Structure-based design and synthesis of novel furan-diketopiperazine-type derivatives as potent microtubule inhibitors for treating cancer |
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| Affiliation: | 1. School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China;2. Innovation Center for Marine Drug Screening and Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266071, China;3. Shandong Peninsula Engineering Research Center of Comprehensive Brine Utilization, Weifang University of Science and Technology, Weifang 262700, Shandong, China;4. Marine Biomedical Research Institute of Qingdao, Qingdao 266071, China;1. Department of Biosciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India;2. Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India;3. Department of Chemistry, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India;4. Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia;5. Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, 48149, Germany;1. Laboratory of Analytical Neurobiology, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku, Nagoya 468-8503, Japan;2. Laboratory of Natural Product, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku, Nagoya 468-8503, Japan;3. Advanced Institute for Materials Research, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan;4. Division of Chemistry and Materials, Graduate School of Science and Technology, Shinshu University, Ueda, Nagano 386-8567, Japan;1. La Trobe Institute for Molecular Science, La Trobe University, Victoria 3086, Australia;2. School of Science, University of New South Wales, Canberra 2610, Australia;3. School of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia;4. Walter and Eliza Hall Institute, Parkville, Victoria 3052, Australia;5. Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia;1. Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China;2. The Key Laboratory for Chemical Biology of Fujian Province, MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China;3. Hangzhou Ipharmacare Co., LTD, Hangzhou, 310000, China;1. Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad 500037, India;2. Department of Chemistry, Anwarul Uloom College, 11-3-918, New Malleypally, Hyderabad 500001, T. S., India;3. Università degli Studi di Firenze, Neurofarba Dept., Sezione di Scienze Farmaceutiche e Nutraceutiche, Via Ugo Schiff 6, 50019 Sesto, Fiorentino, Florence, Italy |
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| Abstract: | Plinabulin, a synthetic analog of the marine natural product “diketopiperazine phenylahistin,” displayed depolymerization effects on microtubules and targeted the colchicine site, which has been moved into phase III clinical trials for the treatment of non-small cell lung cancer (NSCLC) and the prevention of chemotherapy-induced neutropenia (CIN). To develop more potent anti-microtubule and cytotoxic derivatives, the co-crystal complexes of plinabulin derivatives were summarized and analyzed. We performed further modifications of the tert-butyl moiety or C-ring of imidazole-type derivatives to build a library of molecules through the introduction of different groups for novel skeletons. Our structure–activity relationship study indicated that compounds 17o (IC50 = 14.0 nM, NCI-H460) and 17p (IC50 = 2.9 nM, NCI-H460) with furan groups exhibited potent cytotoxic activities at the nanomolar level against various human cancer cell lines. In particular, the 5-methyl or methoxymethyl substituent of furan group could replace the alkyl group of imidazole at the 5-position to maintain cytotoxic activity, contradicting previous reports that the tert-butyl moiety at the 5-position of imidazole was essential for the activity of such compounds. Immunofluorescence assay indicated that compounds 17o and 17p could efficiently inhibit microtubule polymerization. Overall, the novel furan-diketopiperazine-type derivatives could be considered as a potential scaffold for the development of anti-cancer drugs. |
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| Keywords: | Structure-based drug design Furan-diketopiperazine-type SAR Microtubule inhibitor Anticancer |
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