Macrocyclic histone deacetylase inhibitors

Abstract

Histone deacetylase inhibitors (HDACi) are an emerging class of novel anti-cancer drugs that cause growth arrest, differentiation, and apoptosis of tumor cells. In addition, they have shown promise as anti-parasitic, anti-neurodegenerative, anti-rheumatologic and immunosuppressant agents. To date, several structurally distinct small molecule HDACi have been reported including aryl hydroxamates, benzamides, short-chain fatty acids, electrophilic ketones, and macrocyclic peptides. Macrocyclic HDACi possess the most complex cap-groups which interact with HDAC enzyme's outer rim and have demonstrated excellent HDAC inhibition potency and isoform selectivity. This review focuses on the recent progress and current state of macrocyclic HDACi.

Fig. (1)

Selected Examples of HDAC Inhibitors: (a) Linear HDACi, (b) Macrocyclic HDACi.

Fig. (2)

Examples of cyclic tetrapeptide HDACi.

Fig. (3)

Examples of depsipeptide HDACi.

Fig. (4)

Structure of Macrocyclic Succinimide Hydroxamic Acids 4 and 5.

Fig. (5)

a) Macrocyclic peptide mimetic class of HDAC inhibitors; b) Intermediate of the final macrocyclic hydroxamic acid products 7 and 8.

Fig. (6)

Analogs of (a) 15-membered azithromycin and (b) 14-membered clarithromycin classes of HDAC inhibitors.

Fig. (7)

Docked structures of 14- and 15-membered macrolide-derived HDACi at the active site of HDLP. (a) Superposition of the low energy conformation of 13a (blue) and SAHA (yellow) revealed the pocket binding preferences of inhibitors at the HDLP surface. (b) Relative orientation of the macrocyclic rings of 13b (orange) and 15b (yellow) with respect to Phe 338 at the HDLP surface.

Fig. (8)

Non-peptide HDAC inhibitors based on tricyclic ketolide scaffold.

Fig. (9)

Docked structures of ketolide-derived HDACi at the active site of HDLP. (a) Superposition of the low energy conformation of 13b (grey) and 16b (blue) revealed the pocket binding preferences of inhibitors at the HDLP surface. (b) Relative orientation of the macrocyclic rings of 16a (yellow) and 16b (green) within the Phe 338 pocket. (c) Comparison of the orientation of the macrocyclic rings of the C₆-linker compound 16b (grey) and C₉-linker compound 16e (light-blue) within the Phe 338 pocket revealed the structural basis for the chain length dependence of the anti-HDAC activities of ketolide-derived HDACi.

Fig. (10)

Cyclostellettamine A and its congeners.