Yale University, New Haven, CT 06520-8107, USA.
Dalton Trans. 2011 Oct 7;40(37):9580-8. doi: 10.1039/c1dt10805k. Epub 2011 Aug 16.
Since the discovery of the anticancer activity of titanocene dichloride (TDC), many derivatives have been developed and evaluated. MKT4, a soluble, water-stable formulation of TDC, was used for both Phase I and Phase II human clinical trials. This formulation is investigated here by using (1)H and (13)C NMR, FT-ICR mass spectrometry, and UV/vis-detected pH-dependent speciation. DFT calculations are also utilized to assess the likelihood of proposed species. Human serum transferrin has been identified as a potential vehicle for the Ti anticancer drugs; these studies examine whether and how formulation of TDC as MKT4 may influence its interactions, both thermodynamic and kinetic, with human serum transferrin by using UV/vis absorption and fluorescence quenching. MKT4 binds differently than TDC to transferrin, showing different kinetics of binding as well as a different molar absorptivity of binding (7500 M(-1) cm(-1) per site). Malate, used in the buffer for MKT4 administration, acts as a synergistic anion for Ti binding, shifting the tyrosine to Ti charge transfer energy and decreasing the molar absorptivity to 5000 M(-1) cm(-1) per site. These differences may have had consequences after the change from TDC to MKT4 in human clinical trials.
自从发现二氯二茂钛（TDC）的抗癌活性以来，已经开发并评估了许多衍生物。MKT4 是 TDC 的一种可溶性、水稳定的制剂，已用于人体临床试验的 I 期和 II 期。本文通过使用（1）H 和（13）C NMR、FT-ICR 质谱和 UV/vis 检测的 pH 依赖的形态分析来研究这种制剂。还利用 DFT 计算来评估所提出的物种的可能性。人血清转铁蛋白已被确定为 Ti 抗癌药物的潜在载体；这些研究通过使用紫外/可见吸收和荧光猝灭来检查将 TDC 制成 MKT4 是否以及如何影响其与人血清转铁蛋白的相互作用，包括热力学和动力学相互作用。MKT4 与 TDC 与转铁蛋白的结合方式不同，表现出不同的结合动力学以及不同的摩尔吸光率（每个位点 7500 M（-1）cm（-1））。MKT4 给药缓冲液中的苹果酸作为 Ti 结合的协同阴离子，将酪氨酸转移到 Ti 电荷转移能量，并将摩尔吸光率降低至每个位点 5000 M（-1）cm（-1）。在临床试验中从 TDC 改为 MKT4 后，这些差异可能产生了后果。
