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  3. Antitumor agents 7. Synthesis, antiproliferative activity and molecular modeling of new l-lysine-conjugated pyridophenoxazinones as potent DNA-binding ligands and topoisomerase IIα inhibitors

Antitumor agents 7. Synthesis, antiproliferative activity and molecular modeling of new l-lysine-conjugated pyridophenoxazinones as potent DNA-binding ligands and topoisomerase IIα inhibitors

  • Eur J Med Chem. 2020 Feb 1;187:111960. doi: 10.1016/j.ejmech.2019.111960.
Silvana Pedatella 1,  Carmen Cerchia 2,  Michele Manfra 3,  Anna Cioce 4,  Adele Bolognese 1,  Antonio Lavecchia 5
Affiliations

Affiliations

  • 1 Department of Chemical Sciences, University of Naples Federico II, via Cynthia 6, Monte Sant'Angelo, 80126, Naples, Italy.
  • 2 Department of Pharmacy, "Drug Discovery" Laboratory, University of Naples Federico II, via D. Montesano 49, 80131, Naples, Italy.
  • 3 Department of Science, University of Basilicata, viale dell'Ateneo Lucano 10, 85100, Potenza, Italy. Electronic address: michele.manfra@unibas.it.
  • 4 Department of Glycotechnology, CIC biomaGUNE, Paseo Miramón 182, 20009, San Sebastián, Spain.
  • 5 Department of Pharmacy, "Drug Discovery" Laboratory, University of Naples Federico II, via D. Montesano 49, 80131, Naples, Italy. Electronic address: antonio.lavecchia@unina.it.
PMID: 31869654 DOI: 10.1016/j.ejmech.2019.111960
Abstract

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.

Keywords

Antiproliferative activity; DNA damage; Docking studies; Pyridophenoxazinones; Topoisomerase II inhibitors.

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