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, 53 (16), 6100-11

Non-peptide Macrocyclic Histone Deacetylase Inhibitors Derived From Tricyclic Ketolide Skeleton

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Non-peptide Macrocyclic Histone Deacetylase Inhibitors Derived From Tricyclic Ketolide Skeleton

Sandra C Mwakwari et al. J Med Chem.

Abstract

Inhibition of histone deacetylase (HDAC) function is a validated therapeutic strategy for cancer treatment. Of the several structurally distinct small molecule histone deacetylase inhibitors (HDACi) reported, macrocyclic depsipeptides possess the most complex cap groups and have demonstrated excellent HDAC inhibition potency and isoform selectivity. Unfortunately, the development of macrocyclic depsipeptides has been hampered in part because of development problems characteristic of large peptides and the complex reaction schemes required for their synthesis. Herein we report that tricyclic ketolide TE-802 is an excellent mimetic for the peptide backbone of macrocyclic HDACi. Compounds derived from this template are particularly selective against HDACs 1 and 2 with nanomolar inhibitory activity. Interrogation of the association between a subset of these compounds and key HDAC isoforms, using AutoDock, enables a molecular description of the interaction between the HDAC enzyme's outer rim and the inhibitors' macrocyclic cap group that are responsible for compound affinity and presumably isoform selectivity.

Figures

Figure 1
Figure 1
a) Pharmacophoric model of HDACi; representative examples of b) acyclic, c) cyclic peptide, and d) macrolide – based HDAC inhibitors.
Figure 1
Figure 1
a) Pharmacophoric model of HDACi; representative examples of b) acyclic, c) cyclic peptide, and d) macrolide – based HDAC inhibitors.
Figure 2
Figure 2
Representative examples of ketolides
Figure 3
Figure 3
Docked structures of ketolide-derived HDACi at the active site of HDAC1. (a) Superposition of the low energy conformation of IIIb (grey) and 15b (green) revealed the pocket binding preferences of inhibitors at the HDAC1 surface. (b) Relative orientation of the macrocyclic rings of 15a (pink) and 15b (green) within the hydrophobic pocket on HDAC1 outer rim.
Scheme 1
Scheme 1
Synthesis of tricyclic ketolide 9 from clarithromycin 1
Scheme 2
Scheme 2
Synthesis of tricyclic ketolide 9 from ketolide 10
Scheme 3
Scheme 3
Synthesis of triazole-linked tricyclic ketolide hydroxamates 15
Figure 4
Figure 4
Comparison of the orientations of (a) the C6-linker compound 15b (green) and C9-linker compound 15e (yellow) at the outer rim of HDAC1; (b) the C5-linker compound 15a (pink) and C6-linker compound 15b (green) at the outer rim of HDAC8.
Figure 5
Figure 5
Determination of Ki for compounds 15a-e using SAMDI mass spectrometry. (a) Dixon plot of compound 15b. (b) Ki values for compounds 15a-e as determined by SAMDI.

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