A Multitargeted Approach: Organorhodium Anticancer Agent Based on Vorinostat as a Potent Histone Deacetylase Inhibitor

Abstract

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.

Indole-containing arene-ruthenium complexes with broad spectrum activity against antibiotic-resistant bacteria

“…( Silva et al., 2021 ) Medicinal inorganic chemistry has been stimulated by the success of platinum anticancer drugs (used as a component of nearly 50% of all cancer chemotherapy treatments), by the use of gadolinium(III) complexes as MRI contrast agents (about 20 million doses administered per year), and of the radionuclide 99m-technetium radiopharmaceuticals for γ-ray imaging (used in about 20 million radio diagnostic procedures each year). ( Biancalana et al., 2020 , ( Farley et al., 2021 ), Hanif et al., 2020 , Rafols et al., 2021 ) However, the involvement of metals in many other diseases and conditions is of current interest in relation to their causes, their treatment or detection, including neurodegeneration, ( Anthony et al., 2020 ) fungal ( Golbaghi et al., 2020 ), parasitic, ( Minori et al., 2020 , Melis et al., 2021 ) viral ( Yuan et al., 2020 ) infections and inflammation. ( Zhang et al., 2017 ) In the last decades, a wide range of inorganic and organometallic compounds have been investigated for killing or inhibiting microbial growth.…”

Cytostatic Action of Novel Histone Deacetylase Inhibitors in Androgen Receptor-Null Prostate Cancer Cells

“…The Histone Deacetylase (HDAC) Activity Assay Kit (Fluorometric) was purchased from Abcam (Melbourne, Australia). Jazz90 and Jazz167 were synthesized as previously described [23]. SAHA was obtained from AK Scientific (Union City, CA, USA).…”

“…We have previously synthesized the novel HDAC inhibitors N1-hydroxy-N 8 -(4-(pyridine-2-carbothioamido)phenyl)octanediamide(Jazz90)and[chlorido(η 5 -pentamethylcyclopentadienyl) (N1-hydroxy-N 8 -(4-(pyridine-2-carbothioamido-κ 2 N,S)phenyl)octanediamide)rhodium(III)] chloride (Jazz167) (Figure 1), which are structural analogues of SAHA [23]. Substitution of the phenyl group of SAHA for a pyridinecarbothioamide moiety yielded Jazz90.…”

“…Minimal hemolytic activity (10%) was recorded at high concentrations of 200 µM. In comparison, cisplatin, an FDA-approved metal-based drug for bladder cancer, exhibited 100% hemolytic activity at 200 µM [23]. Similarly, organometallic pyridinecarbothioamide compounds featuring osmium and ruthenium centers have also exhibited cytotoxicity against CH1 (ovarian), SW480 (colorectal), and A549 (lung) cancer cells [25].…”

Impact of the Metal Center and Leaving Group on the Anticancer Activity of Organometallic Complexes of Pyridine-2-carbothioamide

“…Osmium complexes have slower ligand exchange reactions compared to their Ru counterparts [31,32]. In addition, half-sandwich rhodium and iridium compounds have emerged as promising chemotherapeutic agents [33].…”