User:Llohman/sandbox
.png){kind=link}
Kaitocephalin is a glutamate receptor antagonist produced by the fungus Eupenicillium shearii. Although similar molecules have been produced synthetically, kaitocephalin is the only known naturally occurring glutamate receptor antagonist.[1][2] There is some evidence that kaitocephalin has neuroprotective properties, as it inhibits the mechanism which causes cell death by excitotoxicity.[3] Because of this, it is of interest as a potential scaffold for drug development. Drugs based on kaitocephalin may be useful in treating neurological conditions, including Alzheimer’s, amyotrophic lateral sclerosis (ALS), and stroke.[4]
Synthesis
[edit]Kaitocephalin was originally isolated in 1997 from Eupenicillium shearii,[5] a fungus in the same genus as those that produce penicillin.[6] Its absolute configuration was determined in 2001. Due to the small amounts of kaitocephalin available, its absolute structure was not determined through chemical degradation. Instead, NMR spectroscopy was performed on derivatives of kaitocephalin. Other methods used to determine its absolute configuration included Mosher’s method and NOESY.[7]
To date, nine syntheses have been reported by seven research groups. The first synthesis was performed in 2001 by a team at the University of Tokyo.[8] In addition, three structure-activity relationship (SAR) studies of kaitocephalin have been performed. Novel reaction mechanisms have been used in at least two syntheses. Difficulties in synthesis include the formation of the substituted pyrrolidine core, the incorporation of the C2 and C9 amino acids, and the formation of the C3 and C4 stereocenters.
Mechanism of action
[edit]Kaitocephalin acts by inhibiting glutamate receptors. Glutamate is the most abundant neurotransmitter in the vertebrate nervous system and is involved in learning, memory, and neuroplasticity.[9] It is an excitatory neurotransmitter, so binding of glutamate to its receptors increases ion flow through the postsynaptic membrane. Excess glutamate can lead to cell death and neurological damage through a phenomenon called excitotoxicity. This occurs when calcium ion influx creates a positive feedback loop, leading to breakdown of the cell membrane and apoptosis. This process is part of the ischemic cascade, when low blood supply (ischemia) causes a series of events leading to cell death.
Glutamate receptors are classified as either metabotropic or ionotropic. The ionotropic receptors are further divided into NMDA, AMPA, and kainate receptors.[10] Kaitocephalin is a potent competitive antagonist of both NMDA and AMPA receptors, although it has a stronger affinity for NMDA receptors.[11] It is also a weak inhibitor of kainate receptors. Since the ischemic cascade involves overstimulation of NMDA and AMPA receptors, kaitocephalin may be able to inhibit this process, giving it neuroprotective properties. This makes it an attractive starting point to develop treatments for neurological conditions, including Alzheimer's disease, ALS, Parkinson's disease, epilepsy, and stroke.
See also
[edit]References
[edit]- ^ Rishi G. Vaswani and A. Richard Chamberlin, "Stereocontrolled Total Synthesis of (-)-Kaitocephalin", J. Org. Chem. 73 (2008): 1661-1681
- ^ Ahmed H. Ahmed et al., "The Structure of Kaitocephalin Bound to the Ligand Binding Domain of the (S)-α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA)/Glutamate Receptor, GluA2", J. Biol. Chem. 287 (2012): 41007-41013
- ^ Yoko Yasuno et al., "(7S)-Kaitocephalin as a potent NMDA receptor selective ligand", Org. Biomol. Chem. 14 (2016): 1206-1210
- ^ Philip Garner et al., "A concise [C+NC+CC] coupling-enabled synthesis of kaitocephalin", Chem. Commun. 50 (2014): 4908-4910
- ^ Wonchul Lee, Joo-Hack Youn, and Sung Ho Kang, "Total synthesis of (-)-kaitocephalin", Chem. Commun. 49 (2013): 5231-5233
- ^ Amelia C. Stolk and De B. Scott, "Studies on the Genus Eupenicillium Ludwig", Persoonia 4 (1967): 391-405
- ^ Hiroyuki Kobayashi et al., "Absolute configuration of a novel glutamate receptor antagonist kaitocephalin", Tetrahedron Letters 42 (2001): 4021-4023
- ^ Hidenori Watanabe et al., "The first synthesis of kaitocephalin based on the structure revision", Tetrahedron Letters 43 (2002): 861-864
- ^ Masanori Kawasaki et al., "Total Synthesis of (-)-Kaitocephalin", Organic Letters 7 (2005): 4165-4167
- ^ Kazuo Shin-ya, "Novel Antitumor and Neuroprotective Substances Discovered by Characteristic Screenings Based on Specific Molecular Targets", Biosci. Biotechnol. Biochem. 69 (2005): 867-872
- ^ Agenor Limon et al., "Kaitocephalin Antagonism of Glutamate Receptors Expressed in Xenopus Oocytes", ACS Chem. Neurosci. 1 (2010): 175-181