2. Academic Validation
  3. Total synthesis of burkholdacs A and B and 5,6,20-tri-epi-burkholdac A: HDAC inhibition and antiproliferative activity

Total synthesis of burkholdacs A and B and 5,6,20-tri-epi-burkholdac A: HDAC inhibition and antiproliferative activity

  • Eur J Med Chem. 2014 Apr 9:76:301-13. doi: 10.1016/j.ejmech.2014.02.044.
Yurie Fukui 1,  Koichi Narita 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 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 Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. Electronic address: katoh@tohoku-pharm.ac.jp.
PMID: 24589486 DOI: 10.1016/j.ejmech.2014.02.044
Abstract

The bicyclic depsipeptide histone deacetylase (HDAC) inhibitors burkholdacs A and B were efficiently synthesized in a highly convergent and unified manner. The synthesis features the amide coupling of a D-valine-D-cysteine- or D-allo-isoleucine-D-cysteine-containing segment with a D-methionine-containing segment to directly assemble the corresponding seco-acids, key precursors for macrolactonization. Using the same methodology, 5,6,20-tri-epi-burkholdac A was also synthesized. HDAC inhibitory assays and cell-growth inhibition analyses of the synthesized depsipeptides demonstrated the potency order of this class of bicyclic depsipeptides as compared to the clinically approved depsipeptide FK228 (romidepsin). Novel structure-activity relationships within this class of compounds were also revealed.

Keywords

Bicyclic depsipeptide; Burkholdacs; Histone deacetylase inhibitors; Natural products; Total synthesis.

Figures