SYNTHESIS OF UNNATURAL 7-SUBSTITUTED-1-(2-DEOXY-β-D-RIBOFURANOSYL)ISOCARBOSTYRILS1†: “THYMINE REPLACEMENT” ANALOGS OF DEOXYTHYMIDINE FOR EVALUATION AS ANTIVIRAL AND ANTICANCER AGENTS

Abstract

A group of unnatural 1-(2-deoxy-β-D-ribofuranosyl)isocarbostyrils having a variety of C-7 substituents [H, 4,7-(NO2)2, I, CF3, CN, (E)-CH=CH-I, -C═CH, -C═C-I, -C═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═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. †Nucleoside-like numbering is used by analogy to nucleoside nomenclature.