Histone deacetylase (HDAC) inhibition is a promising therapeutic strategy for cancer treatment because HDAC inhibitors have shown the ability to arrest proliferation of transformed cell lines by reactivating silenced tumor-suppressor-genes by modulating the condensation status of DNA. Recently, we have reported a new class of hydroxamic acid based HDAC inhibitors containing 14- or 15-membered non-peptide macrolide antibiotic skeletons as surface recognition group. In these HDAC inhibitors, the modified macrolide antibiotic is linked to the zinc chelating hydroxamic acid moiety via 5- or 6-methylene chain linker. Most of the compounds showed low nano-molar HDAC inhibitory activities and many of them inhibited proliferation of human lung, prostate, and breast cancer cell lines. Moreover, azithromycin-hydroxamic acid, with six methylene linker, selectively accumulates in vivo in the lung tissues of Bald/C mice, allowing for tissue targeted anti-cancer therapy. To further understand the depth of the SAR of this class of compounds on HDAC inhibitory activities, we investigated the effects of: (i) varying linker length; and (ii) macrolide modification. We observed that in most of the instances these modifications were well tolerated and the compounds retained their HDAC inhibitory and anti-proliferative activities and in some cases therapeutic profile is even better than previously reported compounds. We also tested all the potent HDAC inhibitors for their anti-inflammatory activities and interestingly some of the potent compounds inhibited bacterium NTHI induced NfkB-dependent inflammatory response in vitro in human lung epithelial cells.

Nonpeptide macrocyclic histone deacetylase inhibitors: Targeting cancer and inflammation

247th National Meeting (2014)

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