2. Academic Validation
  3. Synthesis and biological evaluation of novel FK228 analogues as potential isoform selective HDAC inhibitors

Synthesis and biological evaluation of novel FK228 analogues as potential isoform selective HDAC inhibitors

  • Eur J Med Chem. 2016 Oct 4:121:592-609. doi: 10.1016/j.ejmech.2016.05.031.
Koichi Narita 1,  Keisuke Matsuhara 1,  Jun Itoh 1,  Yui Akiyama 1,  Singo Dan 2,  Takao Yamori 3,  Akihiro Ito 4,  Minoru Yoshida 4,  Tadashi Katoh 5
Affiliations

Affiliations

  • 1 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.
  • 2 Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550, Japan.
  • 3 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.
  • 4 Chemical Genetics Laboratory, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
  • 5 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].
PMID: 27318982 DOI: 10.1016/j.ejmech.2016.05.031
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.

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