PUBLICATION
2-Methoxydiol derivatives as new tubulin and HDAC dual-targeting inhibitors, displaying antitumor and antiangiogenic response
- Authors
- Sun, M., Qin, J., Kang, Y., Zhang, Y., Ba, M., Yang, H., Duan, Y., Yao, Y.
- ID
- ZDB-PUB-220126-50
- Date
- 2022
- Source
- Bioorganic chemistry 120: 105625 (Journal)
- Registered Authors
- Keywords
- 2-Methoxyestradiol, Angiogenesis, HDAC, Microtubule, Zebrafish
- MeSH Terms
-
- Animals
- Antineoplastic Agents*/pharmacology
- Antineoplastic Agents*/therapeutic use
- Apoptosis
- Cell Line, Tumor
- Cell Proliferation
- Drug Screening Assays, Antitumor
- Histone Deacetylase Inhibitors*/pharmacology
- Structure-Activity Relationship
- Tubulin/metabolism
- Tubulin Modulators/pharmacology
- Zebrafish/metabolism
- PubMed
- 35078046 Full text @ Bioorg. Chem.
Citation
Sun, M., Qin, J., Kang, Y., Zhang, Y., Ba, M., Yang, H., Duan, Y., Yao, Y. (2022) 2-Methoxydiol derivatives as new tubulin and HDAC dual-targeting inhibitors, displaying antitumor and antiangiogenic response. Bioorganic chemistry. 120:105625.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping