PUBLICATION
Synthesis and biological evaluation of new 2-methoxyestradiol derivatives: Potent inhibitors of angiogenesis and tubulin polymerization
- Authors
- Sun, M., Zhang, Y., Qin, J., Ba, M., Yao, Y., Duan, Y., Liu, H., Yu, D.
- ID
- ZDB-PUB-210526-12
- Date
- 2021
- Source
- Bioorganic chemistry 113: 104988 (Journal)
- Registered Authors
- Keywords
- Angiogenesis, Breast cancer, Metastasis, Tubulin
- MeSH Terms
-
- 2-Methoxyestradiol/chemical synthesis
- 2-Methoxyestradiol/chemistry
- 2-Methoxyestradiol/pharmacology*
- Angiogenesis Inhibitors/chemical synthesis
- Angiogenesis Inhibitors/chemistry
- Angiogenesis Inhibitors/pharmacology*
- Animals
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Dose-Response Relationship, Drug
- Drug Screening Assays, Antitumor
- Humans
- Molecular Structure
- Neoplasms, Experimental/drug therapy
- Neoplasms, Experimental/metabolism
- Neoplasms, Experimental/pathology
- Neovascularization, Pathologic/drug therapy*
- Neovascularization, Pathologic/metabolism
- Neovascularization, Pathologic/pathology
- Polymerization/drug effects
- Structure-Activity Relationship
- Tubulin/metabolism*
- Tubulin Modulators/chemical synthesis
- Tubulin Modulators/chemistry
- Tubulin Modulators/pharmacology*
- Zebrafish
- PubMed
- 34034135 Full text @ Bioorg. Chem.
Citation
Sun, M., Zhang, Y., Qin, J., Ba, M., Yao, Y., Duan, Y., Liu, H., Yu, D. (2021) Synthesis and biological evaluation of new 2-methoxyestradiol derivatives: Potent inhibitors of angiogenesis and tubulin polymerization. Bioorganic chemistry. 113:104988.
Abstract
Here, we report the structural optimization of a hit natural compound, 2-ME2 (2-methoxyestradiol), which exhibited inhibitory activity but low potency on tubulin polymerization, anti- angiogenesis, MCF-7 proliferation and metastasis in vitro and in vivo. A novel series of 3,17-modified and 17-modified analogs of 2-ME2 were synthesized and investigated for their antiproliferative activity against MCF-7 and another five different human cancer cell lines leading to the discovery of 9i. 9i bind to tubulin colchicine site tightly, inhibited tubulin polymerization and disrupted cellular microtubule networks. Cellular mechanism studies revealed that 9i could induce G2/M phase arrest by down-regulated expression of p-Cdc2, P21 and cell apoptosis by regulating apoptosis-related proteins (Parp, Caspase families) in a dose-dependent manner. Importantly, 9i significantly inhibited HUVEC tube formation, proliferation, migration and invasion. The inhibitory effect against angiogenesis in vivo was confirmed by zebrafish xenograft. Furthermore, 9i could effectively inhibit the proliferation and metastasis of MCF-7 cells in vitro and in zebrafish xenograft. The satisfactory physicochemical property and metabolic stability of 9i further indicated that it can act as a promising and potent anti-angiogenesis, inhibiting proliferation and metastasis of breast cancer agent via targeting tubulin colchicine binding site.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping