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| Names | |
|---|---|
| Systematic IUPAC name (2R,5R)-2-[(1S,2R)-2-Amino-2-carboxy-1-hydroxyethyl]-5-[(2S)-2-carboxy-2-(3,5-dichloro-4-hydroxybenzamido)ethyl]pyrrolidine-2-carboxylic acid | |
| Identifiers | |
3D model (JSmol) | |
| ChemSpider | |
| UNII | |
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| Properties | |
| C18H21Cl2N3O9 | |
| Molar mass | 494.28 g·mol−1 |
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |
Kaitocephalin is a non-selectiveionotropicglutamate receptorantagonist, meaning it blocks the action of the neurotransmitterglutamate. It is produced by thefungusEupenicillium 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 can protect the brain and central nervous system, so it is said to haveneuroprotective properties. Kaitocephalin protects neurons by inhibitingexcitotoxicity, a mechanism which causes cell death by overloading neurons with glutamate.[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, includingAlzheimer's,amyotrophic lateral sclerosis (ALS), andstroke.[4]
Kaitocephalin was originally isolated in 1997 fromEupenicillium shearii,[5] a fungus in the same genus as those that producepenicillin.[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 includedMosher's method andNOESY.[7]
Only small amounts of kaitocephalin are produced naturally, making it an attractive target for synthesis.[8] 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.[9] In addition, threestructure-activity relationship (SAR) studies of kaitocephalin have been performed.[10] Novel reaction mechanisms have been used in at least two syntheses, including the original synthesis in 2001. A key step in this synthesis was the reaction of anitrone and analkyl halide with zinc in aqueous solution and undersonication. This reaction enabled thestereoselective formation of a C-C bond, ensuring that the product's absolute configuration was correct.
Another novel reaction was discovered by a group atthe University of California, Irvine in 2007. To form kaitocephalin'spyrrolidine core, a stereoconvergent cyclization reaction was discovered. A mixture ofanti andsyn isomers that undergoes this reaction will favor thetrans product, regardless of the initial ratios used. This removes the need for an additionalchiral reagent to obtain the desired stereochemistry. The mechanism for this cyclization is not yet understood. Difficulties in synthesis include the formation of the substituted pyrrolidine core, the incorporation of the C2 and C9amino acids, and the formation of the C3 and C4stereocenters.
Kaitocephalin acts by inhibitingglutamate receptors.Glutamate is the most abundant neurotransmitter in the vertebrate nervous system and is involved in learning, memory, andneuroplasticity.[11] It is anexcitatory 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 calledexcitotoxicity. Excitotoxicity occurs when calcium ion influx creates a positive feedback loop, leading to breakdown of the cell membrane andapoptosis. This process is part of theischemic cascade, when low blood supply (ischemia) causes a series of events leading to cell death; this is the mechanism by whichstrokes cause brain damage. High levels of glutamate have also been linked to the neuronal degeneration observed inAlzheimer's disease,Parkinson's disease, andepilepsy.[12]
Glutamate receptors are classified as eithermetabotropic orionotropic. The ionotropic receptors are further divided intoNMDA,AMPA, andkainate receptors.[13] Kaitocephalin is a potentcompetitive antagonist of both NMDA and AMPA receptors, although it has a stronger affinity for NMDA receptors. Kaitocephalin'sIC50 for NMDA receptors is around 75 nM, while its IC50 for AMPA receptors is 200-600 nM.[14] It is also a weak inhibitor of kainate receptors, with an IC50 of around 100 μM. 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.[15]
