Para-Methoxybenzylidene Acetal-Protected D-Glucosamine Derivatives as pH-Responsive Gelators and Their Applications for Drug Delivery

Abstract

Carbohydrate-based low molecular weight gelators (LMWGs) are compounds with the capability to self-assemble into complex molecular networks within a solvent, leading to solvent immobilization. This process of gel formation depends on noncovalent interactions, including Van der Waals, hydrogen bonding, and π-π stacking. Due to their potential applications in environmental remediation, drug delivery, and tissue engineering, these molecules have emerged as an important area of research. In particular, various 4,6-O-benzylidene acetal-protected D-glucosamine derivatives have shown promising gelation abilities. In this study, a series of C-2-carbamate derivatives containing a para-methoxy benzylidene acetal functional group were synthesized and characterized. These compounds exhibited good gelation properties in several organic solvents and aqueous mixtures. Upon removal of the acetal functional group under acidic conditions, a number of deprotected free sugar derivatives were also synthesized. Analysis of these free sugar derivatives revealed two compounds were hydrogelators while their precursors did not form hydrogels. For those protected carbamates that are hydrogelators, removal of the 4,6-protection will result in a more water-soluble compound that produces a transition from gel to solution. Given the ability of these compounds to form gels from solution or solution from gels in situ in response to acidic environments, these compounds may have practical applications as stimuli-responsive gelators in an aqueous medium. In turn, one hydrogelator was studied for the encapsulation and release of naproxen and chloroquine. The hydrogel exhibited sustained drug release over a period of several days, with the release of chloroquine being faster at lower pH due to the acid lability of the gelator molecule. The synthesis, characterization, gelation properties, and studies on drug diffusion are discussed.

Keywords: carbohydrate; hydrogelators; organogelators; pH-responsive; self-assembly; stimuli-responsive.

Figure 1

Structure-based design of potential sugar-based LMWGs and the two drug molecules.

Scheme 1

Synthesis of C-2 carbamate derivatives of D-glucosamine.

Scheme 2

Structures of the deprotected glucosamine carbamate derivatives.

Figure 2

Gel photos for several gelators. (a) A hydrogel formed by compound 9 at 0.9 mg/mL; (b) a gel formed by compound 17 at 0. 8 mg/mL in EtOH:H₂O (1:1); (c) a clear gel formed by compound 20 in toluene at 2.9 mg/mL; (d) a clear to translucent gel formed by compound 21 in water at 0.9 mg/mL.

Figure 3

Optical micrographs of the gels formed by several compounds: (a) Compound 5 in water at 5.0 mg/mL; (b) Compound 7 in water at 1.5 mg/mL; (c) Compound 9 in PBS buffer 2.0 mg/mL; (d) Compound 15 in DMSO:H₂O (v/v, 1:2) at 6.7 mg/mL; (e) Compound 17 in EtOH:H₂O (v/v 1:1) at 0.8 mg/mL; (f) Compound 18 in toluene at 3.3 mg/mL; (g) Compound 18 in water at 10.0 mg/mL; (h) Compound 21 in water at 1.0 mg/mL.

Figure 4

SEMs of the xero gels of hydrogels from (a,b): compound 7 at 1.5 mg/mL; (c,d): compound 9 at 0.9 mg/mL; (e,f): compound 18 at 10.0 mg/mL.

Figure 5

Gel photographs of compound 9 with naproxen in the initial condition (0 h), before and after adding 2 mL water, followed by the gel photos at selected time points after the aqueous phase was removed.

Figure 6

The UV–Vis spectra (a) and percent release profile (b) of naproxen sodium over time from a co-gel formed by compound 9 (2.0 mg/mL gel) with 0.25 mg/mL naproxen sodium in H₂O.

Figure 7

The UV–Vis spectra (a) and percent release profiles (b) of chloroquine diphosphate to a pH 7.0 aqueous phase over time from co-gels formed by compound 9 (2.0 mg/mL gels). Percent release was calculated using absorption values at 343 nm for each time point versus the standard.

Figure 7

The UV–Vis spectra (a) and percent release profiles (b) of chloroquine diphosphate to a pH 7.0 aqueous phase over time from co-gels formed by compound 9 (2.0 mg/mL gels). Percent release was calculated using absorption values at 343 nm for each time point versus the standard.

Figure 8

The UV–Vis spectra (a) and percent release profiles (b) to a pH 3.0 aqueous phase of chloroquine diphosphate over time from the co-gels formed by compound 9 (2.0 mg/mL gels) in H₂O. Others are the same as Figure 7.

Figure 8

The UV–Vis spectra (a) and percent release profiles (b) to a pH 3.0 aqueous phase of chloroquine diphosphate over time from the co-gels formed by compound 9 (2.0 mg/mL gels) in H₂O. Others are the same as Figure 7.