title: N-benzoylated phenoxazines and phenothiazines: synthesis, antiproliferative activity, and inhibition of tubulin polymerization.
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.
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, Westphalian Wilhelms-University, Hittorfstrasse 58-62, D-48149 Münster, Germany.
authors.forename: Helge
authors.initials: H
authors.lastname: Prinz
authors.forename: Behfar
authors.initials: B
authors.lastname: Chamasmani
authors.forename: Kirsten
authors.initials: K
authors.lastname: Vogel
authors.forename: Konrad J
authors.initials: KJ
authors.lastname: Böhm
authors.forename: Babette
authors.initials: B
authors.lastname: Aicher
authors.forename: Matthias
authors.initials: M
authors.lastname: Gerlach
authors.forename: Eckhard G
authors.initials: EG
authors.lastname: Günther
authors.forename: Peter
authors.initials: P
authors.lastname: Amon
authors.forename: Igor
authors.initials: I
authors.lastname: Ivanov
authors.forename: Klaus
authors.initials: K
authors.lastname: Müller
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001704:Biopolymers; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009928:Organ Specificity; D010078:Oxazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010640:Phenothiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001704:Biopolymers; D010078:Oxazines; D010640:Phenothiazines; D014404:Tubulin; D050257:Tubulin Modulators