Design,synthesis and biological evaluation of benzimidazole derivatives as novel human Pin1 inhibitors |
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| Affiliation: | 1. Shenyang Pharmaceutical University, Shenyang 110016, China;2. Key Laboratory of Structure-based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China;1. Discovery Chemistry, Merck & Co., Inc, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA;2. In Vivo Pharmacology, Merck & Co., Inc, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA;3. Process Chemistry, Merck & Co., Inc, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA;4. In Vitro Pharmacology, Merck & Co., Inc, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA;5. Drug Metabolism and Pharmacokinetics, Merck & Co., Inc, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA;6. SALAR Discovery, Merck & Co., Inc, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA;1. Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenyang 110016, PR China;2. College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150086, PR China;1. Anticancer Agent Research Center, KRIBB, Cheongju 28116, Republic of Korea;2. Department of Bioengineering, Hanyang University, Seoul 04763, Republic of Korea;3. Department of Chemistry, Chonnam National University, Gwangju 61186, Republic of Korea;4. Department of Bioscience and Biotechnology, Sejong University, Seoul 05006, Republic of Korea;1. Department of Physics, Periyar University, Salem 636 011, Tamil Nadu, India;2. Facultad de Ingeniería y Tecnología, Universidad San Sebastián, Bellavista 7, Santiago 8420524, Chile;3. Rajah Muthiah Medical College, Annamalai University, Annamalai Nagar – 608 002, Tamil Nadu, India;4. Department of Physics, Thiruvalluvar Government Arts College, Rasipuram, Namakkal 637 401, Tamil Nadu, India;5. PG & Research Department of Biotechnology, Mahendra Arts and Science College (Autonomous), Namakkal 637 501, Tamil Nadu, India |
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| Abstract: | In this work, a series of novel benzimidazole derivatives were designed and synthesized as Pin1 inhibitors. Protease-coupled assay was used to investigate the Pin1 inhibitory potency of all synthesized compounds. Thirteen of them showed preferable Pin1 inhibitory effects with IC50 values lower than 5 μM, and 12a, 15b, 15d and 16c exhibited the most promising Pin1 inhibitory activity at low micromolar level (0.33–1.00 μM) than the positive control compound Juglone. Flow cytometry results showed that treating PC-3 cells with 16c caused slight cycle arrest in a concentration-dependent manner. The structure-activity relationships of R1, R2, R3 and linker of the benzimidazole derivatives were analyzed in detail, which would help further exploration of new Pin1 inhibitors. |
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| Keywords: | Pin1 inhibitors PPIase PC-3 Prostate cancer |
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