School of Chemistry , Cardiff University , Main Building, Park Place , CF10 3AT Cardiff , United Kingdom.
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy , Universidade de Lisboa , 1649-003 Lisboa , Portugal.
Inorg Chem. 2019 Feb 4;58(3):2140-2148. doi: 10.1021/acs.inorgchem.8b03233. Epub 2019 Jan 15.
Following our recent reports on the inhibition of the water and glycerol channel aquaglyceroporin-3 (AQP3) by the coordination complex [Au(1,10-phenanthroline)Cl] (Auphen), a series of six new Au(III) complexes featuring substituted 1,10-phenanthroline ligands (1-6) have been synthesized and characterized. The speciation of the compounds studied in buffered solution by UV-visible spectrophotometry showed that most of the complexes remain stable for several hours. Quantum mechanics (QM) studies of the hydrolysis processes of the compounds suggest that they are thermodynamically less prone to exchange the chlorido ligands with HO or OH in comparison to Au(III) bipyridyl complexes. Preliminary data on the antiproliferative activity against A549 human lung cancer cells indicate that the compounds are able to inhibit cell proliferation in vitro. Stopped-flow spectroscopy showed that these complexes potently inhibit glycerol permeation in human red blood cells (hRBC) through AQP3 blockage. The QM investigation of the ligand exchange with methanethiol, used as a model of Cys40 of AQP3, was carried out for some derivatives and showed that the affinity of the compounds' binding for thiols is higher in comparison to the Aubipy complex ([Au(bipy)Cl]PF, bipy = 2,2'-bipyridine). In addition, both noncovalent and coordinative binding of complex 3 ( [Au(5-chloro-1,10-phenanthroline)Cl]PF) to the protein channel has been investigated in comparison to the benchmark Auphen and Aubipy using a computational workflow, including QM, molecular dynamics (MD), and quantum mechanics/molecular mechanics (QM/MM) approaches. Finally, atoms in molecules (AIM) and natural bond orbital (NBO) analyses corroborate the MD predictions, providing quantification of the noncoordinative interactions between the compounds and AQP3. AQP3 inhibition is the result of protein conformational changes, upon coordinative gold binding, which induce pore closure. The importance of noncoordinative adducts in modulating the AQP3 inhibition properties of the investigated Au(III) compounds has been elucidated, and these interactions should be further considered in the future design of isoform-selective AQP inhibitors.
继我们最近报道了配位化合物 [Au(1,10-菲咯啉)Cl] (Auphen) 对水和甘油通道水通道蛋白-3 (AQP3) 的抑制作用之后，我们合成并表征了一系列带有取代 1,10-菲咯啉配体的六种新型 Au(III) 配合物（1-6）。通过紫外可见分光光度法在缓冲溶液中研究化合物的形态，发现大多数配合物在数小时内保持稳定。对化合物水解过程的量子力学（QM）研究表明，与 Au(III) 联吡啶配合物相比，它们在热力学上不太可能与 HO 或 OH 交换氯配体。对 A549 人肺癌细胞的抗增殖活性的初步数据表明，这些化合物能够在体外抑制细胞增殖。停流光谱表明，这些配合物通过阻断 AQP3 强烈抑制人红细胞（hRBC）中的甘油渗透。用甲硫醇（用作 AQP3 的 Cys40 的模型）进行的配体交换的 QM 研究表明，与 Aubipy 配合物 ([Au(bipy)Cl]PF，bipy = 2,2'-联吡啶) 相比，化合物的硫醇结合亲和力更高。此外，与基准 Auphen 和 Aubipy 相比，使用包括 QM、分子动力学 (MD) 和量子力学/分子力学 (QM/MM) 方法的计算工作流程，还研究了配合物 3（[Au(5-氯-1,10-菲咯啉)Cl]PF）与蛋白质通道的非共价和配位结合。最后，分子中的原子（AIM）和自然键轨道（NBO）分析证实了 MD 的预测，提供了化合物与 AQP3 之间非配位相互作用的定量。AQP3 的抑制是蛋白质构象变化的结果，配位金结合后诱导孔关闭。阐明了非配位加合物在调节所研究的 Au(III) 化合物对 AQP3 抑制特性中的重要性，在未来对同工型选择性 AQP 抑制剂的设计中应进一步考虑这些相互作用。
