A potent ruthenium(II) antitumor complex bearing a lipophilic levonorgestrel group.

Abstract

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.

• Authors: José Ruiz, Venancio Rodríguez, Natalia Cutillas, Arturo Espinosa, Michael J Hannon
• Journal: Inorganic chemistry (Inorg Chem) Vol. 50 Issue 18 Pg. 9164-71 (Sep 19 2011) ISSN: 1520-510X [Electronic] United States
• PMID: 21830785 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Levonorgestrel
• Guanine
• Ruthenium
• 9-ethylguanine

Topics

• Antineoplastic Agents (chemistry, pharmacology)
• Breast Neoplasms (drug therapy)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Design
• Drug Screening Assays, Antitumor
• Female
• Guanine (analogs & derivatives, metabolism)
• Humans
• Levonorgestrel (chemistry)
• Models, Molecular
• Ovarian Neoplasms (drug therapy)
• Ruthenium (chemistry, pharmacology)