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. 2020 May 21;25(10):2383.
doi: 10.3390/molecules25102383.

Anticancer Ruthenium Complexes with HDAC Isoform Selectivity

Jasmine M Cross  1 , Tim R Blower  2 , Alexander D H Kingdon  1 , Robert Pal  1 , David M Picton  2 , James W Walton  1
Affiliations

Anticancer Ruthenium Complexes with HDAC Isoform Selectivity

Jasmine M Cross et al. Molecules. .

Abstract

The histone deacetylase (HDAC) enzymes have emerged as an important class of molecular targets in cancer therapy, with five inhibitors in clinical use. Recently, it has been shown that a lack of selectivity between the 11 Zn-dependent HDAC isoforms may lead to unwanted side-effects. In this paper, we show that piano stool Ru complexes can act as HDAC inhibitors, and variation in the capping arene leads to differences in HDAC isoform selectivity.

Keywords: histone deacetylase inhibitors; ruthenium in medicine; selective enzyme inhibition.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(A) HDAC pan inhibitor SAHA and Ru complexes 8a–f, described in this work. (B) Docking models of SAHA with isoforms HDAC1 (upper) and HDAC6 (lower), showing the differences in active site cavity entrances.
Scheme 1
Scheme 1
(A) Synthesis of complex 1 and (B) synthesis of complexes 8a–f.
Figure 2
Figure 2
HDAC1 and HDAC6 inhibition assays of Ru complexes 1 and 8a–f, and control compounds, measured using commercially available assay kits. All assays carried out in triplicate. See Supplementary Materials for details.
Figure 3
Figure 3
Computational docking studies showing (A) Zn(II) coordination view of SAHA with HDAC1; (B) active site cavity entrance surface view of SAHA with HDAC1; (C) Zn(II) coordination view of SAHA with HDAC6; (D) active site cavity entrance surface view of SAHA with HDAC6; (E) active site cavity entrance surface view of L1 with HDAC1; (F) active site cavity entrance surface view of L1 with HDAC6; (G) Zn(II) coordination view of L1 (gold) and 1 (teal) overlapped with HDAC6; (H) active site cavity entrance surface view of L1 and 1 overlapped with HDAC6.
See this image and copyright information in PMC

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