Synthesis of pyrazolo[4,3-a]phenanthridines,a new scaffold for Pim kinase inhibition |
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| Affiliation: | 1. Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA;2. Department of Oncology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA;3. Department of Molecular Structure and Characterization, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA;4. Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Abbassia, 11566 Cairo, Egypt;2. Department of Chemistry, Faculty of Science, Ain Shams University, Abbassia, 11566 Cairo, Egypt;1. Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA;2. Department of Oncology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA;3. Department of Molecular Structure and Characterization, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA;1. EA GICC - ERL 7001 CNRS « Groupe Innovation et Ciblage Cellulaire », Team Innovation Moléculaire et Thérapeutique, University of Tours, F-37200, Tours, France;2. CNRS ERL7001 LNOx « Leukemic Niche and RedOx Metabolism » - EA GICC, University of Tours, F-37000, Tours, France;3. CHRU de Tours, Service d’Hématologie Biologique, F-37044, Tours, France;4. Université de Nantes, Nantes Atlantique Universités, Département de Chimie Thérapeutique, Cibles et Médicaments des Infections et du Cancer, IICIMED- EA1155, Institut de Recherche en Santé 2, F-44200, Nantes, France;5. UMR University of Orléans-CNRS 7311, Institut de Chimie Organique et Analytique (ICOA), University of Orléans, F-45067, Orléans, France;6. Sorbonne Universités, USR3151 CNRS/UPMC, Plateforme de criblage KISSf (Kinase Inhibitor Specialized Screening Facility), Station Biologique, Place Georges Teissier, F-29688, Roscoff, France;7. UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, University of Lille, Inserm, CHU Lille, F-59000, Lille, France;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy & Drug Manufacturing, Pharos University in Alexandria, Alexandria, Egypt;3. Medical Biotechnology Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Egypt |
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| Abstract: | A new series of nitro or amino substituted pyrazolo[4,3-a]phenanthridines was synthesized in 6 steps from 5-bromo-6-nitroindazole. The evaluation of their inhibitory potency toward Pim kinases demonstrated that the nitro series could be considered as an interesting starting point for the development of new Pim kinase inhibitors, especially Pim-3. A preferential binding mode was suggested by molecular modeling experiments for nitro series and Pim-1/Pim-3 ATP-binding sites. Moreover, the most active compounds exhibited antiproliferative activities toward PC3 cells in the micromolar range. |
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| Keywords: | Kinase inhibitors Pim kinases In vitro antiproliferative activities |
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