Synthesis and biological evaluation of novel FK228 analogues as potential isoform selective HDAC inhibitors
| Autor: | Akihiro Ito, Koichi Narita, Singo Dan, Minoru Yoshida, Yui Akiyama, Tadashi Katoh, Jun Itoh, Takao Yamori, Keisuke Matsuhara |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Gene isoform Stereochemistry Chemistry Techniques Synthetic 01 natural sciences Isozyme Histone Deacetylases 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship Amide Drug Discovery Structure–activity relationship Humans Cell Proliferation Pharmacology 010405 organic chemistry Chemistry Cell growth Organic Chemistry HEK 293 cells Total synthesis General Medicine HDAC1 0104 chemical sciences Histone Deacetylase Inhibitors Isoenzymes 030104 developmental biology HEK293 Cells Biochemistry Drug Design |
| Zdroj: | European journal of medicinal chemistry. 121 |
| ISSN: | 1768-3254 |
| Popis: | Novel C4- and C7-modified FK228 analogues were efficiently synthesized in a highly convergent and unified manner. This synthesis features the amide condensation of glycine-d-cysteine-containing segments with d-valine-containing segments for the direct assembly of the corresponding seco-acids, which are key precursors of macrolactones. The HDAC inhibition assay and cell-growth inhibition analysis of the synthesized analogues revealed novel aspects of their structure-activity relationship. This study demonstrated that simple modification at the C4 and C7 side chains in FK228 is effective for improving both HDAC inhibitory activity and isoform selectivity; moreover, potent and highly isoform-selective class I HDAC1 inhibitors were identified. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect