Abstract
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.
Keywords
Bicyclic depsipeptide
FK228 analogues
Histone deacetylase inhibitors
Structure-activity relationship
Total synthesis
MeSH Terms
Cell Proliferation/drug effects
Chemistry Techniques, Synthetic
Drug Design
HEK293 Cells
Histone Deacetylase Inhibitors/chemical synthesis,chemistry,pharmacology
Histone Deacetylases/metabolism
Humans
Isoenzymes/antagonists & inhibitors
Structure-Activity Relationship
Chemicals
Histone Deacetylase Inhibitors
Isoenzymes
Histone Deacetylases
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Narita Koichi
Laboratory of Synthetic and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
Matsuhara Keisuke
Laboratory of Synthetic and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
Itoh Jun
Laboratory of Synthetic and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
Akiyama Yui
Laboratory of Synthetic and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
Dan Singo
Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550, Japan.
Yamori Takao
Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550, Japan; Pharmaceuticals and Medical Devices Agency (PMDA), 3-3-2 Kasumigaseki, Chiyoda-ku, Tokyo 100-0013, Japan.
Ito Akihiro
Chemical Genetics Laboratory, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
Yoshida Minoru
Chemical Genetics Laboratory, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
Katoh Tadashi
Laboratory of Synthetic and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. Electronic address:
[email protected].
