Design and synthesis of novel and highly-active pan-histone deacetylase (pan-HDAC) inhibitors |
| |
| Institution: | 1. Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmacy, Shandong University, 44 West Wenhua Rd, Ji’nan 250012, China;2. Shandong Provincial Key Laboratory of Neuroprotective Drug, Shandong Qidu Pharmaceutical Co., Ltd, 250012, China;1. Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, Università di Milano, Via Celoria 2, 20133 Milano, Italy;2. R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia, RM, Italy;3. Molecular Pharmacology Unit, Dept. Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Via Amadeo 42, I-20133 Milan, Italy;1. Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, University of Milan, via Celoria 2, 20133 Milan, Italy;2. School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Quai Ernest-Ansermet 30, 1211 Geneva 11, Switzerland;3. Fondazione IRCCS Istituto Nazionale Tumori, Via Amadeo 42, 20133 Milano, Italy;4. R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00071 Pomezia, Roma, Italy;1. Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmacy, Shandong University, Ji’nan, Shandong 250012, PR China;2. School of Pharmacy, University of Wisconsin, 777 Highland Avenue, Madison 53705, USA |
| |
| Abstract: | Histone deacetylase (HDAC) inhibitions are known to elicit anticancer effects. We designed and synthesized several HDAC inhibitors. Among these compounds, compound 40 exhibited a more than 10-fold stronger inhibitory activity compared with that of suberoylanilide hydroxamic acid (SAHA) against each human HDAC isozyme in vitro (IC50 values of 40: HDAC1, 0.0038 μM; HDAC2, 0.0082 μM; HDAC3, 0.015 μM; HDAC8, 0.0060 μM; HDAC4, 0.058 μM; HDAC9, 0.0052 μM; HDAC6, 0.058 μM). The dose of the administered HDAC inhibitors that contain hydroxamic acid as the zinc-binding group may be reduced by 40. Because the carbostyril subunit is a time-tested structural component of drugs and biologically active compounds, 40 most likely exhibits good absorption, distribution, metabolism, excretion, and toxicity (ADMET). Thus, compound 40 is expected to be a promising therapeutic agent or chemical tool for the investigation of life process. |
| |
| Keywords: | Epigenetics Histone deacetylase Histone deacetylase inhibitor Cancer Carbostyril |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
