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

Author(s)

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]

Affiliation

^[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

• Document type: Journal article
• Source: DALTON TRANSACTIONS; v. 49, n. 45, p. 16440-16452, DEC 7 2020.
• Web of Science Citations: 0

Abstract

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)

• FAPESP's process: 18/18060-3 - Use of inorganic supramolecular structures for the development of functional molecules and controlled release of bioactive species
• Grantee: Sofia Nikolaou
• Support Opportunities: Regular Research Grants
• FAPESP's process: 14/25561-8 - Trinuclear ruthenium carboxylates with functional ligands CO, NO and intercalators: chemical study and interactions with biomolecules target
• Grantee: Camila Fontes Neves da Silva
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 17/15202-9 - Photochemical research and systematic in vitro study of the interaction mechanisms in novel trinuclear ruthenium complexes with DNA using different techniques
• Grantee: Camila Fontes Neves da Silva
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate