A SEMIEMPIRICAL AM1 CONFORMATIONAL STUDY OF 3'-SUBSTITUTED DEOXYTHYMIDINES

Semiempirical AM1 calculations of the conformations of thymidine and certain of its 3'-derivatives were performed with a view to identifying structural trends that might correlate with the anti-HIV activity of these compounds. The series examined included high-activity derivatives with N3 or F as the 3'-substituent, low-activity derivatives with CN or NH2, and the moderately active 3'-H and 2',3'-unsaturated compounds. Only small energy differences were found among the different conformers, and all the molecules examined had similar conformations, except the 2',3'-unsaturated compound, whose five-membered ring was less flexible than those of the others and adopted different conformations. Most conformers were anti or syn/anti around the glycoside bond and had N or N/S sugar ring puckering angles. The orientation of the exocyclic sugar moiety and stabilization by intramolecular hydrogen bonds are also discussed.