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Structure–Activity Relationship of Propargylamine‐Based HDAC Inhibitors
Author(s) -
Wünsch Matthias,
Senger Johanna,
Schultheisz Philipp,
Schwarzbich Sabrina,
Schmidtkunz Karin,
Michalek Carmela,
Klaß Michaela,
Goskowitz Stefanie,
Borchert Philipp,
Praetorius Lucas,
Sippl Wolfgang,
Jung Manfred,
Sewald Norbert
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201700550
Subject(s) - chemistry , cytotoxicity , hdac1 , hdac8 , selectivity , hdac6 , docking (animal) , drug , histone , stereochemistry , combinatorial chemistry , pharmacology , biochemistry , histone deacetylase , biology , gene , medicine , in vitro , nursing , catalysis
As histone deacetylases (HDACs) play an important role in the treatment of cancer, their selective inhibition has been the subject of various studies. These continuous investigations have given rise to a large collection of pan‐ and selective HDAC inhibitors, containing diverse US Food and Drug Administration (FDA)‐approved representatives. In previous studies, a class of alkyne‐based HDAC inhibitors was presented. We modified this scaffold in two previously neglected regions and compared their cytotoxicity and affinity toward HDAC1, HDAC6, and HDAC8. We were able to show that R ‐configured propargylamines contribute to increased selectivity for HDAC6. Docking studies on available HDAC crystal structures were carried out to rationalize the observed selectivity of the compounds. Substitution of the aromatic portion by a thiophene derivative results in high affinity and low cytotoxicity, indicating an improved drug tolerance.