Synthesis, antiproliferative and apoptosis induction potential activities of novel bis(indolyl)hydrazide-hydrazone derivatives
| Autor: | Rudraraju Ramesh Raju, Kotthireddy Thirumal Reddy, C. Ganesh Kumar, Reddymasu Sreenivasulu, Pombala Sujitha |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
MAPK/ERK pathway
Indoles MAP Kinase Signaling System p38 mitogen-activated protein kinases Clinical Biochemistry Pharmaceutical Science Antineoplastic Agents Apoptosis 01 natural sciences Biochemistry HeLa Cell Line Tumor Neoplasms Drug Discovery Humans Protein kinase A Molecular Biology Cell Proliferation biology 010405 organic chemistry Cell growth Kinase Chemistry Organic Chemistry Hydrazones biology.organism_classification 0104 chemical sciences Cell biology 010404 medicinal & biomolecular chemistry HEK293 Cells Mitogen-activated protein kinase biology.protein Molecular Medicine Signal transduction Reactive Oxygen Species |
| Zdroj: | Bioorganic & Medicinal Chemistry. 27:1043-1055 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2019.02.002 |
| Popis: | In recent years, indole-indazolyl hydrazide-hydrazone derivatives with strong cell growth inhibition and apoptosis induction characteristics are being strongly screened for their cancer chemo-preventive potential. In the present study, N-methyl and N,N-dimethyl bis(indolyl)hydrazide-hydrazone analog derivatives were designed, synthesized and allowed to evaluate for their anti-proliferative and apoptosis induction potential against cervical (HeLa), breast (MCF-7 and MDA-MB-231) and lung (A549) cancer cell lines relative to normal HEK293 cells. The MTT assay in conjunction with mitochondrial potential assays and the trypan blue dye exclusion were employed to ascertain the effects of the derivatives on the cancer cells. Further, mechanistic studies were conducted on compound 14a to understand the biochemical mechanisms and functional interactions with various signaling pathways triggered in HeLa and MCF-7 cells. Compound 14a induced apoptosis via caspase independent pathway through the participation of mitogen-activated protein kinases (MAPK) such as extracellular signal related kinase (ERK) and p38 as well as p53 pathways. It originates the activation of pro-apoptotic proteins such as Bak and Mcl-1s and also strongly induced the generation of reactive oxygen species. In downstream signaling pathway, activated p53 protein interacted with MAPK pathways, including SAPK/c-Jun N-terminal protein kinase (JNK), p38 and ERK kinases resulting in apoptotic cell death. The involvement of MAPK cascades such as p38, ERK and p38 on compound 14a induced apoptotic cell death was evidenced by the fact that the inclusion of specific inhibitors of p38, ERK1/2 and JNK MAPK (SB2035809, PD98059 and SP600125) prevented the compound 14a towards induced apoptosis. The results clearly showed that MAP kinase cascades were crucial for apoptotic response in compound 14a induced cellular killing and were dependent on p53 activity. Based on the results, compound 14a was identified as a promising candidate for cancer therapeutics and these findings furnish a basis for further in vivo experiments on anti-proliferative activity. |
| Databáze: | OpenAIRE |
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