Ruthenium(II) Diphosphine Complexes with Mercapto Ligands That Inhibit Topoisomerase IB and Suppress Tumor Growth In Vivo

Author(s):Show less -

da Silva, Monize M. ^[1] ; Ribeiro, Gabriel H. ^[1] ; de Camargo, Mariana S. ^[1] ; Ferreira, Antonio G. ^[1] ; Ribeiro, Leandro ^[1] ; Barbosa, Marilia I. F. ^[1] ; Deflon, Victor M. ^[2] ; Castelli, Silvia ^[3] ; Desideri, Alessandro ^[3] ; Correa, Rodrigo S. ^[4] ; Ribeiro, Arthur B. ^[5] ; Nicolella, Heloiza D. ^[5] ; Ozelin, Saulo D. ^[5] ; Tavares, Denise C. ^[5] ; Batista, Alzir A. ^[1]

Affiliation

^[1] Univ Fed Sao Carlos, Dept Quim, BR-13565905 Sao Carlos, SP - Brazil

^[2] Univ Sao Paulo, Inst Quim Sao Carlos, BR-13565905 Sao Carlos, SP - Brazil

^[3] Univ Tor Vergata Roma, Dipartimento Biol, I-00133 Rome - Italy

^[4] Univ Fed Ouro Preto, Dept Quim, BR-35400000 Ouro Preto, MG - Brazil

^[5] Univ Franca, BR-14404600 Sao Paulo - Brazil

• Document type: Journal article
• Source: Inorganic Chemistry; v. 60, n. 18, p. 14174-14189, SEP 20 2021.
• Web of Science Citations: 0

Abstract

Ruthenium(II) complexes (Ru1-Ru5), with the general formula {[}Ru(N-S)(dppe)(2)]PF6, bearing two 1,2-bis(diphenylphosphino)ethane (dppe) ligands and a series of mercapto ligands (N-S), have been developed. The combination of these ligands in the complexes endowed hydrophobic species with high cytotoxic activity against five cancer cell lines. For the A549 (lung) and MDA-MB-231 (breast) cancer cell lines, the IC50 values of the complexes were 288- to 14-fold lower when compared to cisplatin. Furthermore, the complexes were selective for the A549 and MDA-MB-231 cancer cell lines compared to the MRC-5 nontumor cell line. The multitarget character of the complexes was investigated by using calf thymus DNA (CT DNA), human serum albumin, and human topoisomerase IB (hTopIB). The complexes potently inhibited hTopIB. In particular, complex {[}Ru(dmp)(dppe)(2)]PF6 (Ru3), bearing the 4,6-diamino-2-mercaptopyrimidine (dmp) ligand, effectively inhibited hTopIB by acting on both the cleavage and religation steps of the catalytic cycle of this enzyme. Molecular docking showed that the Ru1-Ru5 complexes have binding affinity by active sites on the hTopI and hTopI-DNA, mainly via pi-alkyl and alkyl hydrophobic interactions, as well as through hydrogen bonds. Complex Ru3 displayed significant antitumor activity against murine melanoma in mouse xenograph models, but this complex did not damage DNA, as revealed by Ames and micronucleus tests. (AU)

• FAPESP's process: 18/19342-2 - Metal complexes with dirivative ligands of lawsone and acylthioureas, with anticancer potential activities: study in vitro and in vivo.
• Grantee: Alzir Azevedo Batista
• Support Opportunities: Regular Research Grants