Anticancer and antitrypanosomal activities of trinuclear ruthenium compounds with orthometalated phenazine ligands

Autor(es)

Neves da Silva, Camila Fontes ^[1] ; Hauch Chrispim, Pedro Branco ^[1] ; Possato, Bruna ^[2] ; Portapilla, Gisele Bulhoes ^[2] ; Rohrabaugh, Jr., Thomas N. ^[3] ; Barbosa Ramos, Loyanne Carla ^[2] ; da Silva, Roberto Santana ^[2] ; de Albuquerque, Sergio ^[2] ; Turro, Claudia ^[3] ; Nikolaou, Sofia ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, LABIQSC2 Lab Atividade Biol & Quim Supramol Compo, Dept Quim, Fac Filosofia Ciencias & Letras Ribeirao Preto, Av Bandeirantes 3900, BR-14040901 Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Av Cafe S-N, BR-14040903 Ribeirao Preto, SP - Brazil

^[3] Ohio State Univ, Dept Chem & Biochem, Columbus, OH 43210 - USA

• Tipo de documento: Artigo Científico
• Fonte: DALTON TRANSACTIONS; v. 49, n. 45, p. 16440-16452, DEC 7 2020.
• Citações Web of Science: 0

Resumo

Trinuclear ruthenium complexes with orthometalated phenazines of general formula {[}Ru-3(mu(3)-O)(mu(2)-OAc)(5)(L)(py)(2)]PF6 (L = dppn, benzo{[}i]dipyrido{[}3,2-a:2 `,3 `-c]phenazine, 1; dppz, dipyrido{[}3,2-a:2 `,3 `-c]phenazine, 2; CH3-dppz, 7-methyldipyrido{[}3,2-a:2 `,3 `-c]phenazine, 3; Cl-dppz, 7-chlorodipyrido{[}3,2-a:2 `,3 `-c]phenazine, 4) were investigated for their cytotoxic activity toward the B16F10 murine melanoma and the L929 non-cancer cell lines and against Trypanosoma cruzi (2-4). This study also reports a multi-technique investigation into how complexes 1-4 interact with DNA and human serum albumin, HSA. At concentrations ranging from 2 to 50 mu M, all the complexes reduced B16F10 murine melanoma cell viability by over 50%. Complex 4 had the highest cytotoxic effect in the series, diminishing B16F10 cell viability to 38% at 2 mu M, with an overall order for anticancer activity of 4 > 2 > 3 > 1. Complexes 2-4 showed remarkable activity in inhibiting epimastigote and amastigote forms of T. cruzi. Complex 2 showed better antitrypanosomal activity than the reference drug (IC50 = 1.19 mu M and IC50 = 0.25 mu M for epimastigote and amastigotes forms, respectivily). Ethidium bromide (EB) displacement assays showed that DNA intercalation progressively increases with the extension of the pi-conjugation of the cyclometalating ligand and the presence of substituents in the phenazinic portion (1 > 4-3 > 2), showing that complex 1 is a stronger intercalator than EB itself (K-app > 10(7) M-1). Viscosity measurements followed the same trend. Cytotoxicity against cancer cells and antitrypanosomal activity follow the same order, which is different to the tendency of DNA intercalation, suggesting DNA is not the main target of these complexes. Compound 1-4 showed very high affinity with HSA (K-b similar to 10(9) M-1). Circular dichroism results also showed that the complexes alter significantly the secondary structure of the HSA, lowering the alpha-helix % from 86.2 (pure protein) to less than 5% for compounds 1, 2 and 4 at 2.8 mu M. These findings demonstrated the important role of phenazines for the biological activity of triruthenium compounds. (AU)

• Processo FAPESP: 18/18060-3 - Uso de estruturas supramoleculares inorgânicas com vistas ao desenvolvimento de moléculas funcionais e liberação controlada de espécies bioativas
• Beneficiário: Sofia Nikolaou
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 14/25561-8 - Carboxilatos trinucleares de rutênio com ligantes funcionais CO, NO e intercaladores: estudo químico e de interações com biomoléculas alvo
• Beneficiário: Camila Fontes Neves da Silva
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 17/15202-9 - Pesquisa fotoquímica e estudo sistemático in vitro dos mecanismos de interação em novos complexos trinucleares de rutênio com DNA usando diferentes técnicas
• Beneficiário: Camila Fontes Neves da Silva
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado