S. R. Mustafina

Complex Compounds of Glycyrrhizic Acid with Antimicrobial Drugs

A promising direction in the development of new effective drugs is the synthesis of molecular complexes, for example, with cyclodextrins, which can protect parent substances from premature metabolic decay and provide for their transmembrane transport [1]. Previously, we suggested using 18 -glycyrrhizic acid (GA, I) as a complex-forming agent for the synthesis of new transport forms of the well-known drugs (nonsteroidal antiinflammatory agents, prostaglandins, uracils, etc.) and other biologically active substances [2 – 7]. In continuation of our work in the R&D of new GA-based preparations, we have synthesized a series of new molecular 1 : 1 complexes (II – XI) between antimicrobial drugs and GA (92 2 %) [8]

Crystalline Glycyrrhizic Acid Synthesized from Commercial Glycyrram. Immunomodulant Properties of High-Purity Glycyrrhizic Acid

Glycyrrhizic acid (GA, I) is a triterpene glycoside representing the main active component of licorice root extract obtained from plants of the Glycyrrhiza glabra L., Glycyrrhiza uralensis Fisher, or Glucyrrhiza Korshinskyi Grig. species. GA preparations exhibit various types of pharmacological activity, including antiviral [1, 2] and antitumor properties [3, 4]. Small doses of GA stimulate the production of -interferon both in vitro and in vivo [5, 6]. It was also reported that GA and its derivatives are capable of inhibiting HIV and Marburg viruses [7, 8].

Synthesis and Antiulcer Activity of 3-O-Acylated Glycyrrhetic Acid Methylates

Typically possessing low toxicity and a broad spectrum of biological activity, plant triterpenoids are valuable raw materials for the creation of new drugs [1 – 4]. Of special interest in this respect are the major triterpenoids contained in the root extract obtained from plants of the common licorice (Glycyrrhiza glabra L.) and Ural licorice (Glycyrrhiza uralensis Fisher ) species. These substances are represented by 18 -glycyrrhetic acid (I) and its modified analogs, which serve as the base for effective antiinflammatory, antiallergic, and antiulcer preparations [2, 5 – 9]. The antiulcer drugs include the sodium salt of acid I (glycyrrhenate sodium) [2] and the disodium salt of acid I succinate (carbenoxolone, II) [6, 7]. In continuation of our previous study devoted to the synthetic transformation of triterpenoids extracted from licorice root [10], we have synthesized a series of 3-O-acylates of methyl esters of 18 and 18 -glycyrrhetic acids and their 11-deoxoand 18,19-dehydro analogs (III – IX).

The Synthesis and Antiviral Activity of Glycyrrhizic Acid Conjugates with α-D-Glucosamine and Some Glycosylamines

Glycyrrhizic acid and its 30-methyl ester were conjugated with 2-amino-1,3,4,6-tetra-O-acetyl-2-deoxy-α-D-glucopyranose, 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl amine, 2,3,4-tri-O-acetyl-α-L-arabinopyranosyl amine, 2-acetamido-2-deoxy-β-D-glucopyranosyl amine, and β-D-galactopyranosyl amine using N,N′-dicyclohexylcarbodiimide and its mixtures with N-hydroxybenzotriazole. Structures of the conjugates were confirmed by IR, UV, 1H, and 13C NMR spectroscopy. The glycoconjugate with the residues of 2-acetamido-2-deoxy-β-D-glucopyranosyl amine in the carbohydrate part of its molecule exhibited antiviral activity (ID50 4 μg/ml) toward the herpes simplex type 1 virus (HSV-1) in the VERO cell culture. Two compounds demonstrated anti-HIV-1 activity (50–70% inhibition of p24) in a culture of MT-4 cells at concentrations of 0.5–20 μg/ml.

Transformations of Glycyrrhizic Acid: XV. Synthesis of Triterpene Saponins with Monosaccharide Residues Attached through Ester Bonds

Triterpene saponins, glycoside analogues of glycyrrhizic acid with a modified carbohydrate chain containing monosaccharide residues attached through ester bonds, were synthesized. To this end, peracetylated glycyrrhizic acid or its 30-methyl ester were glycosylated by 2,3,4,6-tetra-O-acetyl-α-D-gluco- or -α-D-galactopyranosyl bromide in dichloroethane in the presence of Ag2CO3. Glycerrhetinic acid saponin with D-Galp residues exhibited a higher antiulcer activity than glycyrrhizic acid in rats at a dose of 25 mg/kg.

Synthesis of Glycyrrhizic Acid from Glycyrram and Pharmaciological Characterization of the Product

Glycyrrhizic acid (I) is an active component of licorice root extract obtained from plants of the Glycyrrhiza glabra L. and Glycyrrhiza uralensis Fisher species. The derivatives of acid I possess a broad spectrum of pharmacological properties, including antiinflammatory, antiulcer, antiallergic, antidote, antiviral, and some other types of activity [1]. Glycyrrhizic acid and its salts were recommended for the treatment of various forms of skin and liver cancer [2, 3] and are successfully used in the form of Stronger Neo-Minophagen C (SNMC) preparation for the therapy of patients with AIDS and hepatitis B [4, 5]. A purified glycoside component enters into the drug Clatraprostin (a veterinary preparation) and is used in the new medicinal forms of nonsteroidal antiinflammatory drugs and some other preparations [6, 7]. Previously [8] we proposed a method of obtaining purified glycyrrhizic acid (84 – 89%) from a commercial dry licorice root extract containing 26 – 28% of glycosides (available from the Urals Licorice Plant). Another commercial raw material that can be used for the synthesis of glycyrrhizic acid is glycyrram – a monoammonium salt of glycyrrhizic acid (available from the Chimkentbiofarm corporation). Glycyrram is an antiinflammatory drug used for the treatment of bronchial asthma, eczemas, and allergic dermatitis [9]. For the synthesis of pure glycyrrhizic acid from a commercial monoammonium salt, Volan and Dumazert [10] recrystallized the commercial product from acetic acid (AcOH) and ethanol, after which the purified glycoside was converted into a tripotassium salt (3K-salt) (II). Finally, salt II was converted into glycyrrhizic acid by acidification with an aqueous H 2 SO 4 solution. I: R = R = H, II: R = R = K, III: R = K, R = H.

Synthesis of N-glycoconjugates of glycyrrhetic acid

New N-glycoconjugates that are analogs of glycyrrhizic acid were synthesized by condensation of α-L-rhamnopyranosylamine and β-D-lactosylamine with acid succinate and phthalate of glycyrrhetic acid methyl ester using N,N′-dicyclohexylcarbodiimide (DCC) or DCC-N-hydroxybenzotriazole.

SYNTHESIS OF TRITERPENE DERIVATIVES OF D-GLUCOSAMINE - MODIFIED ANALOGS OF GLYCYRRHIZIC ACID

Triterpene D-glucosamine amides containing 18α- and 18β-glycyrrhetic acid succinates were synthesized.

Synthesis of benzyl esters of glycyrrhizic acid in the presence of phase-transfer catalysts

Benzyl esters of glycyrrhizic acid were synthesized using PhCH2Br in DMSO-CH2Cl2-NaOH in the presence of phase-transfer catalysts, such as tetraalkylammonium salts and 2-methyl-2-propanol.