Design, synthesis, biological evaluation, structure-activity relationship study, and mode of action of 2-phenol-4,6-dichlorophenyl-pyridines
| Autor: | Eung-Seok Lee, Ganesh Bist, Seojeong Park, Pramila Katila, Tara Man Kadayat, Youngjoo Kwon, Aarajana Shrestha, Somin Shin |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Pyridines medicine.drug_class DNA damage Antineoplastic Agents Apoptosis Biochemistry Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Phenols Cell Line Tumor Drug Discovery medicine Humans Topoisomerase II Inhibitors Structure–activity relationship Poly-ADP-Ribose Binding Proteins Mode of action Molecular Biology Etoposide chemistry.chemical_classification Molecular Structure biology Chemistry Topoisomerase Organic Chemistry G1 Phase Cell Cycle Checkpoints DNA Topoisomerases Type II 030104 developmental biology Enzyme Drug Design 030220 oncology & carcinogenesis biology.protein Drug Screening Assays Antitumor Topoisomerase inhibitor DNA DNA Damage medicine.drug |
| Zdroj: | Bioorganic Chemistry. 79:1-18 |
| ISSN: | 0045-2068 |
| Popis: | Human DNA topoisomerases (Topos) are essential nuclear enzyme whose level of expression is potential indicator for prediction of responsive result of chemotherapy. Topos has become a key cellular target for most of the anticancer agents that regulates topological problems of DNA during cellular metabolic processes such as replication, transcription, and recombination. Inspired by previous studies of 2,4,6-trisubstituted pyridines to find out safer and effective topoisomerase targeted anticancer agent, twenty-seven 2-phenol-4,6-dichlorophenyl-pyridines were designed, synthesized, and tested for their topo I and IIα inhibitory and anti-proliferative activity. Most of the dichlorinated meta- and para-phenolic series compounds (1-18) exhibited potent and selective topo IIα inhibition along with significant anti-proliferative activity in the HCT-15 and T47D cell lines compared to the positive control, etoposide. Interestingly, dichlorinated ortho-phenolic series compounds (19-27) exhibited potent and dual topo inhibition but very weak anti-proliferative activity in the tested cancer cell lines. Structure-activity relationship with previously synthesized compounds revealed the importance of chlorine moiety to improve the potency of topo inhibitory activity. Further mechanistic study confirmed that compounds 2 and 12 acted as non-intercalative specific topo IIα catalytic inhibitor with less DNA damage, and induced G1 arrest and apoptosis in HCT-15 and T47D cell lines, respectively. |
| Databáze: | OpenAIRE |
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