Unprecedented inhibition of P-gp activity by a novel ruthenium-cyclopentadienyl compound bearing a bipyridine-biotin ligand

Leonor Côrte-Real; Brittany Karas; Patrícia Gírio; Alexis Moreno; Fernando Avecilla; Fernanda Marques; Brian T Buckley; Keith R Cooper; Cathleen Doherty; Pierre Falson; M Helena Garcia; Andreia Valente

doi:10.1016/j.ejmech.2018.12.022

Unprecedented inhibition of P-gp activity by a novel ruthenium-cyclopentadienyl compound bearing a bipyridine-biotin ligand

Eur J Med Chem. 2019 Feb 1:163:853-863. doi: 10.1016/j.ejmech.2018.12.022. Epub 2018 Dec 12.

Authors

Affiliations

¹ Centro de Química Estrutural, Faculdade de Ciências da Universidade de Lisboa, Campo Grande, 1749-016, Lisboa, Portugal.
² Environmental and Occupational Health Sciences Institute, Rutgers University, 170 Frelinghuysen Road, Piscataway, NJ, 08854, USA; Department of Biochemistry and Microbiology, Rutgers University, 76 Lipman Drive, New Brunswick, NJ, 08854, USA.
³ Centro de Química Estrutural, Faculdade de Ciências da Universidade de Lisboa, Campo Grande, 1749-016, Lisboa, Portugal; Drug Resistance and Membrane Proteins Team, Molecular Biology and Structural Biochemistry Laboratory, UMR 5086 CNRS-UCBL1, IBCP 7 Passage du Vercors, 69 367, Lyon Cedex 07, France.
⁴ Drug Resistance and Membrane Proteins Team, Molecular Biology and Structural Biochemistry Laboratory, UMR 5086 CNRS-UCBL1, IBCP 7 Passage du Vercors, 69 367, Lyon Cedex 07, France.
⁵ Grupo Xenomar, Centro de Investigacións Científicas Avanzadas (CICA), Departamento de Química, Facultade de Ciencias, Universidade da Coruña, Campus de A Coruña, 15071 A, Coruña, Spain.
⁶ Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10, Km 139.7, 2695-066, Bobadela LRS, Portugal.
⁷ Environmental and Occupational Health Sciences Institute, Rutgers University, 170 Frelinghuysen Road, Piscataway, NJ, 08854, USA.
⁸ Department of Biochemistry and Microbiology, Rutgers University, 76 Lipman Drive, New Brunswick, NJ, 08854, USA.
⁹ Centro de Química Estrutural, Faculdade de Ciências da Universidade de Lisboa, Campo Grande, 1749-016, Lisboa, Portugal. Electronic address: [email protected].

Abstract

Two new ruthenium complexes, [Ru(η⁵-Cp)(PPh₃)(2,2'-bipy-4,4'-R)]⁺ with R = -CH₂OH (Ru1) or dibiotin ester (Ru2) were synthesized and fully characterized. Both compounds were tested against two types of breast cancer cells (MCF7 and MDA-MB-231), showing better cytotoxicity than cisplatin in the same experimental conditions. Since multidrug resistance (MDR) is one of the main problems in cancer chemotherapy, we have assessed the potential of these compounds to overcome resistance to treatments. Ru2 showed exceptional selectivity as P-gp inhibitor, while Ru1 is possibly a substrate. In vivo studies in zebrafish showed that Ru2 is well tolerated up to 1.17 mg/L, presenting a LC₅₀ of 5.73 mg/L at 5 days post fertilization.

Keywords: Anticancer agents; Multidrug resistance; P-gp inhibitor; Ruthenium organometallic compounds.

MeSH terms

2,2'-Dipyridyl / chemistry*
ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
Animals
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Biotin / chemistry*
Breast Neoplasms / drug therapy
Breast Neoplasms / pathology
Coordination Complexes / chemistry
Coordination Complexes / pharmacology*
Drug Resistance, Multiple
Humans
Ligands
Ruthenium / chemistry*
Zebrafish

Substances

ATP Binding Cassette Transporter, Subfamily B, Member 1
Antineoplastic Agents
Coordination Complexes
Ligands
2,2'-Dipyridyl
Biotin
Ruthenium

Abstract

MeSH terms

Substances

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