Synthesis, Ti(IV) intake by apotransferrin and cytotoxic properties of functionalized titanocene dichlorides

Abstract

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)(2)TiCl(2) and (Cp-R)CpTiCl(2), where R is CO(2)CH(3) and CO(2)CH(2)CH(3). These complexes were characterized by elemental analysis and (1)H and (13)C NMR and IR spectroscopies. This report presents the first detailed synthetic route for (Cp-CO(2)CH(2)CH(3))CpTiCl(2) and provides an alternate route for synthesis of (Cp-R)(2)TiCl(2) 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.

Synthesis, Structure, Electrochemistry, and Cytotoxic Properties of Ferrocenyl Ester Derivatives

“…In contrast, (carboethoxycyclopentadienyl)-(carbomethoxycyclopentadienyl)-ferrocene and the bis(carbomethoxycyclopentadienyl)-ferrocene exhibited less cytotoxic activity than ferrocene and ferrocenium. The carbomethoxy functionalization has been shown previously to inactivate or lower the cytotoxic activity of resulting titanocene complexes [19]. The present results clearly show how the presence of the carbomethoxy substituent in the cyclopentadienyl ring lowers the activity of ferrocene in a stepwise manner, being the bis(carbomethoxy)ferrocene less active than (carbomethoxy)(carboethoxy)ferrocene.…”

“…In general, the present synthetic route developed by Busetto et al [17] for the ferrocenyl ester complexes (Cp functionalization and formation of the corresponding functionalized ferrocene) represents a convenient alternative procedure for the functionalization of metallocenes and has been used by our group to synthesize functionalized titanocenes [19]. …”

Structure–activity studies of Ti(IV) complexes: aqueous stability and cytotoxic properties in colon cancer HT-29 cells

“…Modification of ligands in titanocene dichloride is an active area of research since, among the metallocenes, titanocene dichloride is the most effective species [8][9][10][11][12][13][14][15][16][17][18][19][20][21]. As mentioned previously, the lack of hydrolytic stability has hampered its use as a chemotherapeutic drug because the chemical nature of the active species is unknown.…”

Cytotoxicity of a Ti(IV) compound is independent of serum proteins

“…In one study, structurally similar titanocenes that deliver Ti(IV) to Tf at comparably fast rates and degrees of saturation were found not only to poorly induce cytotoxicity in HT-29 colon cancer cells but also to induce at different half-maximal inhibitory concentrations (IC 50 ) (15). In more conclusive studies, the addition of Tf to cell-viability assays did not improve the cytotoxicity of different Ti(IV) compounds in several cell lines, with the exception of titanocene dichloride in some instances (16)(17)(18)(19).…”