Ru(II)-Fenamic-Based Complexes as Promising Human Ovarian Antitumor Agents: DNA Interaction, Cellular Uptake, and Three-Dimensional Spheroid Models

Author(s):Show less -

Teixeira, Tamara ; Palmeira-Mello, Marcos V. ; Machado, Pedro Henrique ; Moraes, Carlos A. F. ; Pinto, Camila ; Costa, Rayane C. ; Badaro, Wladimir ; Gomes Neto, Jose A. ; Ellena, Javier ; Vieira Rocha, Fillipe ; Batista, Alzir A. ; Correa, Rodrigo S.

• Document type: Journal article
• Source: Inorganic Chemistry; v. N/A, p. 12-pg., 2025-02-18.

Abstract

Cancer resistance to chemotherapeutic agents such as cisplatin presents a significant challenge, leading to treatment failure and poor outcomes. Novel metal-based compounds offer a promising strategy to overcome drug resistance and to enhance efficacy. Four Ru(II) complexes with fenamic acid derivatives were synthesized and characterized: [Ru(L)(bipy)(dppp)]PF6, where L represents fenamic acid (HFen, complex 1), mefenamic acid (HMFen, complex 2), tolfenamic acid (HTFen, complex 3), and flufenamic acid (HFFen, complex 4). Their composition was supported by molar conductivity, elemental analysis, Fourier transform infrared spectroscopy, ultraviolet-visible spectroscopy, mass spectrometry, and 31P{1H}, 1H, and 13C nuclear magnetic resonance, with the crystal structure of complex 1 confirmed via X-ray diffraction. Complexes 1-4 exhibited notable cytotoxicity against tested cell lines, particularly A2780 and A2780cisR (cisplatin-resistant ovarian tumors), compared to MDA-MB-231 (breast) and A549 (lung) lines. Mechanistic studies revealed weak DNA interactions through minor grooves or electrostatic binding. Cellular uptake assays showed effective internalization of complexes 1 (3.6%) and 2 (4.5%), correlating with potent IC50 values. These complexes also altered cell morphology, reduced cell density, and inhibited colony formation in the A2780 cells. Staining assays indicated induced cell death and organelle damage, highlighting their potential as promising antitumor agents. (AU)

• FAPESP's process: 24/02879-4 - Development of new applications in inorganic spectroscopic analysis
• Grantee: José Anchieta Gomes Neto
• Support Opportunities: Regular Research Grants
• FAPESP's process: 21/01787-0 - In vitro and in vivo study of Ru(II)/phosphine complexes with anticancer activities
• Grantee: Marcos Vinícius Palmeira de Mello
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 22/14041-0 - Design and antitumor studies on metal-based-complexes against metastatic and/or chemoresistant cells
• Grantee: Adelino Vieira de Godoy Netto
• Support Opportunities: Regular Research Grants
• FAPESP's process: 23/02475-8 - Phosphine Ru(II) complexes with naphthoquinones and derivatives: potential anticancer, estudies in vitro and in vivo
• Grantee: Alzir Azevedo Batista
• Support Opportunities: Regular Research Grants