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Discovery of Potent HDAC Inhibitors Based on Chlamydocin with Inhibitory Effects on Cell Migration
Author(s) -
Wang Shimiao,
Li Xiaohui,
Wei Yingdong,
Xiu Zhilong,
Nishino Norikazu
Publication year - 2014
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.201300372
Subject(s) - trichostatin a , chemistry , histone deacetylase , hdac1 , matrix metalloproteinase , matrix metalloproteinase inhibitor , timp1 , hydroxamic acid , docking (animal) , western blot , apoptosis , cell cycle checkpoint , biochemistry , cell culture , inhibitory postsynaptic potential , cell migration , cell growth , cell , cell cycle , stereochemistry , histone , biology , gene expression , medicine , genetics , nursing , gene , neuroscience
The histone deacetylase (HDAC) family is a promising drug target class owing to the importance of these enzymes in a variety of cellular processes. Docking studies were conducted to identify novel HDAC inhibitors. Subtle modifications in the recognition domain were introduced into a series of chlamydocin analogues, and the resulting scaffolds were combined with various zinc binding domains. Remarkably, cyclo ( L ‐Asu(NHOH)‐ L ‐A3mc6c‐ L ‐Phe‐ D ‐Pro, compound 1 b ), with a methyl group at positions 3 or 5 on the aliphatic ring, exhibited better antiproliferative effects than trichostatin A (TSA) against MCF‐7 and K562 cell lines. In addition to cell‐cycle arrest and apoptosis, cell migration inhibition was observed in cells treated with compound 1 b . Subsequent western blot analysis revealed that the balance between matrix metalloproteinase 2 (MMP2) and tissue inhibitors of metalloproteinase 1 (TIMP1) determines the degree of metalloproteinase activity in MCF‐7 cells, thereby regulating cell migration. The improved inhibitory activity imparted by altering the hydrophobic substitution pattern at the bulky cap group is a valuable approach in the development of novel HDAC inhibitors.