Structural modifications of indolinones bearing a pyrrole moiety and discovery of a multi-kinase inhibitor with potent antitumor activity |
| |
| Institution: | 1. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China;2. School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, PR China;3. Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, PR China;4. Chinese People’s Liberation Army Logistics Support Force No. 967 Hospital, Dalian 116021, PR China;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, 11795 Helwan, Cairo, Egypt;2. Department of Chemistry, Faculty of Science, King Khalid University, 9004 Abha, Saudi Arabia;3. Department of Chemistry, Faculty of Science, Mansoura University, ET-35516 Mansoura, Egypt;4. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafr El-Sheikh 33516, Egypt;5. Drug Bioassay-Cell Culture Laboratory, Pharmacognosy Department, National Research Centre, Dokki, Giza 12622, Egypt;6. Labeled Compounds Department, Hot Labs Center, Atomic Energy Authority, P.O. Box 13759, Cairo, Egypt;7. Department of Microbiology and Immunology, Faculty of Pharmacy, Ahram Canadian University, 12451, Sixth of October City, Giza, Egypt;8. Radioactive Isotopes and Generators Department, Hot Laboratories Centre, Atomic Energy Authority, P.O. Code 13759 Cairo, Egypt;1. Department of Chemistry and Biochemistry, The City College of New York, City University of New York and CUNY Institute for Macromolecular Assemblies, New York, NY 10031, USA;2. Department of Chemistry, Hunter College of CUNY, New York, NY 10065, USA;3. Ph.D. Program in Chemistry, The Graduate Center of the City University of New York (CUNY), New York, NY 10016, USA;4. Ph.D. Program in Biochemistry, The Graduate Center of the City University of New York (CUNY), New York, NY 10016, USA;1. Jagiellonian University Medical College, Faculty of Pharmacy, Department of Medicinal Chemistry, 9 Medyczna Street, 30-688, Kraków, Poland;2. Polish Academy of Sciences, Maj Institute of Pharmacology, Department of Medicinal Chemistry, 12 Sm?tna Street, 31-343, Kraków, Poland;3. Jagiellonian University Medical College, Faculty of Pharmacy, Department of Pharmacobiology, 9 Medyczna Street, 30-688, Kraków, Poland;4. Jagiellonian University Medical College, Faculty of Pharmacy, Department of Pharmacokinetics and Physical Pharmacy, 9 Medyczna Street, 30-688, Kraków, Poland;5. Jagiellonian University Medical College, Faculty of Pharmacy, Department of Clinical Pharmacy, 9 Medyczna Street, 30-688, Kraków, Poland;6. Jagiellonian University Medical College, Faculty of Pharmacy, Department of Technology and Biotechnology of Drugs, Medyczna 9, 30-688, Kraków, Poland;1. Department of Medicine and Division of Endocrinology, Stanford University, Stanford, CA 94305, USA;2. Stanford ChEM-H, Stanford University, Stanford, CA 94305, USA;3. Department of Chemistry, Stanford University, Stanford, CA 94305, USA;4. Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA;5. Stanford Diabetes Research Center, Stanford University, Stanford, CA 94305, USA;1. Department of Chemistry, Centre for Advanced Studies, Guru Nanak Dev University, Amritsar 143005, India;2. Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar 143005, India |
| |
| Abstract: | Structural modifications of compound 2, an angiokinase inhibitor reported by our group were performed, which led to the discovery of methyl (Z)-3-(((4-(2-methyl-5-((4-methylpiperazin-1-yl)methyl)-1H-pyrrol-1-yl)phenyl)amino)(phenyl)methylene)-2-oxoindoline-6-carboxylate (7h). Compound 7h exhibited excellent inhibitory activity against angiokinases including VEGFR-1/2/3, PDGFRα/β, and FGFR-1, as well as LYN and c-KIT kinases. At the cellular level, compound 7h significantly attenuated phosphorylation of AKT and ERK proteins, potently inhibited colony formation of HT-29, MKN74, and HepG2 cancer cells, and induced cell apoptosis. Upon incubation with human liver microsome, 7h exhibited comparable metabolic stability to nintedanib. Compound 7h has emerged as a promising lead compound for future drug design. |
| |
| Keywords: | Structural modification Multi-kinase inhibitor Antitumor activity |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
