Kaitocephalin

Kaitocephalin
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
CAS Number	198710-92-8;
3D model ( JSmol)	Interactive image;
ChemSpider	9504346;
PubChem CID	11329395;
UNII	9B96C79PCS;
	InChI InChI=1S/C18H21Cl2N3O9/c19-8-3-6(4-9(20)12(8)24)14(26)22-10(15(27)28)5-7-1-2-18(23-7,17(31)32)13(25)11(21)16(29)30/h3-4,7,10-11,13,23-25H,1-2,5,21H2,(H,22,26)(H,27,28)(H,29,30)(H,31,32)/t7-,10+,11-,13+,18-/m1/s1 Key: AJQRDRIPQOAJCM-BWOKQULHSA-N;
	SMILES O=C(O)[C@H](N)[C@H](O)[C@]2(C(=O)O)N[C@@H](C[C@H](NC(=O)c1cc(Cl)c(O)c(Cl)c1)C(=O)O)CC2;
Properties
Chemical formula	C18H21Cl2N3O9
Molar mass	494.28 g·mol−1
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Infobox references

Kaitocephalin is a non-selective

amyotrophic lateral sclerosis (ALS), and stroke.^[4]

Synthesis

Kaitocephalin was originally isolated in 1997 from Eupenicillium shearii,

NMR spectroscopy was performed on derivatives of kaitocephalin. Other methods used to determine its absolute configuration included Mosher's method and NOESY.^[7]

Only small amounts of kaitocephalin are produced naturally, making it an attractive target for synthesis.

alkyl halide with zinc in aqueous solution and under sonication. This reaction enabled the stereoselective

formation of a C-C bond, ensuring that the product's absolute configuration was correct.

Another novel reaction was discovered by a group at the University of California, Irvine in 2007. To form kaitocephalin's pyrrolidine core, a stereoconvergent cyclization reaction was discovered. A mixture of anti and syn isomers that undergoes this reaction will favor the trans product, regardless of the initial ratios used. This removes the need for an additional chiral 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 C9 amino acids, and the formation of the C3 and C4 stereocenters.

Mechanism of action

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.^[11] 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. Excitotoxicity 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; this is the mechanism by which strokes cause brain damage. High levels of glutamate have also been linked to the neuronal degeneration observed in Alzheimer's disease, Parkinson's disease, and epilepsy.^[12]

Glutamate receptors are classified as either

ALS, Parkinson's disease, epilepsy, and stroke.^[15]

References

^ 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
^ Keisuke Takahashi et al., "Total Synthesis of (-)-Kaitocephalin Based on a Rh-Catalyzed C-H Amination", Org. Lett. 14 (2012): 1644-1647
^ Hidenori Watanabe et al., "The first synthesis of kaitocephalin based on the structure revision", Tetrahedron Letters 43 (2002): 861-864
^ Yoko Yasuno et al., "Structure-activity relationship study at C9 position of kaitocephalin", Bioorg. Med. Chem. Lett. 26 (2016): 3543-3546
^ Masanori Kawasaki et al., "Total Synthesis of (-)-Kaitocephalin", Organic Letters 7 (2005): 4165-4167
^ Michal Schwartz et al., "Protective autoimmunity against the enemy within: fighting glutamate toxicity", Trends in Neurosciences 26 (2003): 297-302
^ 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
^ Rishi G. Vaswani et al., "Design, synthesis, and biological evaluation of a scaffold for iGluR ligands based on the structure of (-)-kaitocephalin", Bioorg. Med. Chem. Lett. 19 (2009): 132-135

[1] Rishi G. Vaswani and A. Richard Chamberlin, "Stereocontrolled Total Synthesis of (-)-Kaitocephalin", J. Org. Chem. 73 (2008): 1661-1681

[2] 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

[3] Yoko Yasuno et al., "(7S)-Kaitocephalin as a potent NMDA receptor selective ligand", Org. Biomol. Chem. 14 (2016): 1206-1210

[4] Philip Garner et al., "A concise [C+NC+CC] coupling-enabled synthesis of kaitocephalin", Chem. Commun. 50 (2014): 4908-4910

[5] Wonchul Lee, Joo-Hack Youn, and Sung Ho Kang, "Total synthesis of (-)-kaitocephalin", Chem. Commun. 49 (2013): 5231-5233

[6] Amelia C. Stolk and De B. Scott, "Studies on the Genus Eupenicillium Ludwig", Persoonia 4 (1967): 391-405

[7] Hiroyuki Kobayashi et al., "Absolute configuration of a novel glutamate receptor antagonist kaitocephalin", Tetrahedron Letters 42 (2001): 4021-4023

[8] Keisuke Takahashi et al., "Total Synthesis of (-)-Kaitocephalin Based on a Rh-Catalyzed C-H Amination", Org. Lett. 14 (2012): 1644-1647

[9] Hidenori Watanabe et al., "The first synthesis of kaitocephalin based on the structure revision", Tetrahedron Letters 43 (2002): 861-864

[10] Yoko Yasuno et al., "Structure-activity relationship study at C9 position of kaitocephalin", Bioorg. Med. Chem. Lett. 26 (2016): 3543-3546

[11] Masanori Kawasaki et al., "Total Synthesis of (-)-Kaitocephalin", Organic Letters 7 (2005): 4165-4167

[12] Michal Schwartz et al., "Protective autoimmunity against the enemy within: fighting glutamate toxicity", Trends in Neurosciences 26 (2003): 297-302

[13] Kazuo Shin-ya, "Novel Antitumor and Neuroprotective Substances Discovered by Characteristic Screenings Based on Specific Molecular Targets", Biosci. Biotechnol. Biochem. 69 (2005): 867-872

[14] Agenor Limon et al., "Kaitocephalin Antagonism of Glutamate Receptors Expressed in Xenopus Oocytes", ACS Chem. Neurosci. 1 (2010): 175-181

[15] Rishi G. Vaswani et al., "Design, synthesis, and biological evaluation of a scaffold for iGluR ligands based on the structure of (-)-kaitocephalin", Bioorg. Med. Chem. Lett. 19 (2009): 132-135

[4]

[7]

[11]

[12]

[15]

Synthesis

Mechanism of action

See also

References