Bao Yu, Xu Qihao, Wang Lin, Wei Yunfei, Hu Baichun, Wang Jian, Liu Dan, Zhao Linxiang, Jing Yongkui
Department of Pharmacology, Liaoning Key Lab of Targeting Drugs for Hematological Malignancies, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, R. P. China.
Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, China.
ACS Med Chem Lett. 2021 Jan 5;12(1):39-47. doi: 10.1021/acsmedchemlett.0c00369. eCollection 2021 Jan 14.
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 () or replacement with hydroxamic acid () or benzamide (). PsA-SH inhibits HDAC1/2/3 and loses the HDAC inhibition ability. inhibits HDAC1/2/3/6 while shows selective inhibition of HDAC3. PsA-SH and , but neither nor , induce apoptosis in human leukemia HL-60 cells associated with increased acetylation of Histone H3. PsA-SH and 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.
沙马普林A（PsA）是一种具有组蛋白去乙酰化酶（HDAC）抑制作用的溴酪氨酸二硫化物二聚体，通过还原单体PsA-SH发挥作用。我们通过用缺失（）修饰-SH基团或用异羟肟酸（）或苯甲酰胺（）替代，研究了HDAC抑制、细胞生长抑制和PsA-SH诱导凋亡之间的联系。PsA-SH抑制HDAC1/2/3，而失去HDAC抑制能力。抑制HDAC1/2/3/6，而显示出对HDAC3的选择性抑制。PsA-SH和，但不是和，在人白血病HL-60细胞中诱导凋亡，这与组蛋白H3乙酰化增加有关。PsA-SH和在体外抑制几种实体瘤细胞系的生长，并在体内抑制Lewis肺癌细胞的生长。PsA-SH是开发选择性HDAC抑制剂的简单支架，并通过抑制HDAC1/2诱导凋亡。
