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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
- Source :
- Bioorganic Chemistry. 83:367-379
- Publication Year :
- 2019
- Publisher :
- Elsevier BV, 2019.
-
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.
- 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
Subjects
Details
- ISSN :
- 00452068
- Volume :
- 83
- Database :
- OpenAIRE
- Journal :
- Bioorganic Chemistry
- Accession number :
- edsair.doi.dedup.....5cf186f4f519a419ee5524916e15ea6f