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A Multitargeted Approach: Organorhodium Anticancer Agent Based on Vorinostat as a Potent Histone Deacetylase Inhibitor
Author(s) -
Hanif Muhammad,
Arshad Jahanzaib,
Astin Jonathan W.,
Rana Zohaib,
Zafar Ayesha,
Movassaghi Sanam,
Leung Euphemia,
Patel Kamal,
Söhnel Tilo,
Reynisson Jóhannes,
Sarojini Vijayalekshmi,
Rosengren Rhonda J.,
Jamieson Stephen M. F.,
Hartinger Christian G.
Publication year - 2020
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.202005758
Subject(s) - vorinostat , chemistry , histone deacetylase inhibitor , histone deacetylase , biochemistry , hydroxamic acid , histone , pharmacology , cancer research , stereochemistry , biology , dna
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.