Mannich Base Derivatives as the Potential Candidates of Human Topoisomerase II Inhibitors

Mannich bases are pharmacologically important molecules having wide range of bioactivities. We previously synthesized and characterized a number of Mannich base derivatives of planar polycyclic/heterocyclic starting materials of which four of them [MB1 (3-(bis(2-chloroethyl)amino)-1-phenylpropan-1-one hydrochloride), MB2 (3-(bis(2- chloroethyl)amino)-1-(naphthalen-2-yl)propan-1-one hydrochloride), MB3 (3-(bis(2-chloroethyl)amino)-1-(phenanthren- 3-yl)propan-1-one hydrochloride) and MB4(3-morpholino-1-(pyren-1-yl)propan-1-one hydrochloride)] manifested antiproliferative effects in three cancer cell lines (PC3, HeLa, and MCF7) and one non-tumoral cell line (293 HEK). Because several reports covering anti-proliferation address DNA topoisomerases as the cellular targets, we undertook further assays using these four compounds with type I and type II topoisomerases to identify if their effects were mediated through topoisomerase reactions. Our results indicated that the three of these compounds (MB2, MB3 and MB4) target topoisomerase II without affecting type I topoisomerase. However, targeting type II enzyme did not generate considerable strand breaks, which in turn places the compounds MB2, MB3 and MB4 in potential topoisomerase II inhibitors, not poisons.