1. 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
- Author
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Marianna Lauricella, Giuseppe Daidone, Fabiana Plescia, Antonella D'Anneo, Benedetta Maggio, Demetrio Raffa, Raffa, Demetrio, D'Anneo, Antonella, Plescia, Fabiana, Daidone, Giuseppe, Lauricella, Marianna, and Maggio, Benedetta
- Subjects
Indazoles ,Stereochemistry ,Antineoplastic Agents ,Apoptosis ,TRAIL-receptor ,Pyrazole ,01 natural sciences ,Biochemistry ,chemistry.chemical_compound ,Downregulation and upregulation ,Cell Line, Tumor ,2-(3-phenylpropanamido)benzamide ,Drug Discovery ,medicine ,Humans ,Moiety ,Molecular Biology ,Cell Proliferation ,Biological evaluation ,P53 ,Indazole ,010405 organic chemistry ,Drug Discovery3003 Pharmaceutical Science ,2-cinnamamidobenzamide ,Organic Chemistry ,Apoptosi ,2-(2-phenoxyacetamido)benzamide ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,medicine.anatomical_structure ,Proto-Oncogene Proteins c-bcl-2 ,Mechanism of action ,chemistry ,Benzamides ,Pyrazoles ,Drug Screening Assays, Antitumor ,medicine.symptom ,Nucleus - 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.
- Published
- 2019