Coordination chemistry of anticancer active dirhodium complexes with n-based and s-based biomolecules and model ligand systems.

摘要

Dirhodium(II/II) tetracarboxylate complexes are the first dinuclear metal compounds to be recognized as exhibiting significant anticancer activity against a number of tumor cell lines. In sharp contrast to the well-known clinical anticancer drug, cis-[PtCl₂(NH₃) ₂], the chemistry of dirhodium complexes with molecules of biological significance is much less developed. Early reports suggested that DNA is the most likely cellular target which leads to the cytotoxic properties of dirhodium tetracarboxylate compounds. Parallel studies, however, indicated that these dirhodium compounds also exhibit significant reactivity with peptides and proteins, especially those with a sulfhydryl group. In an attempt to understand the reactivities of these dirhodium compounds with biomolecules, this dissertation describes reactivity studies of [Rh₂(μ-O₂CCH ₃)₄] (1) and [Rh₂(μ-O₂CCH ₃)₂(N-N)₂L₂]X₂ (N-N = 2,2 ′-bipyridine and 1,10-phenanthroline; L = solvent molecules; X = halides, acetate, [BF₄]−, [PF₆] −) with thiol-containing biological molecules and model ligands. The syntheses and X-ray crystallographic characterization of the thiolate complexes RhIII(η2-C₆H₆ NS)(η1-C₆H₆NS)₂(phen) (4), [Rh₂III/III(μ-C₆H ₆NS)₂(C₆H₆NS)₂(bpy) ₂]2+ (5), [RhIII(C₆ H₆NS)₂-(bpy)]+ (6), and [RhII(η1-C₆H₅S)(μ-C ₆H₅S)(bpy)]₂·CH₃OH (7 ) will be presented. A proposed mechanistic pathway for the reactions between [Rh₂(μ-O₂CCH₃)₂(N-N) ₂L₂]X₂ compounds and thiol ligands will also be addressed. In addition, axial binding of L-methionine to Rh₂(μ-O ₂CCH₃)₄ was studied by spectrometric titration, yielding approximate binding constants 2.26 × 102 and 1.61 × 102 M−1 for K _b1 and K_b2, respectively.; The chemistry of the anticancer active dirhodium(II/II) complexes and their analogs with purines molecules constitutes a second theme of this dissertation. These dirhodium complexes possess both axial and equatorial binding sites, and the exact interaction mode of the DNA bases guanine and adenine depends on reaction conditions and the nature of the equatorial ligands, as established by NMR spectroscopy and mass spectrometry. The complexes used in these studies are Rh₂(μ-O₂CCH₃)₄ ( 1), [Rh₂(μ-O₂CCH₃)₂(bpy) ₂(CH₃CN)₂][BF₄]₂ ( 2), [Rh₂(μ-O₂CCH₃)₂(phen) ₂(CH₃CN)₂](O₂CCH₃) ₂ (11), [Rh₂(μ-DTolF)₂(CH ₃CN)₆][BF₄]₂ (DTolF = N,N ′ p-tolylformamidinate) (12), Rh₂(μ-O₂CC₆H₃(OH)(H _SO₃))₄ (13), and [Rh₂(μ-O ₂CCH₃)₂(CH₃CN)₆][BF ₄]₂ (