N-benzoylated phenoxazines and phenothiazines: synthesis, antiproliferative activity, and inhibition of tubulin polymerization
| Autor: | Behfar Chamasmani, Eckhard Günther, Klaus Müller, Matthias Gerlach, Helge Prinz, Kirsten Vogel, Konrad J. Böhm, Peter Amon, Igor Ivanov, Babette Aicher |
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| Rok vydání: | 2011 |
| Předmět: |
Stereochemistry
Antineoplastic Agents chemistry.chemical_compound Structure-Activity Relationship Biopolymers Phenothiazines Tubulin Phenothiazine Cell Line Tumor Drug Discovery Oxazines Structure–activity relationship Colchicine Humans Mitosis biology Cell Cycle Cell cycle Tubulin Modulators chemistry Biochemistry Cell culture Drug Resistance Neoplasm Organ Specificity biology.protein Molecular Medicine Drug Screening Assays Antitumor Phenoxazine |
| Zdroj: | Journal of medicinal chemistry. 54(12) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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