CN111574495B

CN111574495B - Water-soluble dibenzo-24-crown-8-based gel and preparation method thereof

Info

Publication number: CN111574495B
Application number: CN202010555287.XA
Authority: CN
Inventors: 郑波; 高玲燕
Original assignee: Northwestern University
Current assignee: Northwestern University
Priority date: 2020-06-17
Filing date: 2020-06-17
Publication date: 2021-08-06
Anticipated expiration: 2040-06-17
Also published as: CN111574495A

Abstract

The invention discloses a water-soluble dibenzo-24-crown-8-base gel and a preparation method thereof, wherein the gel is a potassium salt of a compound shown in a formula (I), DB24C8-COOH and 11-amino ethyl undecanoate are subjected to amidation reaction in dichloromethane, then stirred in a sodium hydroxide aqueous solution and neutralized with hydrochloric acid, leucine methyl ester hydrochloride is added to perform amidation reaction, then further stirred in the sodium hydroxide aqueous solution and neutralized with hydrochloric acid, KOH is added and stirred to obtain a target compound.

Description

Water-soluble dibenzo-24-crown-8-based gel and preparation method thereof

Technical Field

The invention belongs to the technical field of thermal response supermolecule hydrogel, and particularly relates to a water-soluble dibenzo-24-crown-8-based gel and a preparation method thereof.

Background

Since the discovery of crown ethers by Pedersen in 1967, crown ethers have exhibited their unique properties in multiple disciplines, useful for organic synthesis, phase transfer catalysts, and the like. In the field of supramolecular chemistry, the host-guest properties of crown ethers are emphasized more, and metal cations or organic cations and the like can be complexed, but most of the crown ethers are applied and researched in an organic phase. In the eighties of the twentieth century, small crown ethers (15-crown-5, 18-crown-6, etc.) were used to prepare transmembrane ion channels, and until ten years ago, studies have shown that crown ether-prepared ion channels were combined with commercial antibiotics to improve antibacterial activity. The reason for this is that crown ethers are not water soluble and are generally considered toxic and biocompatible, but some of the earlier research and recent work suggest that crown ethers are not highly toxic (18-crown-6 toxicity is not higher than aspirin). More importantly, the crown ether structure can realize water solubility after being modified, thereby expanding the application of the crown ether structure in a water phase system. The supermolecule gel constructed by the low molecular weight gelator is a novel gel system, the structure of the supermolecule gel is simple and flexible to synthesize, and various functions can be endowed more easily. Because of the abundant host-guest chemical properties and stimulus responsiveness of crown ether, the gel prepared by the low molecular weight gelator containing crown ether also has intelligent responsiveness. However, these previous studies have remained in the organic phase, greatly limiting the use of such gels. Therefore, in our work, a water-soluble dibenzo-24-crown-8-based gel is designed and prepared, and a functionalized amino acid structure is introduced on crown ether, so that a gel material with a bacteriostatic effect can be obtained. In addition, it was unexpectedly found to be thermally responsive during the course of the study. The thermal response material is an important class of the supramolecular response material, wherein the Lower Critical Solution Temperature (LCST) phenomenon is a typical thermal response behavior, and is widely applied to many research fields, including controlled drug release, controllable supramolecular self-assembly and the like. The LCST phenomenon in gels is a combination of the two phenomena, and many researches and applications have been carried out, but the supramolecular gels constructed by mostly surrounding (supramolecular) polymer, especially (N-isopropylacrylamide) (PNIPAM) system, and low-molecular-weight gel factors (LMWG) rarely have the thermal responsiveness of LCST. Water-soluble dibenzo-24-crown-8-based gels are capable of imparting thermo-responsive properties to such gels.

Disclosure of Invention

The object of the present invention is to provide a new water-soluble dibenzo-24-crown-8-based gelling agent which is thermally responsive in water, the gelling agent of the invention showing interesting Low Critical Solution Temperature (LCST) behaviour in both solution and gel state. In addition, the hydrogel showed antibacterial ability against gram-positive bacteria due to the introduction of leucine.

In order to achieve the technical purpose, the invention is specifically realized by the following technical scheme:

a water-soluble dibenzo-24-crown-8-yl gelata, said gelata being a compound of formula (I):

in another aspect of the present invention, there is provided a method for preparing the above water-soluble dibenzo-24-crown-8-based gelling agent, comprising the following steps:

1) adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride serving as a condensing agent and 4-dimethylaminopyridine into DB24C8-COOH and 11-aminoundecanoic acid ethyl ester, carrying out amidation reaction in dichloromethane, stirring in an excessive sodium hydroxide aqueous solution, and neutralizing with hydrochloric acid to obtain a compound of a formula (II);

2) adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride serving as a condensing agent and 4-dimethylaminopyridine into the compound of the formula (II) and leucine methyl ester hydrochloride, carrying out amidation reaction in dichloromethane, further stirring in an excessive sodium hydroxide aqueous solution, and neutralizing with hydrochloric acid to obtain a compound of a formula (III);

3) stirring the compound shown in the formula (III) with KOH with a certain equivalent to obtain potassium salt;

wherein the structural formula of the compound of formula (II) is as follows:

the structural formula of the compound of formula (III) is as follows:

furthermore, the amount of KOH is 0.85-0.95 equivalent.

In another aspect of the invention, the invention provides the use of the gel in inhibiting staphylococcus aureus.

The invention has the beneficial effects that:

1. the invention takes functional dibenzo-24-crown-8 as a base, and prepares the water-soluble gel by introducing a hydrophobic alkyl chain and a hydrophilic carboxyl terminal.

2. The leucine unit is introduced into the gel structure, so that the gel has a bacteriostatic effect.

3. The thermal response gel can improve turbidity and reduce light transmission capacity when the thermal response gel is higher than LCST and can restore transparency when the thermal response gel is lower than LCST; the on/off of the LCST can be controlled by adjusting the pH of the solution.

Drawings

FIG. 1 shows the LCST behavior of a 0.85 equivalent aqueous solution of potassium hydroxide (0.6 wt%) at temperatures above 60 ℃ according to the invention;

FIG. 2 is a graph showing the reversible gel-sol transition of a hydrogel of the present invention (1.2 wt%) upon heating and cooling;

FIG. 3 shows acid-base controlled phase separation of a hydrogel (0.6 wt%) of the present invention.

Detailed Description

The technical solutions of the present invention will be described clearly and completely with reference to specific embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

EXAMPLE 1 preparation of gels

Starting from the acid-blocked crown ether, the crown ether is coupled with ethyl 11-aminoundecanoate and the compound obtained is hydrolyzed to give the compound of formula (II). The compound of formula (III) is then obtained by reaction with L-leucine methyl ester and subsequent hydrolysis and protonation, and is stirred with an equivalent of KOH to give its potassium salt. The synthetic route is as follows:

the method comprises the following specific steps:

(S1) DB24C8-COOH (644mg) and ethyl 11-aminoundecanoate (300mg) in CH₂Cl₂Adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC. HCl, 392mg) and 4-dimethylaminopyridine (DMAP, 15mg) into (10mL) to perform amidation reaction to obtain an amidated intermediate product (400mg), then continuing to add sodium hydroxide (230mg) into tetrahydrofuran (15mL) and deionized water (15mL) to perform reaction, and adding excess hydrochloric acid to neutralize alkali to obtain a compound containing a carboxyl terminal in a formula (II);

(S2) A Compound of formula (II) (41mg) was reacted with leucine methyl ester hydrochloride (24mg) in CH₂Cl₂(5mL) was added 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC. HCl, 25mg) and 4-dimethylaminopyridine (DMAP, 17mg) to perform amidation reaction to obtain amidated intermediate (38mg), and then this intermediate was further reacted with sodium hydroxide (8mg) in tetrahydrofuran (5mL) and deionized water (5mL) at 45 ℃ to obtain a compound of formula (III) containing a carboxyl terminal by adding excess hydrochloric acid to neutralize the base.

Example 2

When a solution of 0.85 (below the critical gelling point) of dibenzo-24-crown-8-yl potassium salt was heated until the gelling agent was completely dissolved, the solution became cloudy at about 60 ℃ and returned to transparency once the solution cooled down (fig. 1). In addition, similar temperature-induced phase transition behavior was also observed for dibenzo-24-crown-8-yl potassium salt 0.85 hydrogel (1.2 wt%). By heating the bottom of the nmr tube of the hydrogel, the temperature of the bottom increases more rapidly, the translucent hydrogel breaks up and forms a white precipitate, eventually the entire sample becomes a turbid solution, and after a period of cooling, the turbid mixture again returns to the translucent hydrogel (fig. 2). This LCST phase separation behavior is further confirmed by UV/Vis measurements and the cloud point (T) for hydrogels (1.2 wt%) and solutions (0.6 wt%)_cloud) 57.7 ℃ and 58.2 ℃ respectively.

Example 3

LCST (critical solution temperature) behavior is observed only in solutions of 0.85 to 0.95 equivalents of potassium hydroxide. When 1 equivalent of potassium hydroxide is added to the compound of formula (III), LCST behaviour does not occur even at high concentrations (4 wt%) and temperatures up to 100 ℃. The phase separation process can be reproduced by reducing the degree of deprotonation by adding an acid. Figure 3 clearly demonstrates the acid-base controlled phase separation of a dibenzo-24-crown-8-yl potassium salt solution. The LCST behavior of the respective solutions is on or off by sequential addition of acid and base. In view of the importance of the deprotonation rate of the carboxyl group on the compound of formula (III) on its LCST behavior, we propose the following possible hypotheses. The compounds of formula (III) in solution in both charged and neutral states are critical to LCST behavior. The coexistence of neutral and charged carboxyl groups in dibenzo-24-crown-8-yl potassium salt 0.85 resulted in a different self-assembly process due to the reduction of charge-induced electrostatic repulsion compared to dibenzo-24-crown-8-yl potassium salt 1.0, where all carboxyl groups were charged. The spontaneous co-assembly process between the deprotonated compound of formula (III) and the remaining neutral form may be affected in response to temperature changes. Due to the different solubility of the two forms of the compound of formula (III) in water, self-assembled aggregates may be significantly affected with increasing temperature, eventually leading to a phase transition.

Example 4 antimicrobial experiments

Preparation of a suspension of E.coli and S.aureus (10)^-9CFU/mL), gradually diluting the bacterial liquid concentration to 10^-8，10^-7，10^-6，10^-5，10^-4The concentration of (c). Preparing potassium salt gel (gel forming concentration is higher) of compound of formula (I), placing 50.0mg gel in 96-well plate, adding 0.1ml 10ml^-9，10^-8，10^-7，10^-7，10^-6，10^-5，10^-4The bacterial liquid of (4). In addition, 0.1ml of PBS solution and 50.0mg of gel were placed in a 96-well plate as a blank, incubated at 37 ℃ for 12 hours, and the plate was removed to measure the OD value.

As a result, it was found that the hydrogel partially inhibited the growth of Staphylococcus aureus but did not act on Escherichia coli. Thus, hydrogels prepared from compounds of formula (III) may be potentially useful as antibacterial agents.

Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.

Claims

1. A water-soluble dibenzo-24-crown-8-based gel, which is characterized in that the structural formula of the gel is as shown in formula (I):

2. a process for the preparation of the gel of claim 1, comprising the steps of:

1) adding a condensing agent and 4-dimethylamino pyridine into DB24C8-COOH and 11-aminoundecanoic acid ethyl ester, carrying out amidation reaction in dichloromethane, and stirring in a sodium hydroxide aqueous solution to obtain a compound shown in the formula (II);

2) adding a condensing agent and 4-dimethylaminopyridine into the compound of the formula (II) and leucine methyl ester hydrochloride to perform amidation reaction, and stirring in a sodium hydroxide aqueous solution to obtain a compound of a formula (III);

3) stirring the compound of the formula (III) with KOH to obtain potassium salt;

wherein, DB24C8-COOH structural formula is:

the structural formula of the compound of formula (II) is shown as follows:

the structural formula of the compound of formula (III) is as follows:

3. the method according to claim 2, wherein the KOH is used in an amount of 0.85 to 0.95 equivalents.

4. The method according to claim 2, wherein the condensing agent is 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride.