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Optimization of gefitinib analogues with potent anticancer activity
Affiliation:1. Department of Chemistry, National Dong Hwa University, Soufeng, Hualien 974, Taiwan;2. Department of Biological Science and Technology, National Chiao Tung University, Hsinchu 30068, Taiwan;1. School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China;2. Key Laboratory of Jiangxi Province Natural Active Pharmaceutical Ingredients, College of Chemistry and Biology Engineering, Yichun University, Yichun 336000, PR China;1. Atomic and Molecular Physics Division, Bhabha Atomic Research Centre, Mumbai 400 085, India;2. Homi Bhabha National Institute, Bhabha Atomic Research Centre, Mumbai 400 085, India;1. Depatment of Respirology, National Hospital Organization, Tokyo National Hospital, Kiyose, Tokyo, Japan;2. Division of Respiratory Medicine and Allergology, Showa University School of Medicine, Kiyose, Tokyo, Japan;3. Institute of Molecular Oncology, Showa University, Kiyose, Tokyo, Japan;4. Division of Medical Oncology, Showa University School of Medicine, Shinagawa, Tokyo, Japan;1. Institute of Chemical Research of Catalonia, Barcelona Institute of Science & Technology, Av. Països Catalans 16, 43007 Tarragona, Spain;2. Catalan Institute of Research and Advanced Studies, Pg. Lluis Companys 23, 08010 Barcelona, Spain;1. Center of Drug Discovery, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing 210009, PR China;2. Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China;3. Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing 210023, PR China;1. Department of Biotechnology, Indian Institute of Technology Madras, Chennai, India;2. School of Bioscience and Bioengineering, Indian Institute of Technology Bombay, Mumbai, India;3. Institute of Cardiovascular Diseases, Madras Medical Mission, Chennai, India
Abstract:The interactions of gefitinib (Iressa) in EGFR are hydrogen bonding and van der Waals forces through quinazoline and aniline rings. However the morpholino group of gefitinib is poorly ordered due to its weak electron density. A series of novel piperazino analogues of gefitinib where morpholino group substituted with various piperazino groups were designed and synthesized. Most of them indicated significant anti-cancer activities against human cancer cell lines. In particular, compounds 5254 showed excellent potency against cancer cells. Convergent synthetic approach has been developed for the synthesis of gefitinib intermediate which can lead to gefitinib as well as numerous analogues.
Keywords:Gefitinib  Iressa  Anti-cancer  A549  EGFR
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