6533b838fe1ef96bd12a4737

RESEARCH PRODUCT

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

Marianna LauricellaGiuseppe DaidoneFabiana PlesciaAntonella D’anneoBenedetta MaggioDemetrio Raffa

subject

IndazolesStereochemistryAntineoplastic AgentsApoptosisTRAIL-receptorPyrazole01 natural sciencesBiochemistrychemistry.chemical_compoundDownregulation and upregulationCell Line Tumor2-(3-phenylpropanamido)benzamideDrug DiscoverymedicineHumansMoietyMolecular BiologyCell ProliferationBiological evaluationP53Indazole010405 organic chemistryDrug Discovery3003 Pharmaceutical Science2-cinnamamidobenzamideOrganic ChemistryApoptosi2-(2-phenoxyacetamido)benzamide0104 chemical sciences010404 medicinal & biomolecular chemistrymedicine.anatomical_structureProto-Oncogene Proteins c-bcl-2Mechanism of actionchemistryApoptosisBenzamidesPyrazolesDrug Screening Assays Antitumormedicine.symptomNucleus

description

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.

yearjournalcountryeditionlanguage
2019-03-01Bioorganic Chemistry
https://doi.org/10.1016/j.bioorg.2018.10.055