Extending Cross Metathesis To Identify Selective HDAC Inhibitors: Synthesis, Biological Activities, and Modeling
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2019
Authors
Bouchet, SamuelLinot, Camille
Ružić, Dušan

Agbaba, Danica

Fouchaq, Benoit
Roche, Joelle
Nikolić, Katarina

Blanquart, Christophe
Bertrand, Philippe
Article (Published version)

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Show full item recordAbstract
Dissymmetric cross metathesis of alkenes as a convergent and general synthetic strategy allowed for the preparation of a new small series of human histone deacetylases (HDAC) inhibitors. Alkenes bearing Bocprotected hydroxamic acid and benzamide and trityl-protected thiols were used to provide the zinc binding groups and were reacted with alkenes bearing aromatic cap groups. One compound was identified as a selective HDAC6 inhibitor lead. Additional biological evaluation in cancer cell lines demonstrated its ability to stimulate the expression of the epithelial marker E-cadherin and tumor suppressor genes like SEMA3F and p21, suggesting a potential use of this compound for lung cancer treatment. Molecular docking on all 11 HDAC isoforms was used to rationalize the observed biological results.
Keywords:
Cross metathesis / histone deacetylases / lung cancer / epigenetics / molecular modelingSource:
ACS Medicinal Chemistry Letters, 2019, 10, 6, 863-868Publisher:
- Amer Chemical Soc, Washington
Projects:
DOI: 10.1021/acsmedchemlett.8b00440
ISSN: 1948-5875
PubMed: 31223439