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

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

doi:10.1016/j.jinorgbio.2024.112524

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

J Inorg Biochem. 2024 Jun:255:112524. doi: 10.1016/j.jinorgbio.2024.112524. Epub 2024 Mar 16.

Authors

Helen Soares Valença Ferreira¹, Luana Munique Sousa Ramos², Fernanda Cardoso Silva¹, Daniel Lima Alves², Gabriele de Menezes Pereira³, Pedro Henrique de Oliveira Santiago⁴, Angelina Maria de Almeida⁵, Javier Ellena⁶, Pedro Paulo Corbi⁷, Carolina Gonçalves Oliveira⁸, Mauro Vieira de Almeida⁹, Cristina Ribas Fürstenau¹⁰, Dayanne Silva Borges¹, Raoni Pais Siqueira¹¹, Wendell Guerra¹², Thaise Gonçalves Araújo¹³

Affiliations

¹ Laboratory of Genetics and Biotechnology, Institute of Biotechnology, Universidade Federal de Uberlândia, Patos de Minas, MG, Brazil.
² Institute of Chemistry, Universidade Federal de Uberlândia Uberlândia, Uberlândia, MG, Brazil.
³ Instituto de Química, Universidade Estadual de Campinas-UNICAMP, Campinas, SP, Brazil.
⁴ Institute of Physics of São Carlos, Universidade de São Paulo, São Carlos, SP, Brazil.
⁵ Department of Chemistry, Universidade Federal de Juiz de Fora, Juiz de Fora, MG, Brazil. Electronic address: [email protected].
⁶ Institute of Physics of São Carlos, Universidade de São Paulo, São Carlos, SP, Brazil. Electronic address: [email protected].
⁷ Instituto de Química, Universidade Estadual de Campinas-UNICAMP, Campinas, SP, Brazil. Electronic address: [email protected].
⁸ Institute of Chemistry, Universidade Federal de Uberlândia Uberlândia, Uberlândia, MG, Brazil. Electronic address: [email protected].
⁹ Department of Chemistry, Universidade Federal de Juiz de Fora, Juiz de Fora, MG, Brazil. Electronic address: [email protected].
¹⁰ Laboratory of Vascular Biochemistry, Center for Natural and Human Sciences (CCNH), Universidade Federal do ABC, Santo André, SP, Brazil. Electronic address: [email protected].
¹¹ Laboratory of Genetics and Biotechnology, Institute of Biotechnology, Universidade Federal de Uberlândia, Patos de Minas, MG, Brazil. Electronic address: [email protected].
¹² Institute of Chemistry, Universidade Federal de Uberlândia Uberlândia, Uberlândia, MG, Brazil. Electronic address: [email protected].
¹³ Laboratory of Genetics and Biotechnology, Institute of Biotechnology, Universidade Federal de Uberlândia, Patos de Minas, MG, Brazil; Laboratory of Nanobiotechnology Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnoloy, Universidade Federal de Uberlândia, Uberlandia, MG, Brazil. Electronic address: [email protected].

PMID: 38507993
DOI: 10.1016/j.jinorgbio.2024.112524

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)₂1, [Cu(dech)(1,10-phen)(H₂O)](NO₃)₂2 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 μM 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.

Keywords: 1,10-phenanthroline; Aliphatic hydrazides; Breast cancer; Copper(II) complexes; Purinergic signaling; cancer treatment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Diphosphate
Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Coordination Complexes* / chemistry
Coordination Complexes* / pharmacology
Copper / chemistry
Crystallography, X-Ray
Humans
Hydrazines
Hydrolysis
Phenanthrolines / chemistry
Phenanthrolines / pharmacology
Triple Negative Breast Neoplasms* / drug therapy
Triple Negative Breast Neoplasms* / metabolism

Substances

Copper
1,10-phenanthroline
Coordination Complexes
Hydrazines
Antineoplastic Agents
Phenanthrolines
Adenosine Diphosphate