refluxed in acetone for 10 hours. The mixture is then recrystallized three times with acetonitrile and diethyl ether to obtain a white solid with a yield of 78%. The structure and purity of the product were characterized by ¹H NMR, ¹³C NMR, and HRMS, respectively: ¹H NMR (400 MHz, DMSO d⁶): δ 0.85 (t, J=6.8 Hz, 3H), 1.24 (m, 18H), 1.77 (m, 2H), 2.92 (s, 6H), 3.20–3.23 (m, 2H), 4.49 (s, 2H), 7.46–7.48 (t, J=7.5 Hz, H), 7.55–7.56 (d, J=7.7 Hz, H), 7.88 (s, 1H), 7.91–7.93 (d, J=12.9 Hz, 1H), 8.20 (s, 2H); ¹³C NMR (6 ... d6):14.44, 22.30, 22.57, 26.34, 29.01, 29.20, 29.29, 29.43, 29.50, 31.77, 49.57,63.80, 66.86, 127.69, 128.42, 135.00, 136.23, 139.03; HRMS: m / z 348.3069(calculated), 348.2981(found), [m-BDDA] + .

[0022]

[0023] The BDC synthesized in this invention n The AB molecule has a weakly acidic phenylboronic acid group, and its acid dissociation constant is: the pK of the monomer. a The effect of alkyl chain length on pK was measured using UV spectroscopy. a No significant effect; in the micelle state, intrinsic fluorescence measurements were used to compare p-BDC with the monomer. n pK of AB micelles a Increase, m-BDC n pK of AB micelles a The decrease, taking p-BDDeAB (n=10) as an example, monomer pK a =8.0±0.2 (Figure 1(A)), pK of micelles a =8.6±0.1 (Figure 1(B)).

[0024] The BDC synthesized in this invention nAB molecules exhibit the amphiphilic properties of surfactant molecules, and their critical micelle concentration (CMC) is: This was confirmed by Nile Red fluorescent probe measurements of BDC. n AB can form micelle aggregates, yielding pH-dependent CMC values ​​at pK a The values ​​near the nearest zero reflect the interaction between the quaternary ammonium cation in acidic boric acid and the zwitterionic mixture in basic boric acid. Taking p-BDDAB (n=12) as an example, the CMC is 1.45 mM at pH=6.0, 1.12 mM at pH=8.0, and 1.40 mM at pH=9.0. Figure 2 A typical curve showing the change of Nile Red fluorescence intensity with p-BDDAB concentration is presented.

[0025]

[0026] The BDC synthesized in this invention n AB molecules mixed with dodecyl-dimethyl-1,2-dihydroxypropylammonium chloride (DMHAC) micelle solution, pK a Characterized as follows: Taking a mixed micelle of BDDAB (n=12) and DMHAC as an example (e.g.) Figure 3 As shown), a mixed micelle solution of DMHAC and BDDAB was prepared in 20 mM PBS, with the concentration of DMHAC being 14 mM (CMC). DMHAC =12.01mM), BDDAB concentration was 1.4mM, and pK was measured using intrinsic fluorescence method. a The results showed the presence of mixed micelles pK of the para-isomer of p-BDDAB. a = 6.05, mixed micelles pK of meta-isomer m-BDDAB a =5.63, all significantly lower than the pK without DMHAC. a This indicates that the two formed an asymmetric spacer group, pH-responsive dimer surfactant 12-ABE-12, with dynamic covalent bonding of borate esters in situ within the micelles, as shown above.

[0027] The BDC synthesized in this invention n The CMC of a mixture of AB molecules and DMHAC was characterized by measuring the CMC of the mixed surfactant in 20 mM PBS at pH 7.0. mix At this time, BDC n AB is an amphoteric ion, and the micelles are DMHAC / BDC. n AB / 12-ABE-12 ternary mixed micelles, conductivity as a function of DMHAC / BDC was measured using the conductivity method. nThe total concentration of the AB mixture showed a linear relationship within a certain concentration range before and after micellization. The CMC value of the mixture was obtained graphically, as shown in Figure 4. Due to the formation of a third component, 12-ABE-12, the synergistic effect of the mixed micelles could not be determined. Taking BDDAB as an example, the measured CMC of the mixture... mix The value at CMC (12.01 mM) of DMHAC was compared with that of BDC. n Between the CMCs of AB.

[0028] The above embodiments describe the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are only illustrative of the principles of the present invention. Various changes and modifications can be made to the present invention without departing from the scope of the principles of the present invention, and all such changes and modifications fall within the protection scope of the present invention.

Claims

1. Use of a phenylboronic acid-based zwitterionic surfactant in the manufacture of a dimeric surfactant of asymmetric spacer groups linked by a dynamic covalent boronic ester linkage, wherein the phenylboronic acid group of the phenylboronic acid-based zwitterionic surfactant comprises both the para and meta isomers, i.e. m - BDC n AB or p - BDC n AB, having the general structure: where n = 10, 12 or 14; the specific process is: the phenylboronic acid-based zwitterionic surfactant BDC n AB is mixed with dodecyl-dimethyl-1,2 dihydroxypropyl ammonium chloride DMHAC to prepare mixed micelles, which in situ generate a dynamic covalent boronate-linked asymmetric spacer group dimer surfactant under mild conditions of room temperature and neutral pH.

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