Studies on phenothiazines: New microtubule-interacting compounds with phenothiazine A-ring as potent antineoplastic agents

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• 作者：Alina Ghinet^a ; ^b ; ^c ; Iuliana-Monica Moise^a ; Benoî ; t Rigo^b ; ^c ; Germain Homerin^b ; ^c ; Amaury Farce^b ; ^d ; Joë ; lle Dubois^e ; Elena Bî ; cu^a ; ^{elena@uaic.ro" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Phenothiazine ; Tubulin ; Microtubule-targeting agent ; Anticancer agent
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 May 2016
• 年：2016
• 卷：24
• 期：10
• 页码：2307-2317
• 全文大小：1899 K

文摘

New phenothiazine derivatives rong class="boldFont">6rong>–rong class="boldFont">20rong> have been designed, synthesized and evaluated in vitro for their ability to inhibit tubulin polymerization and antiproliferative activity against 60 cancer cell lines, including several multi-drug resistant (MDR) tumor cell lines. The phenothiazine unit may successfully replace the classical 3,4,5-trimethoxyphenyle A ring of parent combretastatin A-4 or phenstatin, confirming previous studies. The most promising structural modulations have been realized on the B ring, the 2′-fluoro-4′-methoxy substitution in compound rong class="boldFont">6rong> and the 2′-trifluoromethyl-4′-methoxy substitution in compound rong class="boldFont">7rong> providing the best antitubulin and antitumor activity in the current study. Compounds rong class="boldFont">6rong>–rong class="boldFont">8rong> and rong class="boldFont">16rong> exhibited more important cell growth inhibition than parent phenstatin rong class="boldFont">2rong> on human colon Duke’s type D, colorectal adenocarcinoma COLO 205 and on human kidney adenocarcinoma A498 cell lines. 10-Methylphenothiazine derivatives rong class="boldFont">19rong> and rong class="boldFont">20rong> did not show biological activity but exerted bright fluorescence and solvatochromism effects. These molecules deserve further chemical efforts in order to provide valuable tools for biophysical studies.