Antitumor agents 7. Synthesis, antiproliferative activity and molecular modeling of new l-lysine-conjugated pyridophenoxazinones as potent DNA-binding ligands and topoisomerase IIα inhibitors
| Autor: | Antonio Lavecchia, Anna Cioce, Silvana Pedatella, Michele Manfra, Carmen Cerchia, A. Bolognese |
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| Přispěvatelé: | Pedatella, S., Cerchia, C., Manfra, M., Cioce, A., Bolognese, A., Lavecchia, A. |
| Rok vydání: | 2019 |
| Předmět: |
Models
Molecular Molecular model Carboxamide Antiproliferative activity Ligands 01 natural sciences Antineoplastic Agent chemistry.chemical_compound Drug Discovery Topoisomerase II Inhibitors 0303 health sciences Molecular Structure General Medicine DNA Neoplasm Docking studie Linear Model Human Base pair medicine.drug_class DNA damage Stereochemistry Oxazine Ligand Antineoplastic Agents 03 medical and health sciences Structure-Activity Relationship Cell Line Tumor Oxazines medicine Pyridophenoxazinone Humans 030304 developmental biology Cell Proliferation Pharmacology Binding Sites Dose-Response Relationship Drug 010405 organic chemistry Lysine Organic Chemistry Binding Site 0104 chemical sciences DNA Topoisomerases Type II chemistry Docking (molecular) Linear Models Neoplastic cell Topoisomerase-II Inhibitor Drug Screening Assays Antitumor DNA Topoisomerase II inhibitor |
| Zdroj: | European journal of medicinal chemistry. 187 |
| ISSN: | 1768-3254 |
| Popis: | A series of l -lysine-conjugated pyridophenoxazinones 2–5 and 2′-5′ were designed and synthesized for developing compounds with multimodal anticancer potentialities. All compounds inhibited the proliferation of a panel of human liquid and solid neoplastic cell lines. 2 and 5 were the most active compounds with IC50 values in the submicromolar range. UV–vis, 1H NMR, unwinding, and docking experiments demonstrated that they intercalate between the middle 5′-GC-3′ base pairs with the carboxamide side chain lying into major groove. Charge-transfer contribution to the complex stability, evaluated by ab initio calculations, was found to correlate with cytotoxicity. Relaxation and cleavage assays showed that 2 and 5 selectively target Topo IIα over Topo IIβ and stimulate the formation of covalent Topo II–DNA complexes, functioning as poisons. Moreover, compound 5 induced DNA damage and arrested MCF-7 cells at the G2/M phase. Altogether, the work provides interesting structure-activity relationships in the pyridophenoxazinone- l -lysine conjugate series and identifies 5 as a promising candidate for further in vivo evaluation. |
| Databáze: | OpenAIRE |
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