Studies on phenothiazines: New microtubule-interacting compounds with phenothiazine A-ring as potent antineoplastic agents |
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| Institution: | 1. Department of Organic Chemistry, ‘Al. I. Cuza’ University of Iasi, Faculty of Chemistry, Bd. Carol I nr. 11, 700506 Iasi, Romania;2. Inserm U995, LIRIC, Université de Lille, CHRU de Lille, Faculté de médecine—Pôle recherche, Place Verdun, F-59045 Lille Cedex, France;3. Hautes Etudes d’Ingénieur (HEI), Groupe HEI-ISA-ISEN, UCLille, Laboratoire de Pharmacochimie, 13 rue de Toul, F-59046 Lille, France;4. Faculté des Sciences Pharmaceutiques et Biologiques de Lille, 3 Rue du Pr Laguesse, B.P. 83, F-59006 Lille, France;5. Institut de Chimie des Substances Naturelles, UPR2301 CNRS, Centre de Recherche de Gif, Avenue de la Terrasse, F-91198 Gif-sur-Yvette Cedex, France;1. Department of Physics, Karnatak University, Dharwad 580003, Karnataka, India;2. Department of Chemistry, Karnatak University, Dharwad 580003, Karnataka, India;1. Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran;2. Genetics Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran;3. Department of Medicinal Chemistry, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran;4. Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran;5. Department of Medicinal Chemistry, School of Pharmacy, Alborz University of Medical Sciences, Karaj, Iran;6. Department of Environmental Sciences, Faculty of Natural Resources and Marine Sciences, Tarbiat Modares University, Tehran, Iran;1. Department of Pharmacognosy, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia;2. Department of Drug Radiation Research, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority, Cairo 113701, Egypt;3. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt;4. Department of Pharmacology, Faculty of Pharmacy, Misr International University, Cairo, Egypt;5. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt;6. Faculty of Pharmacy, Nahda University, 62511 New Beni Suef (NUB), Egypt |
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| Abstract: | New phenothiazine derivatives 6–20 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 6 and the 2′-trifluoromethyl-4′-methoxy substitution in compound 7 providing the best antitubulin and antitumor activity in the current study. Compounds 6–8 and 16 exhibited more important cell growth inhibition than parent phenstatin 2 on human colon Duke’s type D, colorectal adenocarcinoma COLO 205 and on human kidney adenocarcinoma A498 cell lines. 10-Methylphenothiazine derivatives 19 and 20 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. |
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| Keywords: | Phenothiazine Tubulin Microtubule-targeting agent Anticancer agent |
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