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Chem Biol Drug Des. 2016 Oct;88(4):574-84. doi: 10.1111/cbdd.12787. Epub 2016 Jun 24.

PXD101 analogs with L-phenylglycine-containing branched cap as histone deacetylase inhibitors.

Author information

1
Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Ji'nan, Shandong, China.
2
Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Ji'nan, Shandong, China. zhangyingjie@sdu.edu.cn.

Abstract

Histone deacetylases (HDACs) allow histones to wrap DNA more tightly and finally lead to the repression of some tumor suppressor genes. Histone deacetylase inhibitors (HDACIs) have been proved to have effects on tumorigenesis and tumor progression. In this study, we reported the design, synthesis, and in vitro activity evaluation of novel PXD101 analogs with L-phenylglycine-containing cap as HDACIs. Our results showed that HDACs inhibitory activities of compounds 10k, 10r, and 10s were not only superior to the first approved HDACI SAHA, but also comparable to their parent compound PXD101, a recently approved HDACI in 2014. However, all 6 selected PXD101 analogs exhibited moderate in vitro antiproliferative activities, less potent than PXD101 and SAHA. Representative compound 10s showed similar HDACs isoform selective profile to PXD101, which demonstrated that introduction of L-phenylglycine-containing branched cap group could not change the isoform selectivity of PXD101 dramatically.

KEYWORDS:

HDAC inhibitory activity; HDAC isoform selectivity; HDACs; antiproliferative activity; inhibitor

PMID:
27235003
DOI:
10.1111/cbdd.12787
[Indexed for MEDLINE]

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