A Potent Ruthenium(II) Antitumor Complex Bearing a Lipophilic Levonorgestrel Group
| Autor: | José Ruiz, Natalia Cutillas, Arturo Espinosa, Venancio Rodríguez, Michael J. Hannon |
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| Rok vydání: | 2011 |
| Předmět: |
Models
Molecular Guanine Stereochemistry Electrospray ionization medicine.medical_treatment chemistry.chemical_element Antineoplastic Agents Breast Neoplasms Levonorgestrel Ruthenium Steroid Inorganic Chemistry Metal Cell Line Tumor medicine Humans Moiety Chelation Physical and Theoretical Chemistry Cell Proliferation Ovarian Neoplasms Ligand chemistry Drug Design visual_art visual_art.visual_art_medium Female Drug Screening Assays Antitumor Conjugate |
| Zdroj: | Inorganic Chemistry. 50:9164-9171 |
| ISSN: | 1520-510X 0020-1669 |
| DOI: | 10.1021/ic201388n |
| Popis: | The novel steroidal conjugate 17-α-[2-phenylpyridyl-4-ethynyl]-19-nortestosterone (LEV-ppy) (1) and the steroid-C,N-chelate ruthenium(II) conjugate [Ru(η(6)-p-cymene)(LEV-ppy)Cl] (2) have been prepared. At 48 h incubation time, complex 2 is more active than cisplatin (about 8-fold) in T47D (breast cancer) and also shows an improved efficiency when compared to its nonsteroidal analogue [Ru(η(6)-p-cymene)(ppy)Cl] (ppy = phenylpyridine) (3) in the same cell line. The act of conjugating a levonorgestrel group to a ruthenium(II) complex resulted in synergistic effects between the metallic center and the steroidal ligand, creating highly potent ruthenium(II) complexes from the inactive components. The interaction of 2 with DNA was followed by electrophoretic mobility. Theoretical density functional theory calculations on complex 2 show the metal center far away from the lipophilic steroidal moiety and a labile Ru-Cl bond that allows easy replacement of Cl by N-nucleophiles such as 9-EtG, thus forming a stronger Ru-N bond. We also found a minimum energy location for the chloride counteranion (4(+)·Cl(-)) inside the pseudocavity formed by the α side of the steroid moiety, the phenylpyridine chelating subsystem, and the guanine ligand, i.e., a host-guest species with a rich variety of nonbonding interactions that include nonclassical C-H···anion bonds, as supported by electrospray ionization mass spectra. |
| Databáze: | OpenAIRE |
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