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Fluorinated Analogues of the Histone Deacetylase Inhibitor Vorinostat (Zolinza): Validation of a Chiral Hybrid Bioisostere, BITE.


ABSTRACT: A chiral, hybrid bioisostere of the CF3 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.

SUBMITTER: Erdeljac N 

PROVIDER: S-EPMC6745648 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Fluorinated Analogues of the Histone Deacetylase Inhibitor Vorinostat (Zolinza): Validation of a Chiral Hybrid Bioisostere, BITE.

Erdeljac Nathalie N   Bussmann Kathrin K   Schöler Andrea A   Hansen Finn K FK   Gilmour Ryan R  

ACS medicinal chemistry letters 20190719 9


A chiral, hybrid bioisostere of the CF<sub>3</sub> 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 <i>in vitro</i> potency greater than that of the clinically approved drug itself against HDAC1. This trend was found to be general with the BITE-modified HDAC inhibitor  ...[more]

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