Synthesis, Ti(IV) intake by apotransferrin and cytotoxic properties of functionalized titanocene dichlorides
Functionalization of cyclopentadienyl (Cp) ligands and incorporation of these into a Ti(IV) center require careful design and selection of the appropriate synthetic routes to obtain the desired product in reasonably good yields. As part of our research efforts in the area of titanocene antitumor agents, we have revisited the synthesis of Cp rings with electron-withdrawing groups and their corresponding titanocene dichlorides, (Cp-R)2TiCl2 and (Cp-R)CpTiCl2, where R is CO2CH3 and CO2CH2CH3. These complexes were characterized by elemental analysis and 1H and 13C NMR and IR spectroscopies. This report presents the first detailed synthetic route for (Cp-CO2CH2CH3)CpTiCl2 and provides an alternate route for synthesis of (Cp-R)2TiCl2 complexes. The ability of these complexes to deliver Ti(IV) to apotransferrin was investigated to elucidate how the functionalized Cp ligands affect the titanium intake by apotransferrin. The subject complexes transfer Ti(IV) to human apotransferrin, loading both N- and C-lobes. The antitumor activity of these complexes against HT-29 cancer colon cells was determined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Carboethoxy Cp functionalization results in complexes with a toxicity comparable to that of titanocene dichloride. The carbomethoxy-functionalized complexes proved to be nonactive at the time intervals studied here, regardless of their ability to donate the titanium atom to human apotransferrin.
KeywordsTitanocene dichloride Functionalized cyclopentadienyl Colon cancer Antitumor activity Apotransferrin
E.M. acknowledges the NIH-MBRS SCORE programs at the University of Puerto Rico at Mayaguez and the Ponce School of Medicine for financial support, the NSF-MRI program for providing funds for the purchase of the 500-MHz NMR instrument and the Sloan Foundation for financial support in the form of a graduate fellowship to R.H.
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