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J Med Chem. 2015 May 28;58(10):4325-38. doi: 10.1021/acs.jmedchem.5b00317. Epub 2015 May 7.

Design, synthesis, and antitumor evaluation of novel histone deacetylase inhibitors equipped with a phenylsulfonylfuroxan module as a nitric oxide donor.

Author information

1
†Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan, Shandong 250012, People's Republic of China.
2
‡Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, Medical University of South Carolina, Charleston, South Carolina 29425, United States.
3
§Shandong Academy of Pharmaceutical Sciences, Ji'nan, Shandong 250101, People's Republic of China.
4
∥Weifang Bochuang International Biological Medicinal Institute, Weifang, Shandong 261061, People's Republic of China.

Abstract

On the basis of the strategy of creating multifunctional drugs, a novel series of phenylsulfonylfuroxan-based hydroxamates with histone deacetylase (HDAC) inhibitory and nitric oxide (NO) donating activities were designed, synthesized, and evaluated. The most potent NO donor-HDAC inhibitor (HDACI) hybrid, 5c, exhibited a much greater in vitro antiproliferative activity against the human erythroleukemia (HEL) cell line than that of the approved drug SAHA (Vorinostat), and its antiproliferative activity was diminished by the NO scavenger hemoglobin in a dose-dependent manner. Further mechanism studies revealed that 5c strongly induced cellular apoptosis and G1 phase arrest in HEL cells. Animal experiment identified 5c as an orally active agent with potent antitumor activity in a HEL cell xenograft model. Interestingly, although compound 5c was remarkably HDAC6-selective at the molecular level, it exhibited pan-HDAC inhibition in a western blot assay, which is likely due to class I HDACs inhibition caused by NO release at the cellular level.

PMID:
25906087
PMCID:
PMC4548859
DOI:
10.1021/acs.jmedchem.5b00317
[Indexed for MEDLINE]
Free PMC Article

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