SYNTHESIS, BIOACTIVATION AND ANTI-HIV ACTIVITY OF 4-ACYLOXYBENZYL BIS(NUCLEOSID-5'-YL) PHOSPHATES

4-Acyloxybenzyl bis(nucleosid-5'-yl) phosphates 7a-c and 9a-c were pre pared as potential prodrugs of the anti-HIV nucleosides 3'-azido-3'-de oxythymidine (AZT) and 2',3'-dideoxyinosine (ddI) or their 5'-monophos phates. The anti-HIV activities of these triesters were determined in two T-cell lines. In a C8165 cell line they displayed activities compa rable to and in some cases superior to AZT, but they also exhibited an increase in cytotoxicity. In a thymidine kinase deficient JM T-cell l ine the activity was reduced but was still superior to AZT. In the pre sence of porcine liver carboxyesterase (PLCE), triester 7b biodegrades to the diester 10 which, with phosphodiesterase, gives initially AZT monophosphate 3 and AZT.