Novel 4-(3-phenylpropionamido), 4-(2-phenoxyacetamido) and 4-(cinnamamido) substituted benzamides bearing the pyrazole or indazole nucleus: synthesis,biological evaluation and mechanism of action |
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| Institution: | 1. University of Palermo, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), Medicinal Chemistry and Pharmaceutical Technologies, Via Archirafi 32, 90123 Palermo, Italy;2. University of Palermo, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), Laboratory of Biochemistry, Via del Vespro 129, 90127 Palermo, Italy;3. University of Palermo, Department of Experimental Biomedicine and Clinical Neurosciences, Laboratory of Biochemistry, Via del Vespro 129, 90127 Palermo, Italy;1. Research and Development Centre, Bharathiar University, Coimbatore 641046, India;2. Department of Biotechnology, School of Bio-Sciences and Technology, VIT University, Vellore 632014, India;3. PG & Research Department of Chemistry, Government Arts College, Coimbatore 641018, Tamil Nadu, India;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, ‘Carol Davila’ University of Medicine and Pharmacy, Traian Vuia 6, Bucharest 020956, Romania;2. C.D. Nenitzescu Institute of Organic Chemistry, 202B Spl. Independentei, Bucharest 060023, Romania;3. Stefan S Nicolau Institute of Virology, 285 Mihai Bravu Avenue, Bucharest 030304, Romania;1. Breast Centres Certification and Senonetwork Italia Onlus, Italy;2. EUSOMA – European Society of Breast Cancer Specialists, Italy;3. Health Writer and Editor, London, United Kingdom;4. European School of Oncology, Milan, Italy;5. Europa Donna – The European Breast Cancer Coalition, Milan, Italy;6. Department of Surgery, Netherlands Cancer Institute, Amsterdam, The Netherlands;7. Breast Unit, Champalimaud Clinical Center, Lisbon, Portugal;1. Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 Culture West Road, Jinan 250012, PR China;2. Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA |
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| Abstract: | Based on some common structural features of known compounds interfering with p53 pathways and our previously synthesized benzamides, we synthesized new ethyl 5-(4-substituted benzamido)-1-phenyl-1H-pyrazole-4-carboxylates 26a-c, ethyl 5-(4-substituted benzamido)-1-(pyridin-2-yl)-1H-pyrazole-4-carboxylates 27a-c and N-(1H-indazol-6-yl)-4-substituted benzamides 31a,b bearing in the 4 position of the benzamido moiety the 2-phenylpropanamido or 2-phenoxyacetamido or cinnamamido groups. A preliminary test to evaluate the antiproliferative activity against human lung carcinoma H292 cells highlighted how compound 26c showed the best activity. This last was therefore selected for further studies with the aim to find the mechanism of action. Compound 26c induces intrinsic apoptotic pathway by activating p53 and is also able to activate TRAIL-inducing death pathway by promoting increase of DR4 and DR5 death receptors, downregulation of c-FLIPL and caspase-8 activation. |
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| Keywords: | 2-(3-phenylpropanamido)benzamides 2-(2-phenoxyacetamido)benzamides 2-cinnamamidobenzamides P53 TRAIL-receptors Apoptosis |
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