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.

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 N 1-hydroxy- N 8 -(4-(pyridine-2-carbothioamido)phenyl)octanediamide (Jazz90) and [chlorido(η 5 -pentamethylcyclopentadienyl)( N 1-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 ].…”

Anti-Proliferative, Anti-Angiogenic and Safety Profiles of Novel HDAC Inhibitors for the Treatment of Metastatic Castration-Resistant Prostate Cancer

“…These compounds were also potent HDAC inhibitors with activity superior to SAHA at reducing the expression levels of VEGF-A and VEGFR-2. Jazz90 was 4-fold more potent at inhibiting HDAC6, and Jazz167 was 2-, 4-and 40-fold more potent at inhibiting HDACs 1, 6 and 8 than SAHA [22,23].…”

“…For example, Ye et al ( 2013) added a transition metal phenanthroline moiety to SAHA, which increased its potency by 2-to 23-fold in cervical (HeLa), lung (A549 and A549R) and liver (HepG2 and LO2) cancer cells [21]. With the aforementioned evidence, pyridine carbothioamide was functionalised onto SAHA to produce Jazz90 (N1-hydroxy-N 8 -(4-(pyridine-2-carbothioamido)phenyl)octanediamide), whereas Jazz167 ([chlorido(η 5 pentamethylcyclopentadienyl)(N1-hydroxy-N 8 -(4-(pyridine-2-carbothioamido-κ 2 N,S) phenyl)octanediamide)rhodium(III)] chloride) was obtained by coordinating a rhodium(pentamethylcyclopentadienyl) moiety to Jazz90 (Figure 1), and the pharmacodynamic profiles of these compounds were the same as for SAHA [22]. for hematological malignancies such as peripheral cutaneous T-cell lymphoma and multiple myeloma [8][9][10].…”