Titanocene-Phosphine Derivatives as Precursors to Cytotoxic Heterometallic TiAu2 and TiM (M = Pd Pt) Compounds. Studies of their Interactions with DNA

摘要

A series of tri- and bimetallic titanium-gold, titanium-palladium and titanium-platinum derivatives of general formulas [Ti{η⁵-C5H4(CH2)nPPh2(AuCl)}2].2THF n = 0 (>1); n = 2 (>2); n = 3 (>3) and [TiCl2{η⁵-C5H4κ-(CH2)nPPh2}2(PtCl2)].2THF (M = Pd, n = 0 (>4); n = 2 (>5); n = 3 (>6); M = Pt, n = 0 (>7); n = 2 (>8); n = 3 (>9)) have been synthesized and characterized by different spectroscopic techniques and mass spectrometry. The molecular structures of compounds >1–9 have been investigated by means of density-functional calculations. The calculated IR spectra of the optimized structures fit well with the experimental IR data obtained for >1–9. The stability of the heterometallic compounds in deuterated solvents (CDCl3, d⁶-dmso, mixtures 50:50 d⁶-dmso/D2O, 1:99 d⁶-dmso/D₂O at acidic pH and at neutral pH) has been evaluated by ³¹P and ¹H NMR spectroscopy showing a higher stability for these compounds than for Cp₂TiCl₂ or precursors [Ti{η⁵-C₅H₄(CH₂)_nPPh₂}₂]. The new compounds display a lower acidity (1 to 2 units) than Cp₂TiCl₂. The decomposition products have been identified over time. Complexes >1–9 have been tested as potential anticancer agents and their cytotoxicity properties were evaluated in vitro against HeLa human cervical carcinoma and DU-145 human prostate cancer cells. TiAu₂ and TiPd compounds were highly cytotoxic for these two cell lines. The interactions of the compounds with Calf Thymus DNA have been evaluated by Thermal Denaturation (>1–9) and by Circular Dichroism (>1, 3, 4, 7) spectroscopic methods. All these complexes show a stronger interaction with DNA than that displayed by Cp₂TiCl₂ at neutral pH. The data is consistent with electrostatic interactions with DNA for TiAu₂ compounds and for a covalent binding mode for TiM (M = Pd, Pt) complexes.