The mechanism of binding with the α-glucosidase in vitro and the evaluation on hypoglycemic effect in vivo: Cocrystals involving synergism of gallic acid and conformer.

Cocrystallization of Active Pharmaceutical Ingredients (API) with formers can induce positive or negative synergistic effects on activity; however, the underlying mechanism is unclear. In this study, we screened two cocrystals of gallic acid (GA): GA-p-aminobenzoic acid (cocrystal A) and GA-amino acetic acid (cocrystal B). Solubility, dissolution rate, and oral bioavailability and hypoglycemic effect of the two cocrystals were evaluated. Additionally, we examined the effect induced by cocrystallization of GA with each former on inhibition activity on α-glucosidase, a protein target involved in hypoglycemic effects. Cocrystals A and B were constructed in a 1:1 API/former molar ratio by CO⋯HN and OH⋯OC hydrogen bonds, respectively. As predicted, cocrystallization improved oral bioavailability; AUC0-∞s of cocrystal A and B were 2.24-fold and 1.70-fold higher than that of GA. Interestingly, the α-glucosidase inhibition rate increased with cocrystal A (i.e., positive synergism) and decreased with cocrystal B (i.e., negative synergism) compared to GA alone. For each cocrystal system, an obvious difference in the α-glucosidase inhibition rate between cocrystal and its physical mixture (PM) of API and former was observed. The 1H NMR analysis of two cocrystals and their respective PM indicated that hydrogen bond interactions between API and former molecules were just present in the solutions of cocrystal; but not in that of PMs. Molecular docking indicated that the hydrogen bonds between GA and CCF achieved binding with α-glucosidase in the form of supramolecular. Due to improvements in both oral bioavailability and α-glucosidase inhibition rate, the maximum hypoglycemic rate in diabetic mice treated with cocrystal A was 3.4-fold higher than that of GA alone. Conversely, although cocrystal B displayed improved bioavailability compared with GA alone, the maximum hypoglycemic rate remained almost unchanged due to the negative synergism on α-glucosidase inhibition activity of GA and amino acetic acid. Cocrystallization with each former induced variation not only on physiochemical properties and bioavailability but also on biological profiles involving inhibition rate on target proteins, which likely contributed to the observed positive and negative synergistic effects on API activity.

8-Hydroxyquinoline functionalized covalent organic framework as a pH sensitive carrier for drug delivery.

A porous 8-hydroxyquinoline functionalized organic covalent framework (named COF-HQ) was synthesized. The as-prepared COF-HQ showed stable crystal structure, suitable pore size, excellent dispersibility in physiological solution and pH sensitivity, which would be employed as a potential nanocarrier for drug transport and controlled release. The drug loading experiment with 5-Fluorouracil (5-FU) as the model molecule proved that the drug loading capacity of COF-HQ was significantly improved due to the introduction of quinoline groups. The drug release profiles of 5-FU from 5-FU loaded COF-HQ (termed 5-FU@COF-HQ) under different pH showed that its release was controlled by pH owing to the pH sensitivity of conjugated nitrogen atoms from quinoline groups and CN. The in vitro hemolysis and in vivo biocompatibility experiments further verified the good biocompatibility of COF-HQ. Importantly, 5-FU@COF-HQ-treated B16F10 cell-induced tumor models showed that 5-FU@COF-HQ displayed enhanced anti-tumor efficacy than other groups. These results suggested that the drug-loading COF-HQ delivery system showed the potential for effective cancer therapy with advantages of high drug loading, good biocompatibility and the pH-sensitive release of the tumor microenvironment. Overall, our research provided a new functionalized COF-HQ drug delivery system, which further expanded the application of COFs as carriers in the field of cancer treatment.

Characterizations and Assays of α-Glucosidase Inhibition Activity on Gallic Acid Cocrystals: Can the Cocrystals be Defined as a New Chemical Entity During Binding with the α-Glucosidase?

Cocrystallization with co-former (CCF) has proved to be a powerful approach to improve the solubility and even bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs). However, it is still uncertain whether a cocrystal would exert the pharmacological activity in the form of a new chemical entity, an API-CCF supramolecule. In the present study, gallic acid (GA)-glutaric acid and GA-succinimide cocrystals were screened. The solubility, dissolution rate and oral bioavailability of the two cocrystals were evaluated. As expected, AUCs of GA-glutaric acid and GA-succinimide cocrystals were 1.86-fold and 2.60-fold higher than that of single GA, respectively. Moreover, experimental evaluations on α-glucosidase inhibition activity in vitro and theoretical simulations were used to detect whether the two cocrystals would be recognized as a new chemical entity during binding with α-glucosidase, a target protein in hypoglycemic mechanisms. The enzyme activity evaluation results showed that both GA and glutaric acid displayed α-glucosidase inhibition activity, and GA-glutaric acid cocrystals showed strengthened α-glucosidase inhibition activity at a moderate concentration, which is attributed to synergism of the two components. Molecular docking displayed that the GA-glutaric acid complex deeply entered the active cavity of the α-glucosidase in the form of a supramolecule, which made the guest-enzyme binding configuration more stable. For the GA and succinimide system, succinimide showed no enzyme inhibition activity, however, the GA-succinimide complex presented slightly higher α-glucosidase inhibition activity than that of GA. Molecular docking simulation indicated that the guest molecules entering the active cavity of the α-glucosidase were free GA and succinimide, not the GA-succinimide supramolecule.

RETRACTED: Cocrystals of curcumin-isonicotinamide and curcumin-gallic acid: Does the weak forces in cocrystals effect on binding profiles with BSA and cell cytotoxicity?

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Authors. There were errors in the handling of the data of the BSA binding experiments, which affected the conclusion on the binding affinity of the different cocrystals to BSA. After rigorous discussion, the authors think further investigation should be performed in this project to get the precise results.

A gold nanoparticle based colorimetric and fluorescent dual-channel probe for acetylcholinesterase detection and inhibitor screening.

Based on the competitive host-guest interaction between p-sulfonatocalix[6]arene (p-SC6A) capped AuNPs and Rhodamine B (RhB)/acetylthiocholine, a fluorescent and colorimetric dual channel probe was developed for rapid detection of AChE with high sensitivity and selectivity. The detection limit was estimated to be 0.16 mU mL-1. Crucially, due to the specific host-guest interaction, the high selectivity of the bioassay permitted the discrimination of AChE from other cations and proteins including biothiols and enzymes. Furthermore, the present method was also successfully applied to determinate AChE levels and screen AChE inhibitors in real cerebrospinal fluid (CSF) samples, which suggested that our proposed method has great potential to be applied in monitoring the disease progression and drug treatment effects of Alzheimer's disease (AD).