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.
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