Design,synthesis and evaluation of novel HDAC inhibitors as potential antitumor agents |
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| 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, PR China;2. Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin, Madison 53705, USA;1. Dipartimento di Scienze del Farmaco, Università degli Studi di Catania, V.le A. Doria, 95125 Catania, Italy;2. Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109-1078, USA;3. Dipartimento Farmaco-Chimico, Università di Messina, Viale SS. Annunziata, Messina 98168, Italy;1. Menarini Ricerche, Via Tito Speri 10, 00040 Pomezia, Rome, Italy;2. Menarini Ricerche, Via Rismondo 12A, 50131 Florence, Italy;1. School of Pharmaceutical Sciences, Central South University, Changsha 410013, China;2. Drug Discovery Department, Hisun Group, Taizhou 317700, 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 |
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| Abstract: | Phenyl imidazolidin-2-one was introduced as the linker for novel HDAC inhibitors. A focused library of 20 compounds was designed and synthesized, among which eight compounds showed equivalent or higher potencies against HDAC1 as compared to vorinostat. In vitro antitumor activity assays in HCT-116, PC-3 and HL-60 cancer cells revealed six compounds with potent antitumor activities, and compound 1o showed 6- to 9-fold higher potencies compared to vorinostat. In an HCT-116 nude mice xenograft model, compound 1o displayed significant antitumor activity in both continuous and intermittent dosing schedules. |
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| Keywords: | Histone deacetylases Hydroxamate Antitumor Vorinostat |
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