Journal of medicinal and pharmaceutical chemistry 2011-06-23

N-benzoylated phenoxazines and phenothiazines: synthesis, antiproliferative activity, and inhibition of tubulin polymerization.

Helge Prinz, Behfar Chamasmani, Kirsten Vogel, Konrad J Böhm, Babette Aicher, Matthias Gerlach, Eckhard G Günther, Peter Amon, Igor Ivanov, Klaus Müller

Index: J. Med. Chem. 54 , 4247-63, (2011)

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Abstract

A total of 53 N-benzoylated phenoxazines and phenothiazines, including their S-oxidized analogues, were synthesized and evaluated for antiproliferative activity, interaction with tubulin, and cell cycle effects. Potent inhibitors of multiple cancer cell lines emerged with the 10-(4-methoxybenzoyl)-10H-phenoxazine-3-carbonitrile (33b, IC(50) values in the range of 2-15 nM) and the isovanillic analogue 33c. Seventeen compounds strongly inhibited tubulin polymerization with activities higher than or comparable to those of the reference compounds such as colchicine. Concentration-dependent flow cytometric studies revealed that inhibition of K562 cell growth was associated with an arrest in the G2/M phases of the cell cycle, indicative of mitotic blockade. Structure-activity relationship studies showed that best potencies were obtained with agents bearing a methoxy group placed para at the terminal phenyl ring and a 3-cyano group in the phenoxazine. A series of analogues highlight not only the phenoxazine but also the phenothiazine structural scaffold as valuable pharmacophores for potent tubulin polymerization inhibitors, worthy of further investigation.