Synthesis and evaluation of the anti-HIV activity of aza and deaza analogues 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 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.
Franchetti
P
P
Dipartimento di Scienze Chimiche, Università di Camerino, Italy.
Cappellacci
L
L
Grifantini
M
M
Messini
L
L
abu Sheikha
G
G
Loi
A G
AG
Tramontano
E
E
de Montis
A
A
Spiga
M G
MG
La Colla
P
P
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D016048:Dideoxyadenosine / Q000031:analogs & derivatives* / Q000737:chemistry; D054306:Dideoxynucleotides; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D015498:HIV-2 / Q000187:drug effects*; D015394:Molecular Structure; D010710:Phosphates / Q000138:chemical synthesis / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D018894:Reverse Transcriptase Inhibitors
C090026:8-azaisodideoxyadenosine triphosphate; D000998:Antiviral Agents; D001372:Aza Compounds; D054306:Dideoxynucleotides; D010710:Phosphates; D011994:Recombinant Proteins; D018894:Reverse Transcriptase Inhibitors; C067988:Ro 24-5098; D016048:Dideoxyadenosine; D000255:Adenosine Triphosphate; D054303:HIV Reverse Transcriptase