Comparative studies of oxindolimine-metal complexes as inhibitors of human DNA topoisomerase IB

Autor(es)

Castelli, Silvia ^[1] ; Goncalves, Marcos Brown ^[2] ; Katkar, Prafulla ^[1] ; Stuchi, Gabriela Cristina ^[3] ; Alves Couto, Ricardo Alexandre ^[3] ; Petrilli, Helena Maria ^[4] ; da Costa Ferreira, Ana Maria ^[3]

Afiliação do(s) autor(es)

^[1] Univ Roma Tor Vergata, Dept Biol, Via Ric Sci, I-00133 Rome - Italy

^[2] Univ Tecnol Fed Parana, Dept Fis, BR-80230901 Curitiba, PR - Brazil

^[3] Univ Sao Paulo, Inst Quim, Dept Quim Fundamental, BR-05508000 Sao Paulo, SP - Brazil

^[4] Univ Sao Paulo, Inst Fis, Dept Fis Mat & Mecan, BR-05508090 Sao Paulo, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Journal of Inorganic Biochemistry; v. 186, p. 85-94, SEP 2018.
• Citações Web of Science: 3

Resumo

Copper(II) and zinc(II) complexes with oxindolimine ligands, obtained by a condensation reaction between isatin (1H-indole-2,3-dione) and 2-(2-aminoethyl)pyridine, have been previously shown to activate apoptosis very efficiently in different cancer cell lines. Here, we show that these compounds inhibit human DNA topoisomerase IB (Topo I) activity, and this characteristic may be implicated in its pro-apoptotic and potential antitumor properties. The studied metal complexes prevent DNA relaxation and cleavage reaction, whilst they do not have any effect on the religation process. The protein inhibition occurs in two different ways since the copper compound does not permit the enzyme-DNA complex formation, while the zinc analogue permits this complex formation but inhibits the catalytic cleavage reaction. Other related copper and zinc complexes, one with an asymmetric imine ligand derived from isatin, 1,3-diaminopropane, and salicyladehyde, and another one previously reported, derived from isatin and 1,3-diaminopropane, had their corresponding inhibition results towards Topo I compared. These data demonstrated that such complexes can act as good catalytic inhibitors of Topo I, in a process modulated by the ligand features and the nature of the metal ion. Computational studies complemented and supported experimental data, showing three different characteristics of the metal complexes that influence its interaction and consequent inhibition of Topo I. The ligand planarity when bound to the protein increases the occurring interactions in different binding sites, the total charge of the complex modulates the preferential region of interaction, and the copper(II) complexes are expected to be more efficient inhibitors compared to analogous zinc(II), as verified experimentally. (AU)

• Processo FAPESP: 11/50318-1 - Desenvolvimento de compostos com interesse farmacológico ou medicinal e de sistemas para seu transporte, detecção e reconhecimento no meio biológico
• Beneficiário: Ana Maria da Costa Ferreira
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 12/03080-2 - Estudos de interações entre complexos de cobre com atividade antitumoral e proteínas kinases e topoisomerases
• Beneficiário: Ana Maria da Costa Ferreira
• Modalidade de apoio: Auxílio à Pesquisa - Pesquisador Visitante - Internacional
• Processo FAPESP: 13/07937-8 - Redoxoma
• Beneficiário: Ohara Augusto
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs