Open AccessFluorinated Analogues of the Histone Deacetylase Inhibitor Vorinostat (Zolinza): Validation of a Chiral Hybrid Bioisostere, BITE
Author(s) -
Nathalie Erdeljac,
Kathrin Bussmann,
Andrea Schöler,
Finn K. Hansen,
Ryan Gilmour
Publication year - 2019
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00287
Subject(s) - bioisostere , vorinostat , histone deacetylase , chemistry , histone deacetylase inhibitor , pharmacology , stereochemistry , combinatorial chemistry , histone , in vitro , medicine , biochemistry , chemical synthesis , gene
A chiral, hybrid bioisostere of the CF 3 and Et groups (BITE) was installed in a series of vorinostat (Zolinza) analogues, and their histone deacetylase (HDAC) inhibitory behavior was studied relative to that of their nonfluorinated counterparts. Several of these compounds containing the 1,2-difluoroethylene unit showed in vitro potency greater than that of the clinically approved drug itself against HDAC1. This trend was found to be general with the BITE-modified HDAC inhibitors performing significantly better than the ethyl derivatives. Installed by the direct, catalytic vicinal difluorination of terminal alkenes using an I(I)/I(III) manifold, this underexplored chiral bioisostere shows potential in drug discovery.