Synthesis and Biological Activity of (S)-2-Amino-3-(2, 5-dihydro-5-oxo-4-isoxazolyl)propanoic Acid (TAN-950 A) Derivatives

(S)-2-Amino-3-(2, 5-dihydro-5-oxo-4-isoxazolyl)propanoic acid (TAN-950 A (1)) is a novel amino acid antibiotic which shows a high affinity for glutamate receptors of the central nervous system. To improve the affinity for glutamate receptors, the structure-activity relationships of TAN-950 A derivat...

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Veröffentlicht in:Chemical & pharmaceutical bulletin 1991/05/25, Vol.39(5), pp.1199-1212
Hauptverfasser: TAMURA, Norikazu, MATSUSHITA, Yoshihiro, IWAMA, Toshi, HARADA, Setsuo, KISHIMOTO, Shoji, ITOH, Katsumi
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container_issue 5
container_start_page 1199
container_title Chemical & pharmaceutical bulletin
container_volume 39
creator TAMURA, Norikazu
MATSUSHITA, Yoshihiro
IWAMA, Toshi
HARADA, Setsuo
KISHIMOTO, Shoji
ITOH, Katsumi
description (S)-2-Amino-3-(2, 5-dihydro-5-oxo-4-isoxazolyl)propanoic acid (TAN-950 A (1)) is a novel amino acid antibiotic which shows a high affinity for glutamate receptors of the central nervous system. To improve the affinity for glutamate receptors, the structure-activity relationships of TAN-950 A derivatives 6a-o, 15a-o were investigated. Optically active TAN-950 A analogs 15a-h were synthesized starting with methyl (S)- and (R)-N-Boc-pyroglutamate (8) via acylation at the C-4 position followed by isoxazolone formation with hydroxylamine and subsequent deprotection reactions. The lactam 16, prepared from (RS)-aminoadipic acid, and dimethyl esters 19 of (R)- and (S)-aspartic acid were converted to (RS)-3-methyl-homo-TAN-950 A (15i) and optically active nor-TAN-950 A derivatives 15j-o, respectively, utilizing a similar sequence of reactions.Most of TAN-950 A derivatives 6a-o, 15a-o showed an affinity for glutamate receptors. The 3-alkyl derivatives 15b, d-g, especially, showed a high affinity for the quisqualate subtype-receptor and had a strong activiting effect on the hippocampal neurons (glutamate agonistic activity). The (R)-enantiomer 15a of TAN-950 A had increased selectivity for the N-methyl-D-aspartate (NMDA) subtype-receptor. This selectivity was further enhanced by removal of the methylene group in the amino acid moiety of 15a. The most potent and selective NMDA agonistic activity was observed with (R)-3-methyl-nor-TAN-950 A (15m).
doi_str_mv 10.1248/cpb.39.1199
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To improve the affinity for glutamate receptors, the structure-activity relationships of TAN-950 A derivatives 6a-o, 15a-o were investigated. Optically active TAN-950 A analogs 15a-h were synthesized starting with methyl (S)- and (R)-N-Boc-pyroglutamate (8) via acylation at the C-4 position followed by isoxazolone formation with hydroxylamine and subsequent deprotection reactions. The lactam 16, prepared from (RS)-aminoadipic acid, and dimethyl esters 19 of (R)- and (S)-aspartic acid were converted to (RS)-3-methyl-homo-TAN-950 A (15i) and optically active nor-TAN-950 A derivatives 15j-o, respectively, utilizing a similar sequence of reactions.Most of TAN-950 A derivatives 6a-o, 15a-o showed an affinity for glutamate receptors. The 3-alkyl derivatives 15b, d-g, especially, showed a high affinity for the quisqualate subtype-receptor and had a strong activiting effect on the hippocampal neurons (glutamate agonistic activity). The (R)-enantiomer 15a of TAN-950 A had increased selectivity for the N-methyl-D-aspartate (NMDA) subtype-receptor. This selectivity was further enhanced by removal of the methylene group in the amino acid moiety of 15a. 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Pharm. Bull.</addtitle><description>(S)-2-Amino-3-(2, 5-dihydro-5-oxo-4-isoxazolyl)propanoic acid (TAN-950 A (1)) is a novel amino acid antibiotic which shows a high affinity for glutamate receptors of the central nervous system. To improve the affinity for glutamate receptors, the structure-activity relationships of TAN-950 A derivatives 6a-o, 15a-o were investigated. Optically active TAN-950 A analogs 15a-h were synthesized starting with methyl (S)- and (R)-N-Boc-pyroglutamate (8) via acylation at the C-4 position followed by isoxazolone formation with hydroxylamine and subsequent deprotection reactions. The lactam 16, prepared from (RS)-aminoadipic acid, and dimethyl esters 19 of (R)- and (S)-aspartic acid were converted to (RS)-3-methyl-homo-TAN-950 A (15i) and optically active nor-TAN-950 A derivatives 15j-o, respectively, utilizing a similar sequence of reactions.Most of TAN-950 A derivatives 6a-o, 15a-o showed an affinity for glutamate receptors. The 3-alkyl derivatives 15b, d-g, especially, showed a high affinity for the quisqualate subtype-receptor and had a strong activiting effect on the hippocampal neurons (glutamate agonistic activity). The (R)-enantiomer 15a of TAN-950 A had increased selectivity for the N-methyl-D-aspartate (NMDA) subtype-receptor. This selectivity was further enhanced by removal of the methylene group in the amino acid moiety of 15a. The most potent and selective NMDA agonistic activity was observed with (R)-3-methyl-nor-TAN-950 A (15m).</description><subject>Animals</subject><subject>Antifungal Agents - chemical synthesis</subject><subject>Antifungal Agents - pharmacology</subject><subject>asymmetric synthesis</subject><subject>Chemistry</subject><subject>Exact sciences and technology</subject><subject>excitatory amino acid</subject><subject>glutamate receptor</subject><subject>Heterocyclic compounds</subject><subject>Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms</subject><subject>In Vitro Techniques</subject><subject>Isoxazoles - chemical synthesis</subject><subject>Isoxazoles - pharmacology</subject><subject>isoxazolone</subject><subject>isoxazolyl-L-alanine</subject><subject>kainate</subject><subject>Microbial Sensitivity Tests</subject><subject>N-methyl-D-aspartate</subject><subject>Organic chemistry</subject><subject>Preparations and properties</subject><subject>quisqualate</subject><subject>Rats</subject><subject>receptor binding</subject><subject>Receptors, Glutamate</subject><subject>Receptors, N-Methyl-D-Aspartate - drug effects</subject><subject>Receptors, Neurotransmitter - drug effects</subject><subject>Receptors, Neurotransmitter - metabolism</subject><subject>TAN-950 A</subject><issn>0009-2363</issn><issn>1347-5223</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1991</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkd1r2zAUxcXY6LJuT3seGDZGwqZM37Yevbb7gLI9tHsWN7LcKDhWKjml7l9fmYQW9qIrOD_OudyD0HtKlpSJ6pvdrZZcLynV-gWaUS5KLBnjL9GMEKIx44q_Rm9S2hDCJCn5CTqhSkqm6Qw9XI39sHbJpwL6pvjuQxduvIWuqO3g7_wwFqEt5lcLzHC99X3AHM_Z10Lixq_HJgYscbgPWGCfwj08hG7sFrsYdtAHb7OJb4r5df0Ha0mKelGcu-jvIDu79Ba9aqFL7t1xnqJ_Py6uz37hy78_f5_Vl9gqLgcMpG1LqxuqV5YJS4QWjVStawGqRuSfUrx1K00ko05yXmXFNaUECVoqAfwUfT745rVu9y4NZuuTdV0HvQv7ZEqWr0hJlcGP_4GbsI993s1QoQhTUpUT9eVA2RhSiq41u-i3EEdDiZn6MLkPw7WZ-sj0h6PnfrV1zTN7KCDrn446pHz1NkJvfXrChOYV52XGzg_YJg1w4550iIO3nZsiqZbVFCsPz5T-LK8hGtfzR0Mop7A</recordid><startdate>1991</startdate><enddate>1991</enddate><creator>TAMURA, Norikazu</creator><creator>MATSUSHITA, Yoshihiro</creator><creator>IWAMA, Toshi</creator><creator>HARADA, Setsuo</creator><creator>KISHIMOTO, Shoji</creator><creator>ITOH, Katsumi</creator><general>The Pharmaceutical Society of Japan</general><general>Maruzen</general><general>Japan Science and Technology Agency</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>1991</creationdate><title>Synthesis and Biological Activity of (S)-2-Amino-3-(2, 5-dihydro-5-oxo-4-isoxazolyl)propanoic Acid (TAN-950 A) Derivatives</title><author>TAMURA, Norikazu ; MATSUSHITA, Yoshihiro ; IWAMA, Toshi ; HARADA, Setsuo ; KISHIMOTO, Shoji ; ITOH, Katsumi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c635t-a0ff7c9d19bc24c0494d56fefaa8d456f663feb90521e5338efaed75a5a9564a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1991</creationdate><topic>Animals</topic><topic>Antifungal Agents - chemical synthesis</topic><topic>Antifungal Agents - pharmacology</topic><topic>asymmetric synthesis</topic><topic>Chemistry</topic><topic>Exact sciences and technology</topic><topic>excitatory amino acid</topic><topic>glutamate receptor</topic><topic>Heterocyclic compounds</topic><topic>Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms</topic><topic>In Vitro Techniques</topic><topic>Isoxazoles - chemical synthesis</topic><topic>Isoxazoles - pharmacology</topic><topic>isoxazolone</topic><topic>isoxazolyl-L-alanine</topic><topic>kainate</topic><topic>Microbial Sensitivity Tests</topic><topic>N-methyl-D-aspartate</topic><topic>Organic chemistry</topic><topic>Preparations and properties</topic><topic>quisqualate</topic><topic>Rats</topic><topic>receptor binding</topic><topic>Receptors, Glutamate</topic><topic>Receptors, N-Methyl-D-Aspartate - drug effects</topic><topic>Receptors, Neurotransmitter - drug effects</topic><topic>Receptors, Neurotransmitter - metabolism</topic><topic>TAN-950 A</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>TAMURA, Norikazu</creatorcontrib><creatorcontrib>MATSUSHITA, Yoshihiro</creatorcontrib><creatorcontrib>IWAMA, Toshi</creatorcontrib><creatorcontrib>HARADA, Setsuo</creatorcontrib><creatorcontrib>KISHIMOTO, Shoji</creatorcontrib><creatorcontrib>ITOH, Katsumi</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Chemical &amp; pharmaceutical bulletin</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>TAMURA, Norikazu</au><au>MATSUSHITA, Yoshihiro</au><au>IWAMA, Toshi</au><au>HARADA, Setsuo</au><au>KISHIMOTO, Shoji</au><au>ITOH, Katsumi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and Biological Activity of (S)-2-Amino-3-(2, 5-dihydro-5-oxo-4-isoxazolyl)propanoic Acid (TAN-950 A) Derivatives</atitle><jtitle>Chemical &amp; pharmaceutical bulletin</jtitle><addtitle>Chem. Pharm. Bull.</addtitle><date>1991</date><risdate>1991</risdate><volume>39</volume><issue>5</issue><spage>1199</spage><epage>1212</epage><pages>1199-1212</pages><issn>0009-2363</issn><eissn>1347-5223</eissn><coden>CPBTAL</coden><abstract>(S)-2-Amino-3-(2, 5-dihydro-5-oxo-4-isoxazolyl)propanoic acid (TAN-950 A (1)) is a novel amino acid antibiotic which shows a high affinity for glutamate receptors of the central nervous system. To improve the affinity for glutamate receptors, the structure-activity relationships of TAN-950 A derivatives 6a-o, 15a-o were investigated. Optically active TAN-950 A analogs 15a-h were synthesized starting with methyl (S)- and (R)-N-Boc-pyroglutamate (8) via acylation at the C-4 position followed by isoxazolone formation with hydroxylamine and subsequent deprotection reactions. The lactam 16, prepared from (RS)-aminoadipic acid, and dimethyl esters 19 of (R)- and (S)-aspartic acid were converted to (RS)-3-methyl-homo-TAN-950 A (15i) and optically active nor-TAN-950 A derivatives 15j-o, respectively, utilizing a similar sequence of reactions.Most of TAN-950 A derivatives 6a-o, 15a-o showed an affinity for glutamate receptors. The 3-alkyl derivatives 15b, d-g, especially, showed a high affinity for the quisqualate subtype-receptor and had a strong activiting effect on the hippocampal neurons (glutamate agonistic activity). The (R)-enantiomer 15a of TAN-950 A had increased selectivity for the N-methyl-D-aspartate (NMDA) subtype-receptor. This selectivity was further enhanced by removal of the methylene group in the amino acid moiety of 15a. The most potent and selective NMDA agonistic activity was observed with (R)-3-methyl-nor-TAN-950 A (15m).</abstract><cop>Tokyo</cop><pub>The Pharmaceutical Society of Japan</pub><pmid>1655291</pmid><doi>10.1248/cpb.39.1199</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record>
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ispartof Chemical and Pharmaceutical Bulletin, 1991/05/25, Vol.39(5), pp.1199-1212
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1347-5223
language eng
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source J-STAGE Free; MEDLINE; EZB-FREE-00999 freely available EZB journals; Free Full-Text Journals in Chemistry
subjects Animals
Antifungal Agents - chemical synthesis
Antifungal Agents - pharmacology
asymmetric synthesis
Chemistry
Exact sciences and technology
excitatory amino acid
glutamate receptor
Heterocyclic compounds
Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms
In Vitro Techniques
Isoxazoles - chemical synthesis
Isoxazoles - pharmacology
isoxazolone
isoxazolyl-L-alanine
kainate
Microbial Sensitivity Tests
N-methyl-D-aspartate
Organic chemistry
Preparations and properties
quisqualate
Rats
receptor binding
Receptors, Glutamate
Receptors, N-Methyl-D-Aspartate - drug effects
Receptors, Neurotransmitter - drug effects
Receptors, Neurotransmitter - metabolism
TAN-950 A
title Synthesis and Biological Activity of (S)-2-Amino-3-(2, 5-dihydro-5-oxo-4-isoxazolyl)propanoic Acid (TAN-950 A) Derivatives
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