Synthesis, biological evaluation, and molecular modeling of novel thioacridone derivatives related to the anticancer alkaloid acronycine

The well-reported, but moderate antitumor activity of the acronycine alkaloid led us to synthesize a novel series of thioacridone compounds related to acronycine, as potential anticancer agents. Compounds were designed either as DNA intercalating agents, or as DNA intercalating agents with covalent bond forming potential. Bathochromic shifts of the compounds upon complexation with salmon testis DNA suggested intercalation as the mode of DNA binding. The binding interaction of the compounds was found to be approximately 10(2) M-1, with that of the most potent compound 1-(2-dimethylaminoethylamino)-9(10H)-thioacridone, 10(4) M-1. In vitro cytotoxic activity (IC50) against HL-60 cells was found to range between 3.5 and 22 mug/mL. QSAR analyses yielded a multiple linear regression equation with an r(2) of 0.847 for DNA binding and an r(2) of 0.575 for cytotoxicity. The physicochemical parameters used in the QSAR analyses were logP, polar surface area, and calculated molar refracivity. Docking studies were also performed to compare the binding of the most potent and least potent compounds in the study in order to predict desirable chemical characteristics for further exploitation in drug. design efforts. The thioacridone compounds in this series demonstrate cytotoxic activity in vitro that merit future in vivo evaluation. (C) 2004 Elsevier Ltd. All rights reserved.