Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 121, Issue -, Pages 592-609Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2016.05.031
Keywords
FK228 analogues; Histone deacetylase inhibitors; Structure-activity relationship; Bicyclic depsipeptide; Total synthesis
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Funding
- Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT) [221S0001]
- MEXT [S1511001L, 15K07865, 26221204]
- Grants-in-Aid for Scientific Research [15K07865, 16H06276, 26221204] Funding Source: KAKEN
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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. (C) 2016 Elsevier Masson SAS. All rights reserved.
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