A series of L-lysine-conjugated pyridophenoxazinones 2e5 and 2′-5′ were designed and synthesized fordeveloping 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. UVevis, 1H NMR, unwinding, and docking experiments demonstrated that they intercalate between the middle 50-GC-30 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 IIa over Topo IIb and stimulate the formation of covalent Topo IIeDNA 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.
Antitumor agents 7. Synthesis, antiproliferative activity and molecular modeling of new L-lysine-conjugated pyridophenoxazinones as potent DNA-binding ligands and topoisomerase IIa inhibitors
Michele Manfra
;
2020-01-01
Abstract
A series of L-lysine-conjugated pyridophenoxazinones 2e5 and 2′-5′ were designed and synthesized fordeveloping 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. UVevis, 1H NMR, unwinding, and docking experiments demonstrated that they intercalate between the middle 50-GC-30 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 IIa over Topo IIb and stimulate the formation of covalent Topo IIeDNA 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.File | Dimensione | Formato | |
---|---|---|---|
2020)ejmedchem.pdf
accesso aperto
Tipologia:
Documento in Post-print
Licenza:
Dominio pubblico
Dimensione
2.83 MB
Formato
Adobe PDF
|
2.83 MB | Adobe PDF | Visualizza/Apri |
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.