Betulinic Acid Derivatives:  A New Class of Specific Inhibitors of Human Immunodeficiency Virus Type 1 Entry

A novel series of ω-aminoalkanoic acid derivatives of betulinic acid were synthesized and evaluated for their activity against human immunodeficiency virus (HIV). The anti-HIV-1 activity of several members of this new series was found to be in the nanomolar range in CEM 4 and MT-4 cell cultures. The...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1996-03, Vol.39 (5), p.1069-1083
Main Authors: Soler, Françoise, Poujade, Christèle, Evers, Michel, Carry, Jean-Christophe, Hénin, Yvette, Bousseau, Anne, Huet, Thierry, Pauwels, Rudi, De Clercq, Erik, Mayaux, Jean-François, Le Pecq, Jean-Bernard, Dereu, Norbert
Format: Article
Language:English
Subjects:
AIDS/HIV
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiviral agents
Antiviral Agents - chemical synthesis
Antiviral Agents - pharmacology
Biological and medical sciences
DNA Nucleotidyltransferases - antagonists & inhibitors
Enzyme Inhibitors
HIV Envelope Protein gp120 - metabolism
HIV Protease Inhibitors
HIV-1 - drug effects
HIV-1 - enzymology
human immunodeficiency virus 1
Humans
Integrases
Medical sciences
Molecular Structure
Pharmacology. Drug treatments
Reverse Transcriptase Inhibitors - pharmacology
Structure-Activity Relationship
Triterpenes - chemical synthesis
Triterpenes - chemistry
Triterpenes - pharmacology
Tumor Cells, Cultured
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Summary:A novel series of ω-aminoalkanoic acid derivatives of betulinic acid were synthesized and evaluated for their activity against human immunodeficiency virus (HIV). The anti-HIV-1 activity of several members of this new series was found to be in the nanomolar range in CEM 4 and MT-4 cell cultures. The optimization of the ω-aminoalkanoic acid side chain is described. The presence of an amide function within the side chain was found important for optimal activity. RPR 103611 (14g), a statine derivative, was found to be inactive against HIV-1 protease, reverse transcriptase, and integrase as well as on gp120/CD4 binding. “Time of addition” experiments suggested interaction with an early step of HIV-1 replication. As syncytium formation, but not virus−cell binding, seems to be affected, betulinic acid derivatives are assumed to interact with the postbinding virus−cell fusion process.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm950669u