Open AccessHydroxyl Ketone-Based Histone Deacetylase Inhibitors To Gain Insight into Class I HDAC Selectivity versus That of HDAC6
Author(s) -
Mohamed Dit Mady Traoré,
Vincent Zwick,
Cláudia A. Simões-Pires,
Alessandra Nurisso,
Mark E. Issa,
Muriel Cuendet,
Marjorie Maynadier,
Sharon Wein,
Henri Vial,
Hélène Jamet,
YungSing Wong
Publication year - 2017
Publication title -
acs omega
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.779
H-Index - 40
ISSN - 2470-1343
DOI - 10.1021/acsomega.6b00481
Subject(s) - selectivity , linker , chemistry , hdac6 , hdac1 , gene isoform , histone deacetylase , ketone , biochemistry , combinatorial chemistry , histone , stereochemistry , gene , organic chemistry , computer science , catalysis , operating system
Little is known about the biological and structural features that govern the isoform selectivity for class I histone deacetylases (HDACs) over HDAC6. In addition to that for known inhibitors, like benzamides, psammaplin A, and cyclodepsipeptide-derived thiols, selectivity was also observed for naturally occurring cyclopeptide HDAC inhibitors with an aliphatic flexible linker and ketonelike zinc-binding group (ZBG). The present study reports that this isoform selectivity is mainly due to the linker and ZBG, as replacement of the cyclopeptide cap region by a simple aniline retained class I HDAC isoform selectivity toward HDAC6 in enzymatic assays. The best cyclopeptide-free analogues preserved efficacy against Plasmodium falciparum and cancer cell lines. Molecular modeling provided hypotheses to explain this selectivity and suggests different behaviors of the flexible linker on HDAC1 and HDAC6 pockets, which may influence, on the basis of the strength of the ZBG, its coordination with the zinc ion.