2. Academic Validation
  3. 2-Methoxydiol derivatives as new tubulin and HDAC dual-targeting inhibitors, displaying antitumor and antiangiogenic response

2-Methoxydiol derivatives as new tubulin and HDAC dual-targeting inhibitors, displaying antitumor and antiangiogenic response

  • Bioorg Chem. 2022 Mar;120:105625. doi: 10.1016/j.bioorg.2022.105625.
Moran Sun 1,  Jinling Qin 2,  Yingying Kang 2,  Yixin Zhang 2,  Mengyu Ba 2,  Hua Yang 2,  Yongtao Duan 3,  Yongfang Yao 4
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, and Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
  • 2 School of Pharmaceutical Sciences, and Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China.
  • 3 Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou 450018, China.
  • 4 School of Pharmaceutical Sciences, and Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, China. Electronic address: yongfangyao%20@zzu.edu.cn.
PMID: 35078046 DOI: 10.1016/j.bioorg.2022.105625
Abstract

Multi-target drugs design has become an active research field because of their advantages in Cancer treatment. In present study, HDAC inhibitors pharmacophore and 2-methoxyestradiol(2ME2) were combined into a new hybrid molecule for the first time. Forty-seven 2ME2 derivatives were synthesized and evaluated for antiproliferative activity. In particular, compound 4s exhibited a dual inhibition of tubulin polymerization and HDAC (IC50 = 0.06 µM toward HDAC2) activity, as well as the most potent cytotoxicity IC50 values of 0.37-4.84 µM against six Cancer cell lines. Compound 4s remarkably disrupted microtubule networks, arrested cell cycle at G2/M phase, induced mitochondrial membrane potential collapse and eventually Apoptosis in A549 cells. Notably, 4s was discovered to potently imped the tube-formation of HUVECs and prohibited the proliferation, migration, and invasion of HUVECs, as well as A549 cells. In addition, the anti-angiogenic and anti-metastasis activities were demonstrated via a zebrafish model test. All these beneficial Anticancer activities together with its high selectivity toward noncancer cells, suggested 4s may deserves consideration for Cancer therapy.

Keywords

2-Methoxyestradiol; Angiogenesis; HDAC; Microtubule; Zebrafish.

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