Department of Chemistry, Simon Fraser University, Burnaby, BC, V5A 1S6 (Canada), Fax: (+1) 778-782-3765.
Chemistry. 2013 Dec 9;19(50):17031-42. doi: 10.1002/chem.201302671. Epub 2013 Nov 7.
A series of pyridine-based derivatives of the clinically successful Ru(III)-based complexes indazolium [trans-RuCl4(1H-indazole)2] (KP1019) and sodium [trans-RuCl4(1H-indazole)2] (KP1339) have been synthesized to probe the effect of hydrophobic interactions with human serum albumin (hsA) on anticancer activity. The solution behavior and protein interactions of the new compounds were characterized by using electron paramagnetic resonance (EPR) and UV/Vis spectroscopy. These studies have revealed that incorporation of hydrophobic substituents at the 4'-position of the axial pyridine ligand stabilizes non-coordinate interactions with hsA. As a consequence, direct coordination to the protein is inhibited, which is expected to increase the bioavailability of the complexes, thus potentially leading to improved anticancer activity. By using this approach, the lifetimes of hydrophobic protein interactions were extended from 2 h for the unsubstituted pyridine complex, to more than 24 h for several derivatives. Free complexes were tested for their anticancer activity against the SW480 human colon carcinoma cell line, exhibiting low cytotoxicity. Pre-treatment with hsA improved the solubility of every compound and led to some changes in activity. Particularly notable was the difference in activity between the methyl- and dibenzyl-functionalized complexes. The former shows reduced activity after incubation with hsA, indicating reduced bioavailability due to protein coordination. The latter exhibits little activity on its own but, following treatment with hsA, exhibited significant cytotoxicity, which is consistent with its ability to form non-coordinate interactions with the protein. Overall, our studies demonstrate that non-coordinate interactions with hsA are a viable target for enhancing the activity of Ru(III)-based complexes in vivo.
已经合成了一系列基于吡啶的临床成功的 Ru(III)基配合物的衍生物，包括吲唑鎓[反式-RuCl4(1H-吲唑)2]（KP1019）和[反式-RuCl4(1H-吲唑)2]钠盐（KP1339），以探究与人体血清白蛋白（hsA）的疏水相互作用对抗癌活性的影响。通过电子顺磁共振（EPR）和紫外/可见光谱研究了新化合物的溶液行为和蛋白相互作用。这些研究表明，轴向吡啶配体的 4'-位引入疏水性取代基可以稳定与 hsA 的非配位相互作用。因此，直接与蛋白配位受到抑制，预计会增加配合物的生物利用度，从而可能提高抗癌活性。通过这种方法，疏水性蛋白相互作用的寿命从未取代吡啶配合物的 2 小时延长到几个衍生物的 24 小时以上。游离配合物被测试对 SW480 人结肠癌细胞系的抗癌活性，表现出低细胞毒性。hsA 的预处理提高了每个化合物的溶解度，并导致活性发生一些变化。特别值得注意的是甲基和二苄基功能化配合物之间的活性差异。前者在与 hsA 孵育后活性降低，表明由于蛋白配位导致生物利用度降低。后者本身活性较低，但经 hsA 处理后表现出显著的细胞毒性，这与其与蛋白形成非配位相互作用的能力一致。总体而言，我们的研究表明，与 hsA 的非配位相互作用是增强体内 Ru(III)基配合物活性的可行目标。
