Site-Specific Enzymatic Activation of the Anti-HIV Agent Stampidine

Summary

Stampidine (STAMP, DDE-113, HI-113, N-[p-(4-bromophenyl)-2',3'-didehydro-3'-deoxy-5'-thymidylyl]-L-alanine methyl ester, CAS 217178-62-6) and two stampidine analogs containing ethyl or t-butyl groups were synthesized and their rates of enzymatic activation were compared side-by-side. Enzymes such as lipase, esterase and protease did not hydrolyze the butyl substituted STAMP analog. These experimental results show that the site of attack for the enzymatic hydrolysis of STAMP is the ester side chain of the molecule.

Zusammenfassung

Enzymatische Aktivierung des Anti-HIV-Wirkstoffs Stampidin

Stampidin (STAMP, DDE-113, HI-113, N-[p-(4-Bromphenyl)-2',3'-didehydro-3'-deoxy-5'-thymidylyl]-L-alanin-methylester, CAS 217178-62-6) und zwei verschiedene Stampidin-Analoge mit Ethyl- und t-Butyl-Gruppen wurden synthetisch hergestellt und die Raten ihrer enzymatischen Aktivierung verglichen. Enzyme wie Lipasen, Esterasen oder Proteasen konnten das Butyl-substitutierte STAMP-Analogon nicht hydrolysieren. Diese experimentellen Resultate zeigen, daß die Ester-Seitengruppe des STAMP-Moleküls die Angriffsstelle für die enzymatische Hydrolyse ist.

Key words

Anti-HIV agents - Antiretroviral therapy - N-[p-(4-Bromophenyl)-2',3'-didehydro-3'-deoxy-5'-thymidylyl]-L-alanine methyl ester - CAS 217178-62-6 - DDE-113 - HI-113 - Stampidine, enzymatic activation