The Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel.
The Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel.
J Inorg Biochem. 2021 Aug;221:111492. doi: 10.1016/j.jinorgbio.2021.111492. Epub 2021 May 15.
Titanium(IV) complexes of diaminobis(phenolato)-bis(alkoxo) ligands are promising anticancer drugs, showing marked in-vivo efficacy with no toxic side-effects in mice, hence, it is of interest to elucidate their mechanism of action. Herein, we employed a fluoro-substituted derivative, FenolaTi, for mechanistic analysis of the active species and its cellular target by quantitative F NMR detection to reveal its biodistribution and reactivity in extracellular and intracellular matrices. Upon administration to the serum-containing medium, FenolaTi interacted with bovine serum albumin. 20 h post administration, the cellular accumulation of FenolaTi derivatives was estimated as 37% of the administered compound, in a concentration three orders-of-magnitude higher than the administered dose, implying that active membrane transportation facilitates cellular penetration. An additional 19% of the administered dose that was detected in the extracellular environment had originated from post-apoptotic cells. In the cell, interaction with cellular proteins was detected. Although some intact Ti(IV) complex localized in the nucleus, no signals for isolated DNA fractions were detected and no reactivity with nuclear proteins was observed. Interestingly, higher accumulation of FenolaTi-derived compounds in the endoplasmic reticulum (ER) and interaction with proteins therein were detected, supporting the role of the ER as a possible target for cytotoxic bis(phenolato)-bis(alkoxo) Ti(IV) complexes.
二氨基双（苯酚）双（烷氧基）配体的钛（IV）配合物是很有前途的抗癌药物，在小鼠体内表现出显著的疗效，没有毒副作用，因此，阐明其作用机制很有意义。在此，我们采用了一种氟取代的衍生物 FenolaTi，通过定量 F NMR 检测来研究活性物质及其细胞靶标的作用机制，以揭示其在细胞外和细胞内基质中的生物分布和反应性。在给药至含血清的培养基中后，FenolaTi 与牛血清白蛋白相互作用。给药后 20 小时，FenolaTi 衍生物在细胞内的积累估计为给药化合物的 37%，浓度比给药剂量高三个数量级，这意味着主动的膜转运促进了细胞穿透。在细胞外环境中检测到的给药剂量的另外 19%来源于凋亡后的细胞。在细胞中，检测到与细胞蛋白的相互作用。尽管一些完整的 Ti(IV) 配合物定位于细胞核中，但未检测到分离的 DNA 部分的信号，也未观察到与核蛋白的反应性。有趣的是，在内质网（ER）中检测到 FenolaTi 衍生化合物的更高积累，并与其中的蛋白质相互作用，这支持了 ER 作为细胞毒性双（苯酚）双（烷氧基）Ti(IV) 配合物的可能靶标的作用。
