3D-QSAR-aided design,synthesis, in vitro and in vivo evaluation of dipeptidyl boronic acid proteasome inhibitors and mechanism studies |
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| Institution: | 1. College of Science, Nanjing Forestry University, No. 159 Longpan Road, Nanjing 210037, PR China;2. College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing 210037, PR China;3. Jiangsu Chia Tai Fenghai Pharmaceutical Co. Ltd, No. 9 Weidi Road, Nanjing 210046, PR China;1. Faculty of Pharmacy, Charles University in Prague, 500 05 Hradec Králové, Czech Republic;2. Department of Chemistry, Duke University, Durham, NC 22708, USA;1. Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, 250012, PR China;2. State Key Laboratory of Microbial Technology, School of Life Sciences, Shandong University, Jinan, Shandong, 250100, PR China;1. Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan;2. Graduate School of Infection Control Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan;3. Department of Biomedical Chemistry, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan;1. Rzeszów University of Technology, Faculty of Chemistry, Bioorganic Chemistry Laboratory, 6 Powstańców Warszawy Ave., 35-959 Rzeszów, Poland;2. Nencki Institute of Experimental Biology, 3 Pasteur Street, 02-093 Warsaw, Poland;3. University of Warsaw, Faculty of Chemistry, Quantum Chemistry Laboratory, 1 Pasteur Street, Warsaw 02-093, Poland;4. Pharmaceutical Research Institute, Rydygier Street 8, Warsaw 01-793, Poland;1. Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C23, D-66123 Saarbrücken, Germany;2. ElexoPharm GmbH, Campus A12, D-66123 Saarbrücken, Germany;3. Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus C23, D-66123 Saarbrücken, Germany |
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| Abstract: | Proteasome had been clinically validated as an effective target for the treatment of cancers. Up to now, many structurally diverse proteasome inhibitors were discovered. And two of them were launched to treat multiple myeloma (MM) and mantle cell lymphoma (MCL). Based on our previous biological results of dipeptidyl boronic acid proteasome inhibitors, robust 3D-QSAR models were developed and structure–activity relationship (SAR) was summarized. Several structurally novel compounds were designed based on the theoretical models and finally synthesized. Biological results showed that compound 12e was as active as the standard bortezomib in enzymatic and cellular activities. In vivo pharmacokinetic profiles suggested compound 12e showed a long half-life, which indicated that it could be administered intravenously. Cell cycle analysis indicated that compound 12e inhibited cell cycle progression at the G2M stage. |
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| Keywords: | 3D-QSAR Proteasome inhibitor Pharmacokinetic Cell cycle |
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