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Reprogramming of energy metabolism is pivotal to cancer, so mitochondria are potential targets for anticancer therapy. A prior study has demonstrated the anti-proliferative activity of a new class of mitochondria-targeting rosamines. This present study describes  in vitro  cytotoxicity of second-generation rosamine analogs, their mode of action, and their  in vivo  efficacies in a tumor allografted mouse model. Here, we showed that these compounds exhibited potent cytotoxicity (average IC 50 <0.5 µM), inhibited Complex II and ATP synthase activities of the mitochondrial oxidative phosphorylation pathway and induced loss of mitochondrial transmembrane potential. A NCI-60 cell lines screen further indicated that rosamine analogs  4  and  5  exhibited potent antiproliferative effects with Log 10 GI 50  = −7 (GI 50  = 0.1 µM) and were more effective against a colorectal cancer sub-panel than other cell lines. Preliminary  in vivo  studies on 4T1 murine breast cancer-bearing female BALB/c mice indicated that treatment with analog  5  in a single dosing of 5 mg/kg or a schedule dosing of 3 mg/kg once every 2 days for 6 times (q2d×6) exhibited only minimal induction of tumor growth delay. Our results suggest that rosamine analogs may be further developed as mitochondrial targeting agents. Without a doubt proper strategies need to be devised to enhance tumor uptake of rosamines, i.e. by integration to carrier molecules for better therapeutic outcome.

Rosamines Targeting the Cancer Oxidative Phosphorylation Pathway