Synthesis and Antitumor Activity of 4-Aminomethylthioxanthenone and 5-Aminomethylbenzothiopyranoindazole Derivatives

Two new series of antitumor agents, 4-aminomethylthioxanthenones (6−50) and 5-aminomethylbenzothiopyranoindazoles (51−61), are described and compared. Nearly all members of both series display excellent in vivo activity versus murine pancreatic adenocarcinoma 03 (Panc03) although there is little to distinguish the two series from each other. In both series there is no discernible relationship between structure and in vivo efficacy. Selected analogues were evaluated in vitro; all were observed to have moderate to strong DNA binding via intercalation. However, varying degrees of in vitro P388 cytotoxicity and topoisomerase II inhibition were seen. In general, those molecules which exhibited strong topoisomerase II inhibition were significantly more cytotoxic than those which did not. In both series, those derivatives (48−50, 60, and 61) having a phenolic hydroxy substitution exhibited the most potent P388 cytotoxicity and topoisomerase II inhibition.