Bigham Nicholas P, Novorolsky Robyn J, Davis Keana R, Zou Haipei, MacMillan Samantha N, Stevenson Michael J, Robertson George S, Wilson Justin J
Department of Chemistry and Chemical Biology, Cornell University Ithaca NY 14853 USA
Department of Pharmacology, Faculty of Medicine, Dalhousie University 6th Floor Sir Charles Tupper Medical Building Halifax B3H 4R2 Canada.
Inorg Chem Front. 2024 Jul 11;11(16):5064-5079. doi: 10.1039/d4qi01102c. eCollection 2024 Aug 6.
The transmembrane protein known as the mitochondrial calcium uniporter (MCU) mediates the influx of calcium ions (Ca) into the mitochondrial matrix. An overload of mitochondrial Ca ( Ca) is directly linked to damaging effects in pathological conditions. Therefore, inhibitors of the MCU are important chemical biology tools and therapeutic agents. Here, two new analogues of previously reported Ru- and Os-based MCU inhibitors Ru265 and Os245, of the general formula (CHCO)M(NH)(μ-N)M(NH)(OCCH), where M = Ru (1) or Os (2), are reported. These analogues bear adamantane functional groups, which were installed to act as guests for the host molecule cucurbit-[7]-uril (CB[7]). These complexes were characterized and analyzed for their efficiency as guests for CB[7]. As shown through a variety of spectroscopic techniques, each adamantane ligand is encapsulated into one CB[7], affording a supramolecular complex of 1 : 2 stoichiometry. The biological effects of these compounds in the presence and absence of two equiv. CB[7] were assessed. Both complexes 1 and 2 exhibit enhanced cellular uptake compared to the parent compounds Ru265 and Os245, and their uptake is increased further in the presence of CB[7]. Compared to Ru265 and Os245, 1 and 2 are less potent as Ca uptake inhibitors in permeabilized cell models. However, in intact cell systems, 1 and 2 inhibit the MCU at concentrations as low as 1 μM, marking an advantage over Ru265 and Os245 which require an order of magnitude higher doses for similar biological effects. The presence of CB[7] did not affect the inhibitory properties of 1 and 2. Experiments in primary cortical neurons showed that 1 and 2 can elicit protective effects against oxygen-glucose deprivation at lower doses than those required for Ru265 or Os245. At low concentrations, the protective effects of 1 were modulated by CB[7], suggesting that supramolecular complex formation can play a role in these biological conditions. The biocompatibility of 1 was investigated in mice. The intraperitoneal administration of these compounds and their CB[7] complexes led to time-dependent induction of seizures with no protective effects elicited by CB[7]. This work demonstrates the potential for supramolecular interactions in the development of MCU inhibitors.
被称为线粒体钙单向转运体（MCU）的跨膜蛋白介导钙离子（Ca）流入线粒体基质。线粒体钙（Ca）过载与病理状态下的损伤效应直接相关。因此，MCU抑制剂是重要的化学生物学工具和治疗药物。在此，报道了两种先前报道的基于钌（Ru）和锇（Os）的MCU抑制剂Ru265和Os245的新类似物，通式为(CHCO)M(NH)(μ-N)M(NH)(OCCH)，其中M = Ru（1）或Os（2）。这些类似物带有金刚烷官能团，其被安装用作主体分子葫芦[7]脲（CB[7]）的客体。对这些配合物进行了表征，并分析了它们作为CB[7]客体的效率。通过多种光谱技术表明，每个金刚烷配体被封装到一个CB[7]中，形成化学计量比为1∶2的超分子配合物。评估了这些化合物在存在和不存在两当量CB[7]时的生物学效应。与母体化合物Ru265和Os245相比，配合物1和2均表现出增强的细胞摄取，并且在存在CB[7]的情况下它们的摄取进一步增加。与Ru265和Os245相比，在通透细胞模型中，1和2作为Ca摄取抑制剂的效力较低。然而，在完整细胞系统中，1和2在低至1μM的浓度下就能抑制MCU，这标志着相对于Ru265和Os245的优势，后者需要高一个数量级的剂量才能产生类似的生物学效应。CB[7]的存在并不影响1和2的抑制特性。原代皮层神经元实验表明，与Ru265或Os所需要的剂量相比，1和2在较低剂量下就能对氧糖剥夺产生保护作用。在低浓度下，1的保护作用受CB[7]调节，这表明超分子配合物的形成在这些生物学条件下可能起作用。在小鼠中研究了1的生物相容性。腹腔注射这些化合物及其CB[7]配合物会导致癫痫发作的时间依赖性诱导，且CB[7]未产生保护作用。这项工作证明了超分子相互作用在MCU抑制剂开发中的潜力。
