Betulinic acid derivatives: a new class of human immunodeficiency virus type 1 specific inhibitors with a new mode of action.
A series of omega-undecanoic amides of lup-20(29)-en-28-oic acid derivatives were synthesized and evaluated for activity in CEM 4 and MT-4 cell cultures against human immunodeficiency virus type 1 (HIV-1) strain IIIB/LAI. The potent HIV inhibitors which emerged, compounds 5a, 16a, and 17b, were all derivatives of betulinic acid (3beta-hydroxylup-20(29)-en-28-oic acid). No activity was found against HIV-2 strain ROD. Compound 5a showed no inhibition of HIV-1 reverse transcriptase activity with poly(C).oligo(dG) as template/primer, nor did it inhibit HIV-1 protease. Additional mechanistic studies revealed that this class of compounds interfere with HIV-1 entry in the cells at a postbinding step.
Evers
M
M
Rhône-Poulenc Rorer S.A., Centre de Recherche de Vitry-Alfortville, Vitry sur Seine, France.
Poujade
C
C
Soler
F
F
Ribeill
Y
Y
James
C
C
Lelièvre
Y
Y
Gueguen
J C
JC
Reisdorf
D
D
Morize
I
I
Pauwels
R
R
De Clercq
E
E
Hénin
Y
Y
Bousseau
A
A
Mayaux
J F
JF
Le Pecq
J B
JB
Dereu
N
N
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects*; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; 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; C098648:N-(3,30-dihydroxylup-20(29)-en-28-oyl)-11-aminoundecanoic acid; C098647:N-(3-hydroxy-30-((2'-hydroxyethyl)thio)lup-20(29)-en-28-oyl)-11-aminoundecanoic acid; D053978:Pentacyclic Triterpenes; D018894:Reverse Transcriptase Inhibitors; D014315:Triterpenes; C098645:betulinylaminoundecanoic acid; D000094062:Betulinic Acid