Betulinic acid derivatives: a new class of specific inhibitors of human immunodeficiency virus type 1 entry.
A novel series of omega-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 omega-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.
Soler
F
F
Rhône-Poulenc Rorer, Centre de Recherche de Vitry-Alfortville, Vitry sur Seine, France.
Poujade
C
C
Evers
M
M
Carry
J C
JC
Hénin
Y
Y
Bousseau
A
A
Huet
T
T
Pauwels
R
R
De Clercq
E
E
Mayaux
J F
JF
Le Pecq
J B
JB
Dereu
N
N
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004254:DNA Nucleotidyltransferases / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D017320:HIV Protease Inhibitors; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D019426:Integrases; D015394:Molecular Structure; D053978:Pentacyclic Triterpenes; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014315:Triterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D000094062:Betulinic Acid
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D015699:HIV Envelope Protein gp120; D017320:HIV Protease Inhibitors; D053978:Pentacyclic Triterpenes; D018894:Reverse Transcriptase Inhibitors; D014315:Triterpenes; C098649:RPR 103611; D004254:DNA Nucleotidyltransferases; D019426:Integrases; D000094062:Betulinic Acid