Novel 2-aryl-4-(4′-hydroxyphenyl)-5H-indeno[1,2-b]pyridines as potent DNA non-intercalative topoisomerase catalytic inhibitors
| Autor: | Tara Man Kadayat, Eung-Seok Lee, Ganesh Bist, Aarajana Shrestha, Youngjoo Kwon, Til Bahadur Thapa Magar, Kyu Yeon Jun, Seojeong Park |
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| Rok vydání: | 2017 |
| Předmět: |
Pyridines
Stereochemistry Antineoplastic Agents 01 natural sciences HeLa Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine DU145 Antigens Neoplasm Cell Line Tumor Drug Discovery medicine Humans Topoisomerase II Inhibitors Moiety Etoposide Cell Proliferation Pharmacology biology 010405 organic chemistry Aryl Topoisomerase Organic Chemistry DNA General Medicine biology.organism_classification 0104 chemical sciences DNA-Binding Proteins Molecular Docking Simulation DNA Topoisomerases Type II chemistry Mechanism of action 030220 oncology & carcinogenesis biology.protein medicine.symptom medicine.drug |
| Zdroj: | European Journal of Medicinal Chemistry. 125:14-28 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2016.09.019 |
| Popis: | On the basis of previous reports on the importance of thienyl, furyl or phenol group substitution on 5H-indeno[1,2-b]pyridine skeleton, a new series of rigid 2-aryl-4-(4′-hydroxyphenyl)-5H-indeno[1,2-b]pyridine derivatives were systematically designed and synthesized. Topoisomerase inhibitory activity and antiproliferative activity of all the synthesized compounds were determined using human colorectal (HCT15), breast (T47D), prostate (DU145) and cervix (HeLa) cancer cells. Compounds 9, 10, 12, 13, 15, 16, 18 and 19 with thienyl or furyl moiety at the 2-position and hydroxyl group at the meta or para positions of 4-phenyl ring displayed strong to moderate topoisomerase IIα (topo IIα) inhibitory activity and significant antiproliferative activity. The evaluation of compound 16 to determine its mechanism of action was performed with topo IIα-DNA cleavable complex, topo IIα-mediated ATPase assay, DNA unwinding and in vitro and ex vivo topo IIα relaxation assay. Compound 16 functioned as a DNA non-intercalative topo IIα catalytic inhibitor with better potency than etoposide in T47D breast cancer cells. Molecular docking study revealed that compound 16 cannot intercalate into regularly stacked base-pairs of DNA duplex but can interact or intercalate to topo IIα-bound DNA. |
| Databáze: | OpenAIRE |
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