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Rigshospitalet - a part of Copenhagen University Hospital
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N-Heterocyclic (4-Phenylpiperazin-1-yl)methanones Derived from Phenoxazine and Phenothiazine as Highly Potent Inhibitors of Tubulin Polymerization

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  • Helge Prinz
  • Ann-Kathrin Ridder
  • Kirsten Vogel
  • Konrad J Böhm
  • Igor Ivanov
  • Jahan B Ghasemi
  • Elham Aghaee
  • Klaus Müller
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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.

Original languageEnglish
JournalJournal of Medicinal Chemistry
Volume60
Issue number2
Pages (from-to)749-766
Number of pages18
ISSN0022-2623
DOIs
Publication statusPublished - 26 Jan 2017

    Research areas

  • Alkylating Agents, Antineoplastic Agents, Ethylenediamines, G2 Phase Cell Cycle Checkpoints, Humans, K562 Cells, Molecular Docking Simulation, Oxazines, Phenothiazines, Piperazines, Polymerization, Quantitative Structure-Activity Relationship, Tubulin, Tubulin Modulators, Journal Article

ID: 52167112