SYNTHESIS, IN-VITRO ANTI-HIV ACTIVITY, AND BIOLOGICAL STABILITY OF 5'-O-MYRISTOYL ANALOG DERIVATIVES OF 3'-FLUORO-2',3'-DIDEOXYTHYMIDINE (FLT) AS POTENTIAL BIFUNCTIONAL PRODRUGS OF FLT

A group of 5'-O-myristoyl analogue derivatives of FLT (2) were evaluat ed as potential anti-HIV agents that were designed to serve as prodrug s to FLT. 2',3'-dideoxy-5'-O-(12-methoxydodecanoyl)thymidine (4) (EC50 = 3.8 nM) and o-2',3'-dideoxy-5'-O-(12-azidododecanoyl)thymidine (8) (EC50 = 2.8 nM) were the most effective anti-HIV-1 agents. There was a linear correlation between Log P and HPLC Log retention time for the 5'-O-FLT esters. The in vitro enzymatic hydrolysis half-life (t(1/2)), among the group of esters (3-8) in porcine liver esterase, rat plasma and rat brain homogenate was longer for 3'-fluoro-2',3'-dideoxy-5 '-O -(myristoyl)thymidine (7), with t(1/2) values of 20.3, 4.6 and 17.5 mi n, respectively.