A Multitargeted Approach in the Discovery of an Organorhodium Anticancer Agent Based On Vorinostat as a Potent Histone Deacetylase Inhibitor

: The combination of more than one bioactive moiety in a mulitargeted 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, Rh complex 4c was a potent inhibitor of HDAC6 over HDAC1 and HDAC8. While especially 4c was highly cytotoxic in human cancer cells, it showed low toxicity in hemolysis studies and zebrafish, demonstrating the role of the metal center. For 4c , a slightly reduced expression of vascular endothelial growth factor receptor 2 (VEGFR2) was established, which was upregulated by SAHA. This indicates that the new organometallics display different modes of action than their components, supporting the development of non-conventional anticancer drugs.