Synthesis and structure-activity relationship of thiol-based histone deacetylase 6 inhibitors.
Chem Biol Drug Des
; 100(1): 90-107, 2022 07.
Article
in En
| MEDLINE
| ID: mdl-35404520
ABSTRACT
Selective histone deacetylase 6 (HDAC6) inhibitors are safe and well-tolerated with less off-target effect. However, most available HDAC6 inhibitors contain hydroxamate as a zinc-binding group (ZBG), and their unfavorable pharmacokinetic properties along with potential genotoxicity limited wide application in diverse diseases. Therefore, we designed and synthesized a series of selective HDAC6 inhibitors utilizing thiol as the ZBG and discussed their structure-activity relationship based on molecular docking. In particular, compound 21, obtained by constantly step-by-step simplification and evolution based on Ricolinostat, a specific HDAC6 inhibitor in Phase II, unexpectedly showed high selectivity (29-fold) and moderate potency (73 nM). Utilizing pyrimidine as a linker in thiol-based HDAC6 inhibitors produces an utterly novel structure, which might display different pharmacokinetic properties and genotoxicity.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Sulfhydryl Compounds
/
Histone Deacetylase Inhibitors
Language:
En
Journal:
Chem Biol Drug Des
Journal subject:
BIOQUIMICA
/
FARMACIA
/
FARMACOLOGIA
Year:
2022
Document type:
Article
Affiliation country:
China