Synthesis and anti-HIV evaluation of new 2',3'-dideoxy-3'-thiacytidine prodrugs.
A series of anti-HIV prodrugs possessing various polyaminated side arms have been developed. The incorporation of a N-Boc protected monoamine or diamine side arm into the backbone of the 2',3'-dideoxy-3'-thiacytidine 1 (BCH-189) provided an increase in antiviral potency, which could be several orders magnitude greater than the parent drug (1) depending on the cell culture systems used (MT-4 or MDMs). Twenty six 2',3'-dideoxy-3'-thiacytidine prodrugs which differ from each other by the length, the nature of the 5'-O function and the 5'-O or/and N-4 position on the nucleoside moiety were synthesized. Among this new series of prodrugs, several congeners (12c and 12a) were found to inhibit HIV-1 replication in cell culture with 50% effective concentrations EC50 of 10 and 50 nM respectively, in MT-4 cells. Compound 12c was found more active on infected MDMs cells with 50% effective concentration of 0.01 nM. The synthesis and the antiviral properties of these compounds are discussed.
Mourier
N
N
Laboratoire de Chimie Biomoléculaire, Faculté des Sciences de Luminy, Marseille, France.
Camplo
M
M
Della Bruna
G S
GS
Pellacini
F
F
Ungheri
D
D
Chermann
J C
JC
Kraus
J L
JL
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D003959:Diamines / Q000737:chemistry; D006801:Humans; D019259:Lamivudine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D013058:Mass Spectrometry; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D019380:Anti-HIV Agents; D003959:Diamines; D011355:Prodrugs; D019259:Lamivudine