4.7 Article

A Potent Ruthenium(II) Antitumor Complex Bearing a Lipophilic Levonorgestrel Group

Journal

INORGANIC CHEMISTRY
Volume 50, Issue 18, Pages 9164-9171

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/ic201388n

Keywords

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Funding

  1. MICINN-Spain [CTQ2008-02178, CTQ2008-01402]
  2. Fundacion Seneca [08666/PI/08 and 04509/GERM/06]

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The novel steroidal conjugate 17-alpha-[2-phenylpyridyl-4-ethynyl]-19-nortestosterone (LEV-ppy) (1) and the steroid-C,N-chelate ruthenium(II) conjugate [Ru(eta(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(eta(6)-p-cymene)(ppy)Cl] (ppy = phenylpyridine) (3) in the same cell line. The act of conjugating a levonorgestrel group to a ruthenium(U) complex resulted in synergistic effects between the metallic center and the steroidal ligand, creating highly potent ruthenium(11) 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(+) center dot Cl-) inside the pseudocavity formed by the alpha 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 center dot center dot center dot anion bonds, as supported by electrospray ionization mass spectra.

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