A new copper(II) complex containing long-chain aliphatic hydrazide and 1,10-phenanthroline upregulates ADP hydrolysis in triple-negative breast cancer cells

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Ferreira, Helen Soares Valenca ; Ramos, Luana Munique Sousa ; Silva, Fernanda Cardoso ; Alves, Daniel Lima ; Pereira, Gabriele de Menezes ; Santiago, Pedro Henrique de Oliveira ; de Almeida, Angelina Maria ; Ellena, Javier ; Corbi, Pedro Paulo ; Oliveira, Carolina Goncalves ; de Almeida, Mauro Vieira ; Furstenau, Cristina Ribas ; Borges, Dayanne Silva ; Siqueira, Raoni Pais ; Guerra, Wendell ; Araujo, Thaise Goncalves

• Document type: Journal article
• Source: Journal of Inorganic Biochemistry; v. 255, p. 10-pg., 2024-03-19.

Abstract

Copper can be opportunely complexed to modulate oncogenic pathways, being a promising strategy for cancer treatment. Herein, three new copper(II) complexes containing long -chain aliphatic hydrazides and 1,10-phenanthroline (1,10-phen), namely, [Cu(octh)(1,10-phen)(H2O)](NO3)2 1, [Cu(dech)(1,10-phen)(H2O)](NO3)2 2 and [Cu(dodh)(1,10-phen)(H2O)](NO3)2.H2O 3 (where octh = octanoic hydrazide, dech = decanoic hydrazide, dodh = dodecanoic hydrazide) were successfully prepared and characterized by several physical -chemical methods. Furthermore, X-ray structural analysis of complex 2 indicated that the geometry around the copper(II) ion is distorted square -pyramidal, in which hydrazide and 1,10-phenanthroline act as bidentate ligands. A water molecule in the apical position completes the coordination sphere of the metal ion. All new copper(II) complexes were cytotoxic to breast cancer cell lines (MCF7, MDA-MB-453, MDA-MB-231, and MDA-MB-157) and selective when compared to the non tumor lineage MCF-10A. In particular, complex 2 showed half -maximal inhibitory concentration (IC50) values ranging between 2.7 and 13.4 mu M in MDA-MB231 cells after 24 and 48 h of treatment, respectively. Furthermore, this complex proved to be more selective for tumor cell lines when compared to doxorubicin and docetaxel. Complex 2 inhibited the clonogenicity of MDA-MB231 cells, increasing adenosine diphosphate (ADP) hydrolysis and upregulating ecto-nucleoside triphosphate diphosphohydrolase 1 (ENTPD1) transcriptional levels. In this sense, we suggest that the inhibitory effect on cell proliferation may be related to the modulation of adenosine monophosphate (AMP) levels. Thus, a novel copper(II) complex with increased cytotoxic effects and selectivity against breast cancer cells was obtained, contributing to medicinal chemistry efforts toward the development of new chemotherapeutic agents. (AU)

• FAPESP's process: 21/10265-8 - Cancer Theranostics Innovation Center (CancerThera)
• Grantee: Carmino Antonio de Souza
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 19/12219-3 - Study of vascular responsiveness as a consequence of Cardiorenal Syndrome: participation of purinergic system
• Grantee: Cristina Ribas Fürstenau
• Support Opportunities: Regular Research Grants
• FAPESP's process: 21/08717-8 - Synthesis of copper, silver and gold complexes involving nucleotide analogues in the search of new alternatives for the treatment of ovarian cancer
• Grantee: Pedro Paulo Corbi
• Support Opportunities: Regular Research Grants