Novel tricyclic poly (ADP-ribose) polymerase-1/2 inhibitors with potent anticancer chemopotentiating activity: Design,synthesis and biological evaluation |
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| Institution: | 1. Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 21009, China;2. Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 21009, China;3. Hefei YiGong Pharmaceutical Co. Ltd, Hefei 230088, China;1. Departamento de Química Orgánica, Universidad de Alcalá, Alcalá de Henares, Madrid 28871, Spain;2. CAI Cartografía Cerebral, Instituto Pluridisciplinar UCM, Paseo Juan XXIII, 1, Madrid 28040, Spain;3. Instituto Tecnológico PET, Calle Manuel Bartolomé Cossío 10, Madrid 28040, Spain;1. Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan;2. Computational Science Department, Science and Technology Systems Division, Ryoka Systems Inc., Tokyo Skytree East Tower, 1-1-2 Oshiage, Sumida-ku, Tokyo 131-0045, Japan;1. Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China;2. Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China;1. Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA;2. Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, 421 Curie Boulevard, Philadelphia, PA 19104, USA;1. Department of Chemistry, Tsinghua University, Beijing, 100084, PR China;2. The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen, 518055, PR China;3. Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing, 100084, PR China;4. National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The Graduate School at Shenzhen, Tsinghua University, Shenzhen, 518055, PR China |
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| Abstract: | 8,9-Dihydro-2,4,7,9a-tetraazabenzocd]azulen-6(7H)-ones were designed and synthesized as a new class of PARP-1/2 inhibitors. The compounds displayed a variable pattern of PARP-1/2 enzymes inhibition profile that, in part, paralleled the antiproliferative activity in cell lines. Among them, compound 9e exhibited not only the significant IC50 value of 28 nM in the PARP-1 and 7.7 nM in PARP-2 enzyme assay, but also a profound synergic efficacy combined with temozolomide with PF50 values of 2.6, 2.5, and 6.5 against MDA-MB-468, SW-620 and A549 and cell line, respectively. |
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| Keywords: | PARP-1/2 Inhibitors Tricyclic Anticancer |
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