Glycyrrhizic acid (GA, 1) is the main triterpene glycoside from roots of Glycyrrhiza glabra L. and G. uralensis Fisch. and a leading natural glycoside with potential as a medicine for developing new immunomodulators and antiviral agents [1,2]. Several conjugates of GA with amino acids and dipeptides displayed pronounced antiviral activity against human immunodeficiency (HIV) [3,4], atypical pneumonia of SARS-CoV [5], Epstein-Barr [6], and flu A/H1N1 viruses [7]. Previously, we proposed methods for preparing conjugates of GA with alkyl and benzyl esters of L-and D-amino acids via activation of the GA carboxylic acids using N-hydroxybenzotriazole (HOBt) and N,N′-dicyclohexylcarbodiimide (DCC) [8], N-hydroxyphthalimide and DCC [9], or N-hydroxysuccinimide (HOSu) and DCC [3]. The main drawback of these methods for preparing amino-acid conjugates of GA is their two steps (preparation of GA activated ester and subsequent reaction of it with an amine). Furthermore, the dicyclohexylurea formed if DCC is used contaminates the target conjugates. Therefore, water-soluble carbodiimides, in particular 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (DEC), which does not form dicyclohexylurea, are more attractive as condensing reagents.The present communication reports the selective synthesis of amino-acid conjugates of GA with free amino acids in the glycoside carbohydrate part using DEC and L-amino-acid t-butyl ester hydrochlorides.Condensation of GA with amino-acid t-butyl ester hydrochlorides (amino-component, AC) was carried out at room temperature in DMF in the presence of DEC with GA-AC/DEC mole ratios 1:2.5-3.0:3.0-3.2 in the presence of an excess of Et 3 N. The ACs were L-amino-acid t-butyl esters (valine, leucine, isoleucine, phenylalanine, methionine). The obtained carboxy-substituted conjugates were deblocked by CF 3 COOH in CH 2 Cl 2 . The target GA conjugates (2-6) were isolated by column chromatography in 55-60% yields. Compounds 2 and 3 were prepared first. The physicochemical properties of 4-6 agreed with those reported earlier [3]. The structures of 3-5 were confirmed by high-resolution PMR (500 MHz) and 13 C NMR spectra (125 MHz). 13 C NMR spectra of the obtained GA conjugates showed additional resonances for the amino-
The hypoglycemic activity of glycyrrhizic acid (GA, I), its trisodium (II) and sodium-dilithium salts (III), and a conjugate with L-methionine methyl ester (IV) was studied using an alloxan diabetes model after peroral administration to male Wistar rats. It was found that GA and its conjugate IV at a dose of 100 mg/kg exhibited hypoglycemic activity and reduced the blood glucose content of the animals by 35.5 and 42.6%, respectively, after 120 min. GA conjugate IV had low toxicity and hypoglycemic activity superior to those of GA and acarbose.
Endophytic Bacillus subtilis is a non-pathogenic beneficial bacterium which promotes plant growth and tolerance to abiotic stresses, including drought. However, the underlying physiological mechanisms are not well understood. In this study, the potential role that endogenous salicylic acid (SA) plays in regulating endophytic B. subtilis-mediated drought tolerance in wheat (Triticum aestivum L.) was examined. The study was conducted on genotypes with contrasting levels of intrinsic drought tolerance (drought-tolerant (DT) cv. Ekada70; drought-susceptible (DS) cv. Salavat Yulaev). It was revealed that B. subtilis 10-4 promoted endogenous SA accumulation and increased the relative level of transcripts of the PR-1 gene, a marker of the SA-dependent defense pathway, but two wheat cultivars responded differently, with the highest levels exhibited in DT wheat seedlings. These had a positive correlation with the ability of strain 10-4 to effectively protect DT wheat seedlings against drought injury by decreasing osmotic and oxidative damages (i.e., proline, water holding capacity (WHC), and malondialdehyde (MDA)). However, the use of the SA biosynthesis inhibitor 1-aminobenzotriazole prevented endogenous SA accumulation under normal conditions and the maintenance of its increased level under stress as well as abolished the effects of B. subtilis treatment. Particularly, the suppression of strain 10-4-induced effects on proline and WHC, which are both contributing factors to dehydration tolerance, was found. Moreover, the prevention of strain 10-4-induced wheat tolerance to the adverse impacts of drought, as judged by the degree of membrane lipid peroxidation (MDA) and plant growth (length, biomass), was revealed. Thus, these data provide an argument in favor of a key role of endogenous SA as a hormone intermediate in triggering the defense responses by B. subtilis 10-4, which also afford the foundation for the development of the bacterial-induced tolerance of these two different wheat genotypes under dehydration.
Preparation of stable hydrogels using physically (electrostatically) interacting charge-complementary polyelectrolyte chains seems to be more attractive from a practical point of view than the use of organic crosslinking agents. In this work natural polyelectrolytes—chitosan and pectin—were used, due to their biocompatibility and biodegradability. The biodegradability of hydrogels is confirmed by experiments with hyaluronidase as an enzyme. It has been shown that the use of pectins with different molecular weights makes it possible to prepare hydrogels with different rheological characteristics and swelling kinetics. These polyelectrolyte hydrogels loaded with cytostatic cisplatin as a model drug provide an opportunity for its prolonged release, which is important for therapy. The drug release is regulated to a certain extent by the choice of hydrogel composition. The developed systems can potentially improve the effects of cancer treatment due to the prolonged release of cytostatic cisplatin.
Dengue virus (DENV) is one of the most geographically distributed mosquito-borne flaviviruses, like Japanese encephalitis virus (JEV), and Zika virus (ZIKV). In this study, a library of the known and novel Glycyrrhizic acid (GL) derivatives bearing amino acid residues or their methyl/ethyl esters in the carbohydrate part were synthesized and studied as DENV inhibitors in vitro using the cytopathic effect (CPE), viral infectivity and virus yield assays with DENV1 and DENV-2 in Vero E6 and A549 cells. Among the GL conjugates tested, compound hits GL-D-ValOMe 3, GL-TyrOMe 6, GL-PheOEt 11, and GL-LysOMe 21 were discovered to have better antiviral activity than GL, with IC50 values ranging from <0.1 to 5.98 μM on the in vitro infectivity of DENV1 and DENV2 in Vero E6 and A549 cells. Compound hits 3, 6, 11, and 21 had a concentration-dependent inhibition on the virus yield in Vero E6, in which GL-D-ValOMe 3 and GL-PheOEt 11 were the most active inhibitors of DENV2 yield. Meanwhile, the time-of-addition assay indicated that conjugates GL-D-ValOMe 3 and GL-PheOEt 11 exhibited a substantial decrease in the DENV2 attachment stage. Subsequently, chimeric single-round infectious particles (SRIPs) of DENV2 C-prM-E protein/JEV replicon and DENV2 prM-E/ZIKV replicon were utilized for the DENV envelope I protein-mediated attachment assay. GL conjugates 3 and 11 significantly reduced the attachment of chimeric DENV2 C-prM-E/JEV and DENV2 prM-E/ZIKV SRIPs onto Vero E6 cells in a concentration-dependent manner but did not impede the attachment of wild-type JEV CprME/JEV and ZIKV prM-E/ZIKV SRIPs, indicating the inhibition of Compounds 3 and 11 on DENV2 E-mediated attachment. Molecular docking data revealed that Compounds 3 and 11 have hydrophobic interactions within a hydrophobic pocket among the interfaces of Domains I, II, and the stem region of the DENV2 envelope (E) protein. These results displayed that Compounds 3 and 11 were the lead compounds targeting the DENV E protein. Altogether, our findings provide new insights into the structure–activity relationship of GL derivatives conjugated with amino acid residues and can be the new fundamental basis for the search and development of novel flavivirus inhibitors based on natural compounds.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.