A Multitargeted Approach: Organorhodium Anticancer Agent Based on Vorinostat as a Potent Histone Deacetylase Inhibitor
| Autor: | Stephen M. F. Jamieson, Rhonda J. Rosengren, Kamal Patel, Muhammad Hanif, Jahanzaib Arshad, Jonathan W. Astin, Sanam Movassaghi, Christian G. Hartinger, Euphemia Leung, Ayesha Zafar, Tilo Söhnel, Vijayalekshmi Sarojini, Zohaib Rana, Jóhannes Reynisson |
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| Rok vydání: | 2020 |
| Předmět: |
medicine.drug_class
Antineoplastic Agents Pharmacology 010402 general chemistry 01 natural sciences Catalysis chemistry.chemical_compound Cell Line Tumor medicine Organometallic Compounds Humans Rhodium Vorinostat Hydroxamic acid biology 010405 organic chemistry Drug discovery Histone deacetylase inhibitor HDAC8 General Medicine General Chemistry HDAC6 HDAC1 0104 chemical sciences Histone Deacetylase Inhibitors Histone chemistry biology.protein medicine.drug |
| Zdroj: | Angewandte Chemie (International ed. in English). 59(34) |
| ISSN: | 1521-3773 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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