Synthesis of unnatural 7-substituted-1-(2-deoxy-beta-D-ribofuranosyl)isocarbostyrils: "thymine replacement" analogs of deoxythymidine for evaluation as antiviral and anticancer agents.

A group of unnatural 1-(2-deoxy-beta-D-ribofuranosyl)isocarbostyrils having a variety of C-7 substituents [H, 4,7-(NO2)2, I, CF3, CN, (E)-CH=CH-I, -C triple bond CH, -C triple bond C-I, -C triple bond C-Br, -C=C-Me], designed as nucleoside mimics, were synthesized for evaluation as anticancer and antiviral agents. This class of compounds exhibited weak cytotoxicity in a MTT assay (CC50 = 10(-3) to 10(-5) M range) with the 4,7-dinitro derivative being the most cytotoxic, relative to thymidine (CC50 = 10(-3) to 10(-5) M range), against a variety of cancer cell lines. The 4,7-dinitro, 7-I and 7-C triple bond CH compounds exhibited similar cytotoxicity against non-transfected (KBALB, 143B), and HSV-1 TK+ gene transfected (KBALB-STK, 143B-LTK) cancer cell lines possessing the herpes simplex virus type 1 (HSV-1) thymidine kinase gene (TK+). This observation indicates that these compounds are not substrates for HSV type-1 TK, and are therefore unlikely to be useful in gene therapy based on the HSV gene therapy paradigm.