Synthesis and Evaluation of the Anti-HIV Activity of Aza and Deaza Analogs of IsoddA and Their Phosphates as Prodrugs

Some aza and deaza analogues of the anti-HIV agent 2',3'-dideoxy-3'-oxoadenosine (isoddA) (8-aza-, 8-aza-1-deaza, 8-aza-3-deaza-, 1-deaza-, and 3-deaza-isoddA) were synthesized and found inactive against HIV in vitro. The hypothesis that the inactivity of these isonucleosides might be...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1994-10, Vol.37 (21), p.3534-3541
Main Authors: Franchetti, Palmarisa, Cappellacci, Loredana, Grifantini, Mario, Messini, Lea, Sheikha, Ghassan Abu, Loi, Anna Giulia, Tramontano, Enzo, De Montis, Antonella, Spiga, Maria Grazia, La Colla, Paolo
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - analogs & derivatives
Adenosine Triphosphate - chemical synthesis
Adenosine Triphosphate - pharmacology
AIDS/HIV
Antiviral Agents - chemical synthesis
Antiviral Agents - pharmacology
Aza Compounds - chemical synthesis
Aza Compounds - pharmacology
Carbohydrates. Nucleosides and nucleotides
Chemistry
Dideoxyadenosine - analogs & derivatives
Dideoxyadenosine - chemistry
Dideoxynucleotides
Exact sciences and technology
HIV Reverse Transcriptase
HIV-1 - drug effects
HIV-1 - enzymology
HIV-2 - drug effects
human immunodeficiency virus
Molecular Structure
Nucleosides, nucleotides and oligonucleotides
Organic chemistry
Phosphates - chemical synthesis
Phosphates - pharmacology
Preparations and properties
Recombinant Proteins - antagonists & inhibitors
Reverse Transcriptase Inhibitors
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Summary:Some aza and deaza analogues of the anti-HIV agent 2',3'-dideoxy-3'-oxoadenosine (isoddA) (8-aza-, 8-aza-1-deaza, 8-aza-3-deaza-, 1-deaza-, and 3-deaza-isoddA) were synthesized and found inactive against HIV in vitro. The hypothesis that the inactivity of these isonucleosides might be due to their poor affinity for cellular nucleoside kinases was checked by the synthesis of a series of 5'-[bis(2,2,2-trichloroethyl) phosphate] triesters and 5'-phenyl phosphoramidate derivatives which, acting as membrane soluble prodrugs, could release the free phosphate form inside the cell. The 5'-(phenylmethoxy)alaninyl phosphate derived from 8-aza-isoddA was found active against HIV-1 and HIV-2 with a potency similar to that of isoddA, while the anti-HIV potency of 5'-(phenylmethoxy)alaninyl phosphate of isoddA proved remarkably higher than that of isoddA, in particular against HIV-2, being similar to that of AZT. Further evidence that 8-aza-isoddA could behave as anti-HIV agent, provided that it is activated as phosphate, was obtained by the synthesis of its 5'-triphosphate derivative, which proved to be an active inhibitor of HIV-1 recombinant reverse transcriptase.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00047a011