Synthesis and biological evaluation of cinnamido linked benzophenone hybrids as tubulin polymerization inhibitors and apoptosis inducing agents |
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| Institution: | 1. Medicinal Chemistry and Pharmacology, CSIR—Indian Institute of Chemical Technology, Hyderabad 500007, India;2. Department of Chemistry, Sri Venkateswara University, Tirupati 517502, India;1. Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Su Zhou, Jiangsu 215021, PR China;2. BeiGene (Beijing) Co., Ltd, No. 30 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, PR China;1. Department of Electrical and Computer Engineering, New Jersey Institute of Technology, Newark, NJ 07102, USA;2. National Research Council, Ottawa, ON, Canada KIA 0R6;1. Department of Chemistry, Al.I. Cuza University of Iasi, 11 Carol I, 700506 Iasi, Romania;2. Department of Biology, Al.I. Cuza University of Iasi, 11 Carol I, 700506 Iasi, Romania;1. Institute of Biotechnology, Academy of Sciences of the Czech Republic, v.v.i., Laboratory of Structural Biology, Vídeňská 1083, 14220 Prague 4, Czech Republic;2. Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, 1550 Orleans Street, Baltimore, MD 21231, USA;3. College of Pharmacy, Korea University, 2511 Sejong-ro, Sejong 339-700, South Korea;4. Center for Cancer Research, Frederick National Laboratory for Cancer Research, Macromolecular Crystallography Laboratory, Frederick, MD 21702, USA |
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| Abstract: | A new class of hybrid molecules containing cinnamide subunit linked to benzophenone as inhibitors of tubulin polymerization were synthesized and evaluated for their anticancer potential. These hybrids exhibit anticancer activity with IC50 values ranging from 0.06 to 16.3 μM. Compounds 4f and 4g possessing fluoro and trifluoromethyl on the cinnamido subunit showed significant cytotoxic activity with IC50 values 0.06 and 0.09 μM against HeLa cell line, respectively. These compounds showed cell cycle arrest at G2/M phase of the cell cycle and inhibited tubulin polymerization followed by activation of caspase-3 activity and apoptotic cell death. Further in vitro tubulin polymerization assay showed that the level of tubulin inhibition was comparable to that of 2a for the compounds 4f and 4g. Moreover, Hoechst 33258 staining and DNA fragmentation assay suggested that these compounds induce cell death by apoptosis. Overall, the current study demonstrates that the synthesis of benzophenone linked cinnamide subunit conjugates as promising anticancer agents with G2/M arrest and apoptotic-inducing ability via targeting tubulin. |
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| Keywords: | Tubulin polymerization Apoptosis Caspase-3 Hoechst staining FACS analysis |
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