Discovery of ortho-Carborane-Conjugated Triazines as Selective Topoisomerase I/II Inhibitors

The cell growth inhibition profile of 2,4-(2-methyl-ortho-carboranyl)-4-(dimethylamino)-1,3,5-triazine (TAZ-6) was found to be similar to that of ICRF-193, a topoisomerase II inhibitor, as revealed by COMPARE analysis (correlation coefficient (r) = 0.724). Various mono-and di-ortho-carborane-substituted 1,3,5-triazines were synthesized based on the structure of TAZ-6 and tested for their ability to inhibit cell growth and the activities of topoisomerases I and II. Among the compounds synthesized, 3c, 4c, and 4f completely inhibited topoisomerase I activity without affecting topoisomerase II activity, whereas 3a and 3d completely inhibited topoisomerase II activity without affecting topoisomerase I activity, at 100 mu M.