2. Academic Validation
  3. Discovery of a tetrahydroisoquinoline-based HDAC inhibitor with improved plasma stability

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

  • Bioorg Med Chem. 2017 Sep 1;25(17):4614-4619. doi: 10.1016/j.bmc.2017.06.039.
Nan Zhou 1,  Yugang Yan 2,  Chunxi Liu 3,  Jinning Hou 2,  Wenfang Xu 2,  Yingjie Zhang 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Ji'nan, Shandong 250012, PR China; Drug Research and Development Center, Shandong Drug and Food Vocational College, Weihai, Shandong 264210, PR China.
  • 2 Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Ji'nan, Shandong 250012, PR China.
  • 3 Department of Pharmacy, Qilu Hospital, Shandong University, Ji'nan, Shandong 250012, PR China.
  • 4 Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Ji'nan, Shandong 250012, PR China; Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Ji'nan, Shandong 250012, PR China. Electronic address: zhangyingjie@sdu.edu.cn.
PMID: 28757101 DOI: 10.1016/j.bmc.2017.06.039
Abstract

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.

Keywords

Antitumor; Epigenetics; Pharmacokinetics; Plasma stability.

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