Synthesis and anti-HIV evaluation of some phosphoramidate derivatives of AZT: studies on the effect of chain elongation on biological activity.
A series of phosphoramidate derivatives of the anti-HIV drug AZT has been prepared as membrane soluble pro-drugs of the bio-active nucleotide forms and evaluated in vitro against HIV-1. Terminal substituted alkyl amines have a pronounced anti-HIV effect: this effect declines upon increasing the length of the methylene spacer. The results are consistent with a mechanism of action involving intracellular cleavage of the phosphoramidate bond, and release of the nucleotide, or a derivative thereof. Full spectroscopic data are included on the products and their phosphorochloridate precursors.
Curley
D
D
Department of Chemistry, University College London, U.K.
McGuigan
C
C
Devine
K G
KG
O'Connor
T J
TJ
Jeffries
D J
DJ
Kinchington
D
D
D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D003854:Deoxyribonucleotides / Q000138:chemical synthesis / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D006678:HIV / Q000187:drug effects*; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013942:Thymine Nucleotides / Q000138:chemical synthesis / Q000737:chemistry; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry
D003854:Deoxyribonucleotides; D011355:Prodrugs; D013942:Thymine Nucleotides; D015215:Zidovudine; D004247:DNA