Development of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates containing piperazine as inhibitors of PI3Kα |
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| Institution: | 1. Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People’s Republic of China;2. State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People’s Republic of China;3. School of Chemistry & Environmental Engineering, Jiangsu University of Technology, 1801 Zhongwu Rd., Changzhou, Jiangsu 213001, People’s Republic of China;4. Polymers and Composites Division, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, 1219 Zhongguan West Rd, Zhenhai District, Ningbo 315201, People’s Republic of China;1. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo 11566, Egypt;2. Pharmaceutical Chemistry Department, College of Pharmacy, Al-Ayen University, Ti-Qar, Iraq;3. Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, Menoufia, Egypt;1. State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China;2. Polymers and Composites Division, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Zhongguan West Road 1219, Zhenhai District, Ningbo 315201, China;1. Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia;2. Atta-ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA (UiTM), Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor D. E., Malaysia;3. Faculty of Pharmacy, Universiti Tecknologi MARA Puncak Alam, 42300 Bandar Puncak Alam, Selangor D. E., Malaysia;4. Faculty of Applied Science UiTM, 40450 Shah Alam, Selangor, Malaysia;5. Department of Chemistry, Hazara University, Mansehra 21300, Pakistan;6. H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan;1. School of Chemistry, College of Science, University of Tehran, Tehran, Iran;2. Department of Chemistry, Tarbiat Modares University, P.O. Box 14115‐175, Tehran, Iran;3. Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran |
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| Abstract: | PI3K pathway has been heavily studied and is one of the most potential targets for various cancer treatment. Herein, we designed and synthesized a series of novel chromeno4,3-c]pyrazol-4(2H)-one derivates contained piperazine based on our previous research. They were evaluated for their PI3Kα wild-type and H1047R mutant inhibitory activities and anticancer effects in vitro. Most of these compounds displayed the potential antiproliferative activities against four cancer cell lines (HCT-116, A549, Huh7 and HL60). Among them, Compound 4p revealed the remarkable antiproliferative activity and was selected for further biological evaluation. Compound 4p displayed the potent activity against both PI3Kα wild-type and H1047R mutant, and a certain degree of selectivity for PI3Kα over PI3Kβ, γ and δ, and meanwhile it can remarkable down-regulate the phosphorylation of Akt. In addition, compound 4p was found to induce cell apoptosis via upregulation of Bax and cleaved-caspase 3/9, and downregulation of Bcl-2. The above results suggested that compound 4p could be considered as a promising PI3Kα inhibitor. |
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| Keywords: | Selectivity Antitumor PI3Kα |
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