Lead to hit ruthenium-cyclopentadienyl anticancer compounds: Cytotoxicity against breast cancer cells, metabolic stability and metabolite profiling

Inês Maximiano; Catarina Henriques; Ricardo G Teixeira; Fernanda Marques; Andreia Valente; Alexandra M M Antunes

doi:10.1016/j.jinorgbio.2023.112436

Lead to hit ruthenium-cyclopentadienyl anticancer compounds: Cytotoxicity against breast cancer cells, metabolic stability and metabolite profiling

J Inorg Biochem. 2024 Feb:251:112436. doi: 10.1016/j.jinorgbio.2023.112436. Epub 2023 Nov 23.

Authors

Inês Maximiano¹, Catarina Henriques¹, Ricardo G Teixeira², Fernanda Marques³, Andreia Valente⁴, Alexandra M M Antunes⁵

Affiliations

¹ Centro de Química Estrutural, Institute of Molecular Sciences and Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, Lisboa 1749-016, Portugal; Centro de Química Estrutural (CQE), Institute of Molecular Sciences, Departamento de Engenharia Química, Instituto Superior Técnico (IST), Universidade de Lisboa, Lisboa 1049-001, Portugal.
² Centro de Química Estrutural, Institute of Molecular Sciences and Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, Lisboa 1749-016, Portugal.
³ Centro de Ciências e Tecnologias Nucleares (C(2)TN) and Departamento de Engenharia e Ciências Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10, Bobadela LRS 2695-066, Portugal.
⁴ Centro de Química Estrutural, Institute of Molecular Sciences and Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, Lisboa 1749-016, Portugal. Electronic address: amvalente@ciencias.ulisboa.pt.
⁵ Centro de Química Estrutural (CQE), Institute of Molecular Sciences, Departamento de Engenharia Química, Instituto Superior Técnico (IST), Universidade de Lisboa, Lisboa 1049-001, Portugal. Electronic address: alexandra.antunes@tecnico.ulisboa.pt.

PMID: 38016328
DOI: 10.1016/j.jinorgbio.2023.112436

Abstract

The successful choice of hit compounds during drug development programs involves the integration of structure-activity relationship (SAR) studies with pharmacokinetic determinations, including metabolic stability assays and metabolite profiling. A panel of nine ruthenium-cyclopentadienyl (RuCp) compounds with the general formula [Ru(η⁵-C₅H₄R)(PPh₃)(bipyR')]⁺ (with R = H, CHO, CH₂OH; R' = H, CH₃, CH₂OH, CH₂Biotin) has been tested against hormone-dependent MCF-7 and triple negative MDA-MB-231 breast cancer cells. In general, all compounds showed important cytotoxicity against both cancer cell lines and were able to inhibit the formation of MDA-MB-231 colonies in a dose-dependent manner, while showing selectivity for cancer cells over normal fibroblasts. Among them, four compounds stood out as lead structures to be further studied. Cell distribution assays revealed their preference for the accumulation at cell membrane (Ru quantification by ICP-MS) and the mechanism of cell death seemed to be mediated by apoptosis. Potential structural liabilities of lead compounds were subsequently flagged upon in vitro metabolic stability assays and metabolite profiling. The implementation of this integrated strategy led to the selection of RT151 as a promising hit compound.

Keywords: Anticancer; Breast cancer cells; Metabolic stability; Metabolite profile; Preclinical toxicological studies; Ruthenium compounds.

Publication types

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

MeSH terms

Antineoplastic Agents* / chemistry
Breast Neoplasms* / drug therapy
Cell Line
Cell Line, Tumor
Cell Proliferation
Coordination Complexes* / chemistry
Drug Screening Assays, Antitumor
Female
Humans
Ruthenium Compounds / pharmacology
Ruthenium* / chemistry

Substances

Antineoplastic Agents
Ruthenium
Ruthenium Compounds
Coordination Complexes