2. Academic Validation
  3. Discovery of thiosemicarbazone-containing compounds with potent anti-proliferation activity against drug-resistant K562/A02 cells

Discovery of thiosemicarbazone-containing compounds with potent anti-proliferation activity against drug-resistant K562/A02 cells

  • Bioorg Med Chem Lett. 2020 Dec 15;30(24):127638. doi: 10.1016/j.bmcl.2020.127638.
Xiaoke Gu 1,  Xin Li 2,  Mingyu Guan 2,  Chunyu Jiang 2,  Qinghua Song 2,  Nan Sun 2,  Yueting Zou 3,  Qingqing Zhou 3,  Jing Chen 3,  Jingying Qiu 4
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, People's Republic of China. Electronic address: gu_xk@xzhmu.edu.cn.
  • 2 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, People's Republic of China.
  • 3 Department of Pharmaceutical Analysis, School of Pharmacy, Xuzhou Medical University, Xuzhou 221004, People's Republic of China.
  • 4 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, People's Republic of China; Department of Pharmaceutical Analysis, School of Pharmacy, Xuzhou Medical University, Xuzhou 221004, People's Republic of China. Electronic address: jingyqiu@xzhmu.edu.cn.
PMID: 33132117 DOI: 10.1016/j.bmcl.2020.127638
Abstract

P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a major obstacle to successful chemotherapy for leukemia. In this study, a series of thiosemicarbazone-containing compounds (4a-b, 7a-q) were synthesized. Biological evaluation showed that the most active compound 7e displayed potent anti-leukemia activity against P-gp overexpressing drug-resistant K562/A02 cells, with an IC50 value of 0.44 μM. Notably, compound 7e exhibited a selective killing effect on K562/A02 cells by dose-dependently increasing the intracellular levels of Reactive Oxygen Species (ROS), thus exerting a potential collateral sensitivity (CS)-promoting effect in vitro. Moreover, compound 7e could inhibit HDAC1 and HDAC6, and induce the Apoptosis of K562/A02 cells by increasing the expression of Bax, decreasing Bcl-2 protein level, and promoting the cleavage of Caspase-3 and PARP, respectively. Overall, 7e may be a potential anti-cancer agent against drug-resistant myelogenous leukemia.

Keywords

Collateral sensitivity; HDACs inhibitor; Multidrug resistance; P-glycoprotein; Thiosemicarbazones.

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