Anti-AIDS agents--XXVII. Synthesis and anti-HIV activity of betulinic acid and dihydrobetulinic acid derivatives.

Journal Article (Journal Article)

Two series of lupane-type triterpenoic acid derivatives were synthesized and evaluated for their inhibitory activity against HIV-1 replication in acutely infected H9 cells, based on the fact that betulinic acid (1) and dihydrobetulinic acid (9) were identified as anti-HIV agents. Among the derivatives, 3-O-(3',3'-dimethylsuccinyl)-betulinic acid (3) and 3-O-(3',3'-dimethylsuccinyl)-dihydrobetulinic acid (11) both demonstrated extremely potent inhibitory activity with EC50 values of < 3.5 x 10(-4) microM, and remarkable in vitro therapeutic index (TI) values of 20,000 and 14,000, respectively. 3-O-(3',3'-dimethylglutaryl)-betulinic acid (4) and-dihydrobetulinic acid (12), 3-O-diglycolyl-betulinic acid (5) and -dihydrobetulinic acid (13) and 3-O-glutaryl-betulinic acid (6) were also potent inhibitors of HIV replication with EC50 values ranging from 0.04 to 2.3 x 10(-3) microM and TI values from 292 to 2344. In addition, compounds 11 and 12 were also active against HIV replication in a monocyte cell line and in peripheral blood mononuclear cells. Our in vitro assay indicated that these compounds are not inhibitors of HIV-1 reverse transcriptase, whereas they inhibited syncytia formation completely in a concentration range of 20-40 micrograms/mL. However, 3-O-(2',2'-dimethylsuccinyl)-betulinic acid (2) was also found to be an inhibitor of HIV-induced membrane fusion with an IC100 value of 20 micrograms/mL, though it displayed significantly lower anti-HIV activity than foregoing compounds with an EC50 value of 2.7 microM and TI of 6.7. Further study is underway to determine the mechanisms of action of these compounds.

Full Text

Duke Authors

Cited Authors

  • Hashimoto, F; Kashiwada, Y; Cosentino, LM; Chen, CH; Garrett, PE; Lee, KH

Published Date

  • December 1997

Published In

Volume / Issue

  • 5 / 12

Start / End Page

  • 2133 - 2143

PubMed ID

  • 9459011

International Standard Serial Number (ISSN)

  • 0968-0896

Digital Object Identifier (DOI)

  • 10.1016/s0968-0896(97)00158-2


  • eng

Conference Location

  • England