2. Academic Validation
  3. Structure-activity relationship study at C9 position of kaitocephalin

Structure-activity relationship study at C9 position of kaitocephalin

  • Bioorg Med Chem Lett. 2016 Aug 1;26(15):3543-6. doi: 10.1016/j.bmcl.2016.06.026.
Yoko Yasuno 1,  Makoto Hamada 1,  Yuya Yoshida 1,  Keiko Shimamoto 2,  Yasushi Shigeri 3,  Toshifumi Akizawa 4,  Motomi Konishi 4,  Yasufumi Ohfune 1,  Tetsuro Shinada 5
Affiliations

Affiliations

  • 1 Graduate School of Science, Osaka City University, 3-3-138, Sugimoto, Sumiyoshi, Osaka 558-8585, Japan.
  • 2 Bioorganic Research Institute, Suntory Foundation for Life Sciences, 8-1-1, Seikadai, Seika-cho, Soraku-gun, Kyoto 619-0284, Japan.
  • 3 National Institute of Advanced Industrial Science and Technology, 1-8-31, Midorigaoka, Ikeda, Osaka 563-8577, Japan.
  • 4 Analytical Chemistry, Pharmaceutical Science, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan.
  • 5 Graduate School of Science, Osaka City University, 3-3-138, Sugimoto, Sumiyoshi, Osaka 558-8585, Japan. Electronic address: [email protected].
PMID: 27329796 DOI: 10.1016/j.bmcl.2016.06.026
Abstract

Kaitocephalin (KCP) isolated from Eupenicillium shearii PF1191 is an unusual amino acid natural product in which serine, proline, and alanine moieties are liked with carbon-carbon bonds. KCP exhibits potent and selective binding affinity for one of the ionotropic glutamate receptor subtypes, NMDA receptors (Ki=7.8nM). In this study, new structure-activity relationship studies at C9 of KCP were implemented. Eleven new KCP analogs with different substituents at C9 were prepared and employed for binding affinity tests using native ionotropic glutamate receptors. Replacement of the 3,5-dichloro-4-hydroxybenzoyl group of KCP with a 3-phenylpropionyl group resulted in significant loss of binding affinity for NMDARs (Ki=1300nM), indicating an indispensable role of the aromatic ring of KCP in the potent and selective binding to NMDARs. Other analogs showed potent binding affinity in a range of 11-270nM. These findings would directly link to develop useful chemical tools toward imaging and labeling of NMDARs.

Keywords

Ionotropic glutamate receptors; Kaitocephalin; NMDA receptors; Natural product; Structure–activity relationship study.

Figures
Products