Hydrolytic metal with a hydrophobic periphery: titanium(IV) complexes of naphthalene-2,3-diolate and interactions with serum albumin.

Arthur D Tinoco, Emily V Eames, Christopher D Incarvito, Ann M Valentine

Index: Inorg. Chem. 47(18) , 8380-90, (2008)

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Abstract

Serum albumin, the most abundant protein in human plasma (700 microM), binds diverse ligands at multiple sites. While studies have shown that serum albumin binds hard metals in chelate form, few have explored the trafficking of these metals by this protein. Recent work demonstrated that serum albumin may play a pivotal role in the transport and bioactivity of titanium(IV) complexes, including the anticancer drug candidate titanocene dichloride. The current work explores this interaction further by using a stable Ti(IV) complex that presents a hydrophobic surface to the protein. Ti(IV) chelation by 2,3-dihydroxynaphthalene (H2L1) and 2,3-dihydroxynaphthalene-6-sulfonate (H2L2) affords water soluble complexes that protect Ti(IV) from hydrolysis at pH 7.4 and bind to bovine serum albumin (BSA). The solution and solid Ti(IV) coordination chemistry were explored by aqueous spectropotentiometric titrations and X-ray crystallography, respectively, and with complementary electrochemistry, mass spectrometry, and IR and NMR spectroscopies. Four Ti(IV) species of L2, TiLH0, TiL2H0, TiL3H0, and TiL3H(-1), adequately represent the pH-dependent speciation. The isolation of Ti(C10H6O2)2 x 1.75 H2O at pH approximately 3 and K2[Ti(C10H6O2)3] x 3 H2O and Cs5[Ti(C10H5O5S)3] x 2.5 H2O at pH approximately 7 correlates well with the solution studies. At pH 7.4 and micromolar concentrations, the TiL3H0 species are favored. The Ti(naphthalene-2,3-diolate)3(2-) complex binds with moderate affinity to multiple sites of BSA. The primary site (K = 2.05 +/- 0.34 x 10(6) M(-1)) appears to be hydrophobic as indicated by competition studies with different ligands and a hydrophilic Ti(IV) complex. The Ti(naphthalene-2,3-diolate)3(2-) interaction with the Fe(III)-binding protein human serum transferrin (HsTf), a protein also important for Ti(IV) transport, and DNA was examined. The complex does not deliver Ti(IV) to HsTf and while it does bind to DNA, no cleavage promotion activity is observed. This investigation provides insight into the use of ligands to direct metal binding at different sites of albumin, which may facilitate transport to distinct targets.