Anti-AIDS Agents. 34. Synthesis and Structure−Activity Relationships of Betulin Derivatives as Anti-HIV Agents

Abstract

Succinyl and 3'-substituted glutaryl betulin derivatives showed stronger anti-HIV activity and higher therapeutic index (TI) values than their dihydrobetulin counterparts, with ratios of 1.2:1 to 15:1 (cf. 7 and 15, 9 and 17, 10 and 18, 11 and 19, and 12 and 20). For various 3'-substituted glutaryl compounds, the order of anti-HIV effects, from strong to weak inhibition, was 3',3'-dimethyl, 3'-methyl, 3'-ethyl-3'-methyl, followed by 3',3'-tetramethylene glutaryl derivatives (10 > 9 > 11 > 12, 18 > 17 > 19 > 20). The most potent compound, 10, has two 3',3'-dimethylglutaryl groups and displays significant anti-HIV potency with an EC50 value of 0.000 66 microM and a TI of 21 515. Results for compounds (22 and 23) without a C-3 acyl group confirmed the importance of the C-3 acyl group to the anti-HIV effect. With 3',3'-tetramethylene glutaryl derivatives, triacyl 29 showed stronger inhibition than diacyl 12; in contrast, 3',3'-dimethylglutaryl compounds displayed opposite results. 3-Keto compounds (35 and 36) and 2,3-dihydro compounds (39 and 40) had EC50 values in the range of 4.3-10.0 microM, suggesting that A ring modification led to decreased potency. The reduced activity of amide (33 and 34), ester (41), and oxime (42) analogues suggested that the orientation and linkage of the C-3 acyl side chain play crucial roles in the potent anti-HIV activity. Finally, replacing the C-28 acyl group with a bulky non-carboxylic group produced a less potent compound (44). In the study of mechanism of action, our results indicated that fusion is not the primary target for the anti-HIV activity of 10. It appears to inhibit HIV replication at a late stage of the viral life cycle, i.e., after viral protein synthesis.

Role of Human Immunodeficiency Virus (HIV) Type 1 Envelope in the Anti-HIV Activity of the Betulinic Acid Derivative IC9564

“…Our previous results indicate that betulinic acid derivatives possess anti-HIV activity (7,15,17,22,28,41). These betulinic acid derivatives can inhibit HIV-1 envelope-mediated membrane fusion at concentrations ranging from 10 to 40 g/ml, which is at least 1,000-fold higher than that required to inhibit viral replication.…”

“…Betulinic acid derivatives have been shown to inhibit human immunodeficiency virus type 1 (HIV-1) replication (7,15,17,20,22,28,29,32,34,40,41,43). Dependent upon chemical structure, betulinic acid derivatives have been reported as inhibitors of HIV-1 entry (29,40), HIV-1 protease (43) or reverse transcriptase (RT) (34).…”

“…Development of anti-HIV agents with a novel mode of action is one of our ongoing efforts to improve current AIDS therapy (7,15,17,22,28,41). Betulinic acid derivatives are one of the chemical classes that have been identified to have potent anti-HIV activity.…”

Antitumoractive Endoperoxides from Triterpenes

“…Allylic oxidation applying Nhydroxysuccinimide/Na 2 Cr 2 O 7 in acetone furnished the 11-keto-derivatives 10 and 11, respectively. Elimination reaction of 10 under Mitsunobu conditions [25,26] afforded the alkene 13, whereas from 11 compound 14 was obtained. Finally, reaction of 13 with sodium dichromate in the presence of sodium dichromate furnished the endoperoxide 15.…”

Chemical Diversity in Nature Produces Potent Drugs of Various Ailments; Natural Products

“…Betulinic acid isolated from Syzigium claviflorum, has been found to contain anti-HIV activity in lymphocytes. The quassinoside glycoside isolated from Allanthus altissima has been found to inhibit HIV replication [34]. Artemisinin,is of special interest because of its novel structure and activity against Pneumocystis carinii.…”