PUBLICATION
Discovery of novel tubulin/HDAC dual-targeting inhibitors with strong antitumor and antiangiogenic potency
- Authors
- Wang, Y., Sun, M., Wang, Y., Qin, J., Zhang, Y., Pang, Y., Yao, Y., Yang, H., Duan, Y.
- ID
- ZDB-PUB-210829-14
- Date
- 2021
- Source
- European Journal of Medicinal Chemistry 225: 113790 (Journal)
- Registered Authors
- Keywords
- Antiangiogenesis, Antitumor, HDAC, Tubulin
- MeSH Terms
-
- Molecular Structure
- Histone Deacetylases/metabolism*
- Cell Line, Tumor
- Dose-Response Relationship, Drug
- Structure-Activity Relationship
- Angiogenesis Inhibitors/chemical synthesis
- Angiogenesis Inhibitors/chemistry
- Angiogenesis Inhibitors/pharmacology*
- Zebrafish/embryology
- Cell Proliferation/drug effects
- Tubulin Modulators/chemical synthesis
- Tubulin Modulators/chemistry
- Tubulin Modulators/pharmacology*
- Animals
- Membrane Potential, Mitochondrial/drug effects
- Tubulin/metabolism
- Antineoplastic Agents/chemical synthesis
- Antineoplastic Agents/chemistry
- Antineoplastic Agents/pharmacology*
- Drug Screening Assays, Antitumor
- Apoptosis/drug effects
- Histone Deacetylase Inhibitors/chemical synthesis
- Histone Deacetylase Inhibitors/chemistry
- Histone Deacetylase Inhibitors/pharmacology*
- Drug Discovery*
- Polymerization/drug effects
- Neoplasms, Experimental/drug therapy
- Neoplasms, Experimental/metabolism
- Neoplasms, Experimental/pathology
- Humans
- Neovascularization, Physiologic/drug effects*
- PubMed
- 34454126 Full text @ Eur. J. Med. Chem.
Citation
Wang, Y., Sun, M., Wang, Y., Qin, J., Zhang, Y., Pang, Y., Yao, Y., Yang, H., Duan, Y. (2021) Discovery of novel tubulin/HDAC dual-targeting inhibitors with strong antitumor and antiangiogenic potency. European Journal of Medicinal Chemistry. 225:113790.
Abstract
A novel series of cis-diphenylethene and benzophenone derivatives as tubulin/HDAC dual-targeting inhibitors were designed and synthesized. Among them, compound 28g exhibited the most potent antiproliferative activities against six different human cancer cell lines, 28g could not only inhibited tubulin polymerization, disrupted cellular microtubule networks but also selectively inhibited class IIa HDACs, especially HDAC7 activity. Further molecular docking demonstrated 28g could occupy the binding pockets of tubulin and HDAC7 meanwhile. Cellular mechanism studies revealed that 28g could induce G2/M phase arrest by down-regulated expression of p-cdc2 and cell apoptosis by regulating mitochondrial membrane potential, reactive oxygen species (ROS) levels and apoptosis-related proteins (PARP, Caspase families) in a dose-dependent manner. Importantly, 28g significantly inhibited HUVEC tube formation, proliferation, migration and invasion. The inhibitory effect against angiogenesis in vivo was confirmed by zebrafish xenograft. Furthermore, 28g could effectively suppress the proliferation and metastasis of MGC-803 cells in vitro and in zebrafish xenograft. All above results indicated that 28g can act as a promising antitumor and antiangiogenic agent via targeting tubulin and class IIa HDACs.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping