Aqueous Coordination Chemistry of Vanadocene Dichloride, V(η⁵-C₅H₅)₂C1₂, with Nucleotides and Phosphoesters. Mechanistic Implications for a New Class of Antitumor Agents

This paper reports an investigation of the mode of interaction of the organometallic antitumor agent Cp₂VCl₂(Cp =η⁵-C₅H₅) with nucleotides and phosphoesters, in aqueous solution near physiological pH, employing high-field ¹H and ³¹P FT NMR and EPR. Paramagnetic (d¹) aqueous Cp₂VCl₂is found to selectively interact with the phosphate functionalities of nucleotides and to significantly shorten the ³¹P nuclear relaxation times. A quantitative analysis of the paramagnetic contributions to the longitudinal (T₁) and transverse (T₂) relaxation rates of the ³¹P nucleus of 2’-deoxyadenosine-5’-monophosphate reveals that the average internuclear vanadium-phosphorus distance in the solution complex is 6.2 (2) or 5.5 (1) A, depending on whether each vanadium ion interacts with one or two phosphate moieties, respectively. The temperature dependence of the ^3lP relaxation rates yields kinetic parameters characterizing the labile outer-sphere complexation of aqueous Cp₂VCl₂to the phosphate groups. At 25 °C, the mean lifetime of the metal-nucleotide complex is estimated to be 0.49 (8) ms. Activation parameters for the ligand dissociation at 25 °C are the following: AG* = 19.5 (2.6) kcal/mol, ΔH* = 13.8 (1.0) kcal/mol, and AS* = -19.1 (4.3) e.u. Nucleotide-nucleotide Watson-Crick base-pairing is not disrupted by Cp₂VCl₂in aqueous solution, as shown by ¹H NMR. An X-ray crystallographic study was also carried out on the model compound, Cp₂V(OH₂)₂•2O₂P(OPh)₂ (1). The crystal structure of 1 serves to define the coordination of the Cp₂V²⁺ unit to a diesterified phosphoric acid, which possesses metrical parameters similar to those of polynucleotides. The complex crystallizes in the monoclinic space group P2₁ (No. 4) with four molecules in a unit cell of dimensions a = 10.571 (2) A, b = 12.108 (3) A, c = 25.277 (6) A, and (3 = 98.50 (2)° at 163 (2) K. Least-squares refinement led to a value for the conventional R index (on F) of 0.031 for 6197 unique reflections having 2θ_MoKα ≤ 55° and I > 3σ (I). The molecular structure consists of pseudotetrahedral V(η⁵-C₅H₅)₂(OH₂)₂²⁺cations connected to diphenyl phosphate anions via strong hydrogen bonds. Average metrical parameters for the V(η⁵-C₅H₅)₂(OH₂)₂²⁺cation are as follows: V-C distance, 2.297 (5) A; V-O(water) distance, 2.050 (8) A; ring centroid-V-ring centroid angle, 133.0 (4)°. Average metrical parameters for the P0₂(OPh)₂^-anion are P-OPh distance, 1.601 (6) A; P-0 (non-ester), 1.480 (2) A; and C-O distance, 1.392 (3) A, and these are typical for a phosphodiester anion. The vanadium-phosphorus nonbonded contacts are in the range 5.07-6.44 Å, in good agreement with the nucleotide NMR results in solution. Implications of these results for the observed biological activity of Cp₂VCl₂are briefly discussed.