title: N-Heterocyclic (4-Phenylpiperazin-1-yl)methanones Derived from Phenoxazine and Phenothiazine as Highly Potent Inhibitors of Tubulin Polymerization.
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 GI50values (16o, mean GI50of 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.
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, Westphalian Wilhelms-University , Corrensstraße 48, D-48149 Münster, Germany.
authors.forename: Helge
authors.identifier: 0000-0002-6704-2112
authors.initials: H
authors.lastname: Prinz
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, Westphalian Wilhelms-University , Corrensstraße 48, D-48149 Münster, Germany.
authors.forename: Ann-Kathrin
authors.initials: AK
authors.lastname: Ridder
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, Westphalian Wilhelms-University , Corrensstraße 48, D-48149 Münster, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Vogel
authors.affiliation: Leibniz Institute on Aging-Fritz Lipmann Institute (FLI) , Beutenbergstrasse 11, D-07745 Jena, Germany.
authors.forename: Konrad J
authors.initials: KJ
authors.lastname: Böhm
authors.affiliation: Oncolead GmbH & Co. KG , Zugspitzstraße 5, D-85757 Karlsfeld, Germany.
authors.forename: Igor
authors.initials: I
authors.lastname: Ivanov
authors.affiliation: Drug Design in Silico Lab, Chemistry Faculty, School of Sciences, University of Tehran , Teheran, Iran.
authors.forename: Jahan B
authors.identifier: 0000-0002-0380-8000
authors.initials: JB
authors.lastname: Ghasemi
authors.affiliation: Drug Design in Silico Lab, Chemistry Faculty, School of Sciences, University of Tehran , Teheran, Iran.
authors.forename: Elham
authors.initials: E
authors.lastname: Aghaee
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, Westphalian Wilhelms-University , Corrensstraße 48, D-48149 Münster, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Müller
mesh_terms: D000477:Alkylating Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D005029:Ethylenediamines / Q000494:pharmacology; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D020014:K562 Cells; D062105:Molecular Docking Simulation; D010078:Oxazines / Q000737:chemistry / Q000494:pharmacology*; D010640:Phenothiazines / Q000737:chemistry / Q000494:pharmacology*; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D058105:Polymerization; D021281:Quantitative Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D050257:Tubulin Modulators / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000620976:10-(4-(3-methoxyphenyl)piperazine-1-carbonyl)-10H-phenoxazine-3-carbonitrile; D000477:Alkylating Agents; D000970:Antineoplastic Agents; D005029:Ethylenediamines; D010078:Oxazines; D010640:Phenothiazines; D010879:Piperazines; D014404:Tubulin; D050257:Tubulin Modulators; C032156:N,N'-ethylenebis(iodoacetamide)