SYNTHESIS, IN-VITRO BIOLOGICAL STABILITY, AND ANTI-HIV ACTIVITY OF 5-HALO (OR METHOXY)-6-ALKOXY (AZIDO OR ROXY)-5,6-DIHYDRO-2',3'-DIDEHYDRO-3'-DEOXYTHYMIDIN DIASTEREOMERS AS POTENTIAL PRODRUGS OF 2',3'-DIDEHYDRO-3'-DEOXYTHYMIDINE (D4T)

A new class of 5-halo (or methoxy)-6-alkoxy (azido or xy)-5,6-dihydro- 2',3'-didehydro-3'-deoxythymidines (4-17) were investigated as potenti al anti-AIDS drugs. These 5,6-dihydro derivatives, which are also pote ntial prodrugs of 2',3'-didehydro-3'-deoxythymidine (D4T) were designe d to have properties which would enhance their duration of action, lip ophilicity and cephalic delivery to the central nervous system. The 5, 6-dihydro derivatives of D4T (4-15), which differ in configuration at the C-5 and C-6 positions, were synthesized by the regiospecific addit ion of XR (X = Br, Cl, I; R = OMe, OEt, N-3, OH) to the 5,6-olefinic b ond of D4T. These 5,6-disubstituted-5,6-dihydro analogs of D4T are mor e lipophilic (P = 0.70 - 4.0 range) than D4T (P = 0.12) and are stable to E, coli thymidine phosphorylase. Regeneration of the 5,6-olefinic bond to give D4T, upon incubation of the 5-bromo- and 5-iodo-6-methoxy -5,6-dihydro derivatives (6, 7, 10, 11) with glutathione or a mouse li ver soluble enzyme fraction, was extensive (50-95%). The most potent a nti-HIV-1 agents, 5-iodo-6-methoxy (10, 11), 5-bromo-6-azido (14, 15) and 5-methoxy-6-hydroxy (16, 17) derivatives of D4T, exhibited anti-HI V activities comparable to D4T.