SYNTHESIS AND EVALUATION OF THE ANTI-HTV 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'-ox oadenosine (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 mig ht be due to their poor affinity for cellular nucleoside kinases was c hecked by the synthesis of a series of 5'-[bis(2,2,2-trichloroethyl) p hosphate] triesters and 5'-phenyl phosphoramidate derivatives which, a cting as membrane soluble prodrugs, could release the free phosphate f orm inside the cell. The 5'-(phenylmethoxy)alananyl phosphate derived from 8-aza-isoddA was found active against HIV-1 and HIV-2 with a pote ncy similar to that of isoddA, while the anti-HIV potency of 5'-(pheny lmethoxy)alaninyl phosphate of isoddA proved remarkably higher than th at of isoddA, in particular against HIV-2, being similar to that of AZ T. Further evidence that 8-aza-isoddA could behave as anti-HIV agent, provided that it is activated as phosphate, was obtained by the synthe sis of its 5'-triphosphate derivative, which proved to be an active in hibitor of HIV-1 recombinant reverse transcriptase.