Studying Histone Deacetylase Inhibition and Apoptosis Induction of Psammaplin A Monomers with Modified Thiol Group
- ACS Med Chem Lett. 2021 Jan 5;12(1):39-47. doi: 10.1021/acsmedchemlett.0c00369.
- 1. Department of Pharmacology, Liaoning Key Lab of Targeting Drugs for Hematological Malignancies, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, R. P. China.
- 2. Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, China.
Psammaplin A (PsA) is a bromotyrosine disulfide dimer with histone deacetylase (HDAC) inhibition and acts through reduced monomer PsA-SH. We studied the connection of HDAC inhibition, cell growth inhibition, and Apoptosis induction of PsA-SH by modifying the -SH group with deletion (6a) or replacement with hydroxamic acid (10b) or benzamide (12g). PsA-SH inhibits HDAC1/2/3 and 6a loses the HDAC inhibition ability. 10b inhibits HDAC1/2/3/6 while 12g shows selective inhibition of HDAC3. PsA-SH and 10b, but neither 6a nor 12g, induce Apoptosis in human leukemia HL-60 cells associated with increased acetylation of Histone H3. PsA-SH and 10b inhibit growth of several solid tumor cell lines in vitro and Lewis lung Cancer cell growth in vivo. PsA-SH is a simple scaffold for developing selective HDAC inhibitors and induces Apoptosis through inhibiting HDAC1/2.