Based on the lessons learned from our project on carbocyclic nucleosides (Z01 BC 006174) regarding the mechanism of """"""""delayed chain termination"""""""", two lines of investigation have been implemented this year to exploit each of the critical parameters necessary for efficient activity against HIV: (1) attachment of 4'-alkyl groups (methyl and ethyl) to a 2'-deoxyribose moiety; and (2) incorporation of a double bond onto the carbocyclic moiety of bicyclo[3.1.0]hexane nucleosides converting them into flat bicyclo[3.1.0]hex-3-ene nucleosides. Ring flatness is a property deemed essential for efficient phosphorylation by cellular kinases. Progress in these two areas is highlighted: (1) Synthesis of the thymidine series bearing 4'-methyl and ethyl groups was successfully completed. The 4'-methyl analogue showed excellent properties as a delayed chain terminator when used in vitro against HIV-RT as a 5'-triphosphate, but failed to be recognized by cellular kinases. The synthesis of an analogous series with adenine as nucleobase is in progress; and (2) The synthesis of the first South analogue with a flat bicyclo[3.1.0]hex-3-ene containing thymi
