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.
- 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: [email protected].
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.