Inhibition of human DNA topoisomerase I by new DNA minor groove ligands: Derivatives of oligo-1,3-thiazolecarboxamides

A series of novel thiazole-containing oligopeptides (oligo-1,3-thiazolecarb oxamides) interesting specifically with the minor groove of DNA was shown t o inhibit human DNA topoisomerase I (topo I). Inhibitory effects of thiazol e-containing oligopeptides (TCO) increase with the number of thiazole units in such compounds. Inhibitory properties of TCO containing 3 or 4 thiazole units were shown to be 3-10 times better than those of the well-known natu ral antibiotic, distamycin A containing pyrrole rings. The structure of var ious additional groups attached to the N-terminus and C-terminus of TCO had no significant effect on TCO interaction with the complex of DNA and topo I. TCO were shown to be capable of binding with double-stranded DNA (ds-DNA ), and the majority of TCO analyzed were more effective in binding with dsD NA than distamycin A. Possible reasons for the different effects of distamy cin A and TCO on the reaction of relaxation catalyzed by topo I are discuss ed.