PUBLICATION
Design, synthesis and antitumor activity evaluation of novel HDAC inhibitors with tetrahydrobenzothiazole as the skeleton
- Authors
- Sun, S., Zhao, W., Li, Y., Chi, Z., Fang, X., Wang, Q., Han, Z., Luan, Y.
- ID
- ZDB-PUB-210128-10
- Date
- 2021
- Source
- Bioorganic chemistry 108: 104652 (Journal)
- Registered Authors
- Keywords
- Antitumor, Histone deacetylase, Inhibitor, Molecular docking, Small molecule
- MeSH Terms
-
- Animals
- Antineoplastic Agents/chemical synthesis
- Antineoplastic Agents/chemistry
- Antineoplastic Agents/pharmacology*
- Apoptosis/drug effects
- Cell Cycle/drug effects
- Cell Proliferation/drug effects
- Dose-Response Relationship, Drug
- Drug Design*
- Drug Screening Assays, Antitumor
- Histone Deacetylase Inhibitors/chemical synthesis
- Histone Deacetylase Inhibitors/chemistry
- Histone Deacetylase Inhibitors/pharmacology*
- Histone Deacetylases/metabolism*
- Humans
- Microsomes, Liver/chemistry
- Microsomes, Liver/metabolism
- Molecular Structure
- Neoplasms, Experimental/drug therapy
- Neoplasms, Experimental/metabolism
- Neoplasms, Experimental/pathology
- Rats
- Structure-Activity Relationship
- Thiazoles/chemical synthesis
- Thiazoles/chemistry
- Thiazoles/pharmacology*
- Tumor Cells, Cultured
- Wound Healing/drug effects
- Zebrafish
- PubMed
- 33497873 Full text @ Bioorg. Chem.
Citation
Sun, S., Zhao, W., Li, Y., Chi, Z., Fang, X., Wang, Q., Han, Z., Luan, Y. (2021) Design, synthesis and antitumor activity evaluation of novel HDAC inhibitors with tetrahydrobenzothiazole as the skeleton. Bioorganic chemistry. 108:104652.
Abstract
HDACs as important targets for cancer therapy have attracted extensive attentions. In this work, a series of sixteen hydroxamic acid based HDAC inhibitors were designed and synthesized with 4,5,6,7-tetrahydrobenzothiazole as the structural core. Majority of them exhibited potent inhibitory activities against HDACs and one leading compound 6h was dug out. 6h was proven to be a pan-HDAC inhibitor and displayed high cytotoxicity against seven human cancer cell lines with IC50 values in low micromolar range. 6h could arrest cell cycle in G2/M phase and induce apoptosis in A549 cells. Moreover, compound 6h exhibited remarkable anti-migration and anti-angiogenesis activities. At the same time, 6h was able to elevate the expression of acetylated α-tubulin and acetylated histone H3 in a dose-dependent manner. Docking simulation revealed that 6h fitted well into the active sites of HDAC2 and 6. Finally, compound 6h also exerted potent antitumor effects in an A549 zebrafish xenograft model. Our study demonstrated that compound 6h was a promising candidate for further preclinical studies.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping