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  2. N-Heterocyclic (4-Phenylpiperazin-1-yl)methanones Derived from Phenoxazine and Phenothiazine as Highly Potent Inhibitors of Tubulin Polymerization

N-Heterocyclic (4-Phenylpiperazin-1-yl)methanones Derived from Phenoxazine and Phenothiazine as Highly Potent Inhibitors of Tubulin Polymerization

  • J Med Chem. 2017 Jan 26;60(2):749-766. doi: 10.1021/acs.jmedchem.6b01591.
Helge Prinz 1 Ann-Kathrin Ridder 1 Kirsten Vogel 1 Konrad J Böhm 2 Igor Ivanov 3 Jahan B Ghasemi 4 Elham Aghaee 4 Klaus Müller 1
Affiliations

Affiliations

  • 1 Institute of Pharmaceutical and Medicinal Chemistry, Westphalian Wilhelms-University , Corrensstraße 48, D-48149 Münster, Germany.
  • 2 Leibniz Institute on Aging-Fritz Lipmann Institute (FLI) , Beutenbergstrasse 11, D-07745 Jena, Germany.
  • 3 Oncolead GmbH & Co. KG , Zugspitzstraße 5, D-85757 Karlsfeld, Germany.
  • 4 Drug Design in Silico Lab, Chemistry Faculty, School of Sciences, University of Tehran , Teheran, Iran.
Abstract

We report here a series of 27 10-(4-phenylpiperazin-1-yl)methanones derived from tricyclic heterocycles which were screened for effects on tumor cell growth, inhibition of tubulin polymerization, and induction of cell cycle arrest. Several analogues, among them the 10-(4-(3-methoxyphenyl)piperazine-1-carbonyl)-10H-phenoxazine-3-carbonitrile (16o), showed excellent antiproliferative properties, with low nanomolar GI50 values (16o, mean GI50 of 3.3 nM) against a large number (93) of Cancer cell lines. Fifteen compounds potently inhibited tubulin polymerization. Analysis of cell cycle by flow cytometry revealed that inhibition of tumor cell growth was related to an induction of G2/M phase cell cycle blockade. Western blotting and molecular docking studies suggested that these compounds bind efficiently to β-tubulin at the colchicine binding site. Our studies demonstrate the suitability of the phenoxazine and phenothiazine core and also of the phenylpiperazine moiety for the development of novel and potent tubulin polymerization inhibitors.

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