Discovery of a tetrahydroisoquinoline-based HDAC inhibitor with improved plasma stability

Publication date: 1 September 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 17
Author(s): Nan Zhou, Yugang Yan, Chunxi Liu, Jinning Hou, Wenfang Xu, Yingjie Zhang
Histone deacetylase inhibitors with desirable pharmacokinetic profiles which can be delivered to solid tumor tissues in large amount might be promising to treat solid tumor effectively. Herein, structural modification of a previously reported tetrahydroisoquinoline-based HDAC inhibitor 1 was carried out to improve its plasma stability for more feasible drug delivery. Among three newly synthesized analogs, the in vitro rat plasma stability of compound 2 (t1/2=630min) was over 5-fold improved than its parent 1 (t1/2=103min). In vitro activity evaluation showed that compound 2 and 1 exhibited similar HDACs inhibitory activity, which was validated by western blot analysis and antiproliferative assay. Moreover, compared with 1, compound 2 exhibited comparable, if not higher, in vivo antitumor activity in a human breast carcinoma (MDA-MB-231) xenograft model.

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