A fluorine scan on the Zn2+-binding thiolate side chain of HDAC inhibitor largazole: Synthesis, biological evaluation, and molecular modeling.

A fluorine scan on the Zn2+-binding thiolate side chain of HDAC inhibitor largazole: Synthesis, biological evaluation, and molecular modeling. Eur J Med Chem. 2019 Sep 04;182:111672 Authors: Zhang B, Liu J, Gao D, Yu X, Wang J, Lei X Abstract Based on the unique role of a common unit in a family of sulfur-containing natural histone deacetylases (HDACs) inhibitors, we have chosen largazole as an example of these inhibitors and adopted a "fluorine scan" strategy towards modification of this common unit. Thus a set of fluoro largazole analogues has been designed, synthesized and evaluated in enzymatic as well as cellular assays. The preliminary results indicate that introduction of fluorine at the various position of the unit has an important impact on the activity and selectivity of HDACs. Unlike other modifications which often led to significant reduction or complete loss of activity as reported in the literature, most of these fluoro thiols have displayed comparable or enhanced activity and selectivity in enzymatic assays. Two of the sulfhydryl esters have also exhibited excellent inhibitory activity in cellular assays with a few selected cell lines. The C19-fluorinated analogue has been further studied by immunoblot analysis, confirming that it is a potent selective class I HDAC inhibitor and supporting that the potent cellular antiproliferative activity is due to HDAC inhibition. The molecular docking study reveals that introducing...
Source: European Journal of Medicinal Chemistry - Category: Chemistry Authors: Tags: Eur J Med Chem Source Type: research