School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.
School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.
Angew Chem Int Ed Engl. 2020 Aug 17;59(34):14609-14614. doi: 10.1002/anie.202005758. Epub 2020 Jun 17.
The combination of more than one bioactive moiety in a multitargeted anticancer agent may result in synergistic activity of its components. Using this concept, bioorganometallic compounds were designed to feature a metal center, a 2-pyridinecarbothioamide (PCA), and a hydroxamic acid, which is found in the anticancer drug vorinostat (SAHA). The organometallics showed inhibitory activity in the nanomolar range against histone deacetylases (HDACs) as the key target for SAHA. In particular, the Rh complex was a potent inhibitor of HDAC6 over HDAC1 and HDAC8. Whereas this complex was highly cytotoxic in human cancer cells, it showed low toxicity in hemolysis studies and zebrafish, demonstrating the role of the metal center. For this complex a slightly reduced expression of vascular endothelial growth factor receptor 2 (VEGFR2) was established, which was upregulated by SAHA. This finding indicates that the new organometallics display different modes of action than their bioactive components.
将多种生物活性部分组合在一种多靶点抗癌剂中，可能会导致其成分的协同活性。基于这一概念，设计了生物金属化合物，其特征是金属中心、2-吡啶甲硫酰胺 (PCA) 和羟肟酸，这是抗癌药物伏立诺他 (SAHA) 中的成分。这些金属有机化合物对组蛋白去乙酰化酶 (HDACs) 具有纳米级别的抑制活性，是 SAHA 的关键靶点。特别是，该铑配合物是 HDAC6 的有效抑制剂，对 HDAC1 和 HDAC8 的抑制作用较弱。虽然该配合物在人类癌细胞中具有高细胞毒性，但在溶血研究和斑马鱼中显示出低毒性，表明了金属中心的作用。对于这种配合物，确定了血管内皮生长因子受体 2 (VEGFR2) 的表达略有降低，而 SAHA 可上调其表达。这一发现表明，新的金属有机化合物的作用模式与它们的生物活性成分不同。
