Hanif, M, Arshad, J, Astin, J, Rana, Z, Zafar, A, Movassaghi, S, Leung, E, Patel, K, Soehnel, T, Reynisson, J, Sarojini, V, Rosengren, R, Jamieson, S and Hartinger, C (2020) A Multitargeted Approach in the Discovery of an Organorhodium Anticancer Agent Based On Vorinostat as a Potent Histone Deacetylase Inhibitor. Angew Chem Int Ed Engl. ISSN 1521-3773

[thumbnail of J Reynisson - manuscript 2020-03-16-AngChem-Word.pdf]
J Reynisson - manuscript 2020-03-16-AngChem-Word.pdf - Accepted Version
Available under License Creative Commons Attribution Non-commercial.

Download (427kB) | Preview


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.

Item Type: Article
Uncontrolled Keywords: anticancer agents; bioorganometallics; HDAC inhibitors; multitargeted compounds; pyridinecarbothioamide ligands
Subjects: R Medicine > R Medicine (General)
R Medicine > RS Pharmacy and materia medica
Divisions: Faculty of Medicine and Health Sciences > School of Pharmacy and Bioengineering
Related URLs:
Depositing User: Symplectic
Date Deposited: 15 Jun 2020 13:41
Last Modified: 19 May 2021 01:30
URI: https://eprints.keele.ac.uk/id/eprint/8161

Actions (login required)

View Item
View Item