Anticancer Ru^II and Rh^III Piano‐Stool Complexes that are Histone Deacetylase Inhibitors

Abstract

The first examples of RuII and RhIII piano‐stool complex histone deacetylase (HDAC) inhibitors are presented. The novel complexes have antiproliferative activity against H460 non‐small‐cell lung carcinoma cells that is comparable to the clinically used HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). Strong evidence for HDAC inhibition as a primary mechanism of action is provided. The complexes reported here represent an important step towards the design of highly active and selective HDAC inhibitors.

Cell‐based studies of the first‐in‐class half‐sandwich Ir(III) complex containing histone deacetylase inhibitor 4‐phenylbutyrate

“…The obtained results imply that the HDAC inhibitory efficiency of complex 1‐PB is induced not only by the released PB ligand but by both the Ir‐containing species and the released PB ligand. Similarly to the results obtained for complex 1‐PB , a slightly higher HDAC activity inhibitory efficiency was recently reported for half‐sandwich Ru(II) (98.4% efficiency) and Rh(III) (98.9% efficiency) complexes containing the SAHA‐like derivative of 1,10‐phenanthroline, as compared with the free ligand (95.1% efficiency); SAHA = a known HDAC inhibitor suberoylanilide hydroxamic acid (99.5% efficiency) …”

Perfluorinated HDAC inhibitors as selective anticancer agents

“…23 Hyperacetylation has the opposite effect, increasing tumourrepressor gene expression. As a result, the development of HDAC inhibitors as anticancer agents has been actively pursued, [24][25][26][27][28][29][30][31] with four drugs, including vorinostat (suberoyl anilide hydroxamic acid, SAHA,), 32 approved for treatment of cutaneous T-cell lymphomas and multiple myeloma. SAHA (Figure 1) comprises a hydroxamic acid group that chelates Zn 2+ in a cavity in the enzyme active site, a hydrophobic chain that penetrates the narrow cavity and a phenyl head group that sits at the entrance to the cavity.…”

Pojamide: An HDAC3-Selective Ferrocene Analogue with Remarkably Enhanced Redox-Triggered Ferrocenium Activity in Cells

“…Transition metal-based anticancer agents are interesting due to their novel ligand exchange and redox chemistry, the ability of a heavy metal atom to facilitate phasing in protein x-ray crystallography and the availability of geometries and oxidation states unachievable with carbon-based therapeutics [10][11][12][13] . Ferrocene-based JAHAs and other metal-based analogues, many containing a hydroxamic acid zinc-binding group (ZBG), are effective HDACis with good activity vs. Class I HDACs [14][15][16][17][18][19][20][21][22][23][24][25] . Guided by docking studies of a standard "cap-linker-ZBG" arrangement, we wished to extend the chemistry of JAHAs to ortho-anilide analogues, anticipating that this may lead to HDAC3-selectivity and alleviate toxicity issues documented for hydroxamate ZBGs 26 .…”