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Design and Synthesis of Dihydroxamic Acids as HDAC6/8/10 Inhibitors
Author(s) -
Morgen Michael,
Steimbach Raphael R.,
Géraldy Magalie,
Hellweg Lars,
Sehr Peter,
Ridinger Johannes,
Witt Olaf,
Oehme Ina,
HerbstGervasoni Corey J.,
Osko Jeremy D.,
Porter Nicholas J.,
Christianson David W.,
Gunkel Nikolas,
Miller Aubry K.
Publication year - 2020
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.202000149
Subject(s) - hdac8 , hdac6 , chemistry , combinatorial chemistry , stereochemistry , small molecule , computational biology , biochemistry , histone deacetylase , biology , histone , gene
We report the synthesis and evaluation of a class of selective multitarget agents for the inhibition of HDAC6, HDAC8, and HDAC10. The concept for this study grew out of a structural analysis of the two selective inhibitors Tubastatin A (HDAC6/10) and PCI‐34051 (HDAC8), which we recognized share the same N ‐benzylindole core. Hybridization of the two inhibitor structures resulted in dihydroxamic acids with benzyl‐indole and ‐indazole core motifs. These substances exhibit potent activity against HDAC6, HDAC8, and HDAC10, while retaining selectivity over HDAC1, HDAC2, and HDAC3. The best substance inhibited the viability of the SK‐N‐BE(2)C neuroblastoma cell line with an IC 50 value similar to a combination treatment with Tubastatin A and PCI‐34051. This compound class establishes a proof of concept for such hybrid molecules and could serve as a starting point for the further development of enhanced HDAC6/8/10 inhibitors.