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

作者：Zhou, Nan; Yan, Yugang; Liu, Chunxi; Hou, Jinning; Xu, Wenfang; Zhang, Yingjie^*

来源：Bioorganic & Medicinal Chemistry, 2017, 25(17): 4614-4619.

DOI：10.1016/j.bmc.2017.06.039

• Pharmacokinetics
• Epigenetics
• Antitumor
• Plasma stability

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 (t(1/2) = 630 min) was over 5-fold improved than its parent 1 (t(1/2) = 103 min). 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.

• 出版日期2017-9-1
• 单位山东大学