Synthesis and anti-HIV activity of triterpene 3-O-galactopyranosides, analogs of glycyrrhizic acid

Abstract

The synthesis of model triterpene glycosides that are analogs of glycyrrhizic acid (GA) with a modified carbohydrate chain is of great interest for studying the molecular mechanisms of GA biological activity, toxicity, and structure-activity relationships [1][2][3][4][5].The sugar moiety in most natural triterpene glycosides is bonded to the sapogenin 3-OH through a 1,2-trans-glycosidic bond [6]. Therefore, a key step in the synthesis of saponins is 3-O-glycosylation of the corresponding triterpene sapogenins by mono-and disaccharide glycosyl donors (GD). Forming such a bond between GD and sterically hindered 3-OH of triterpene alcohols is a rather complicated problem. Glycosylation of natural triterpenoids by readily available GD such as glycosylhalides is usually carried out using compounds of mercury [Hg(CN) 2 , HgBr 2 ] and silver (Ag 2 O, Ag 2 CO 3 , AgOTf) as promoters [1][2][3][4][5]7]. Use of mercury salts for practical syntheses of triterpene glycosides is limited by their high toxicity whereas silver salts are expensive. As a rule, both methods produce a mixture of D-and E-O-glycosides in 30-70% yields [1][2][3][4].In continuation of our studies of the synthesis of biologically active GA analogs [8], we studied glycosylation of triterpenoids from licorice root using the convenient and inexpensive reagent iodine monobromide (I-Br), which was proposed earlier by Field and Kartha for synthesizing various simple glycosides and disaccharides [9,10]. However, it has not yet been used to synthesize triterpene glycosides.We used methyl esters of 18E-glycyrrhetic acid (MeGLA) (3) and 18,19-dehydro-GLA (7) as alcohol components for glycosylation; 2,3,4,6-tetra-O-acetyl-D-D-galactopyranosylbromide (GalBr), as the GD [11], because glycosylation of sterically hindered triterpene alcohols by galactopyranosyl GD is rather complicated and poorly studied from a chemical viewpoint. Table 1 gives the results from the glycosylation. Carrying out the reaction in a mixture of anhydrous CH 3 CN:CH 2 Cl 2 (5:1, v/v) at -20 o -10°C for 18 h with GalBr:MeGLA:I-Br (2:1:2) formed a mixture of D-and E-D-galactopyranosides 4 and 5 in overall yield 35.6% (Scheme 1). The ratio of D-and E-anomers was 6:1 after separation of the reaction products over a column of silica gel (SG), i.e., the major product was the D-anomer 4, which was easily isolated from the product mixture also by recrystallization from EtOH. MeGLA 3-O-acetate 6 was isolated in small quantities as a side product.

Recent advances in natural anti‐HIV triterpenoids and analogs

“…When tested for inhibition of accumulated HIV‐1‐specific protein p24, Compound 97 exhibited an index of selectivity 2.9‐fold greater than that of glycyrrhizic acid. Compound 98 was more cytotoxic toward MT‐4 cells and exhibited only weak anti‐HIV‐1 activity 79 …”