title: Importance of the alanine methyl ester side chain for the biological activity profile of dual-function phenyl phosphate derivatives of bromo-methoxy-zidovudine.
abstract: In a systematic search for developing a virucidal spermicide with potent anti-human immunodeficiency virus (HIV) and spermicidal activities, we synthesized and evaluated 14 phosphoramidate derivatives of 5-bromo-6-methoxy-zidovudine (PP-BMZ) with differing amino acid ester side chains and para substitutions on the phenyl moiety. Anti-HIV activity was tested by measuring viral p24 antigen production as a marker of viral replication in HIV-1-infected human peripheral blood mononuclear cells. The effect of various PP-BMZ compounds on human sperm motion kinematics was analysed by computer-assisted sperm analysis. Varying the Ala side chain of the phosphoramidate group to other non-polar amino acids, including the cyclic amino acids proline and tryptophan, led to significant alterations in both anti-HIV and spermicidal activities. Our findings highlight the necessity of the Ala side chain and the presence of an electron-withdrawing para-bromo substituent on the phenyl moiety in addition to the bromo-methoxy functional groups on the thymine ring for the PP-BMZ compounds to be effective virucidal spermicides. These membrane permeable dual-function nucleoside analogues may provide the basis for a new strategy aimed at prevention of the sexual transmission of HIV while providing fertility control for women.
authors.affiliation: Drug Discovery Program, Department of Chemistry, Hughes Institute, St Paul, MN 55113, USA.
authors.forename: T K
authors.initials: TK
authors.lastname: Venkatachalam
authors.forename: O J
authors.initials: OJ
authors.lastname: D'Cruz
authors.forename: F M
authors.initials: FM
authors.lastname: Uckun
mesh_terms: D000409:Alanine / Q000737:chemistry*; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004952:Esters; D005260:Female; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008297:Male; D010710:Phosphates / Q000737:chemistry*; D013057:Spectrum Analysis; D013081:Sperm Motility / Q000187:drug effects; D013089:Spermatocidal Agents / Q000737:chemistry / Q000494:pharmacology*; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D004952:Esters; D010710:Phosphates; D013089:Spermatocidal Agents; D015215:Zidovudine; D000409:Alanine