3-[(Phenylacetyl)amino]-2,6-piperidinedione Hydrolysis Studies with Improved Synthesis and Characterization of Hydrolysates
In an attempt to clarify ambiguities in earlier reports on the preclinical chemistry of Antineoplaston A10 (3-[(phenylacetyl)amino]-2,6-piperidinedione; PAP), we detail herein hydrolysis studies with improved synthesis and characterization of PAP hydrolysis products, (phenylacetyl)-glutamine (PAG),...
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| Veröffentlicht in: | Journal of pharmaceutical sciences 1996-10, Vol.85 (10), p.1049-1052 |
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| container_title | Journal of pharmaceutical sciences |
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| creator | Revelle, Larry K. d'Avignon, D. André Wilson, Joe A. |
| description | In an attempt to clarify ambiguities in earlier reports on the preclinical chemistry of Antineoplaston A10 (3-[(phenylacetyl)amino]-2,6-piperidinedione; PAP), we detail herein hydrolysis studies with improved synthesis and characterization of PAP hydrolysis products, (phenylacetyl)-glutamine (PAG), (phenylacetyl)isoglutamine (PAIG), and (phenylacetyl)-glutamic acid (PAGA). Flash chromatography proved superior to extraction in the isolation of synthetic standards and hydrolysates. Synthesis of PAIG directly from commercial isoglutamine showed consistently better yields than the previously reported method. The 1H and 13C NMR and HPLC–MS data from the synthesized standards matched the data from the isolated PAP hydrolysates formed under acid and alkaline degradation conditions. Multiple quantum coherence NMR methods (HMQC and HMBC) and HPLC–MS–MS methods were applied to provide unambiguous structural assignments for key isomers PAG and PAIG. Previous PAP hydrolysis studies are shown to be reproducible, and the structures of hydrolysis products are elucidated in detail. |
| doi_str_mv | 10.1021/js960120y |
| format | Article |
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André ; Wilson, Joe A.</creator><creatorcontrib>Revelle, Larry K. ; d'Avignon, D. André ; Wilson, Joe A.</creatorcontrib><description>In an attempt to clarify ambiguities in earlier reports on the preclinical chemistry of Antineoplaston A10 (3-[(phenylacetyl)amino]-2,6-piperidinedione; PAP), we detail herein hydrolysis studies with improved synthesis and characterization of PAP hydrolysis products, (phenylacetyl)-glutamine (PAG), (phenylacetyl)isoglutamine (PAIG), and (phenylacetyl)-glutamic acid (PAGA). Flash chromatography proved superior to extraction in the isolation of synthetic standards and hydrolysates. Synthesis of PAIG directly from commercial isoglutamine showed consistently better yields than the previously reported method. The 1H and 13C NMR and HPLC–MS data from the synthesized standards matched the data from the isolated PAP hydrolysates formed under acid and alkaline degradation conditions. Multiple quantum coherence NMR methods (HMQC and HMBC) and HPLC–MS–MS methods were applied to provide unambiguous structural assignments for key isomers PAG and PAIG. Previous PAP hydrolysis studies are shown to be reproducible, and the structures of hydrolysis products are elucidated in detail.</description><identifier>ISSN: 0022-3549</identifier><identifier>EISSN: 1520-6017</identifier><identifier>DOI: 10.1021/js960120y</identifier><identifier>PMID: 8897269</identifier><identifier>CODEN: JPMSAE</identifier><language>eng</language><publisher>New York: Elsevier Inc</publisher><subject>Antineoplastic agents ; Antineoplastic Agents - chemistry ; Benzeneacetamides ; Biological and medical sciences ; Chromatography, High Pressure Liquid ; General aspects ; Glutamic Acid - analogs & derivatives ; Glutamic Acid - chemical synthesis ; Glutamic Acid - chemistry ; Glutamine - analogs & derivatives ; Glutamine - chemical synthesis ; Glutamine - chemistry ; Hydrolysis ; Magnetic Resonance Spectroscopy ; Mass Spectrometry ; Medical sciences ; Pharmacology. Drug treatments ; Piperidones - chemistry ; Reference Standards</subject><ispartof>Journal of pharmaceutical sciences, 1996-10, Vol.85 (10), p.1049-1052</ispartof><rights>1996 Wiley-Liss, Inc., A Wiley Company</rights><rights>Copyright © 1996 Wiley‐Liss, Inc. and the American Pharmaceutical Association</rights><rights>1996 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4275-e36446e3ed8c1c6f87f09a4c2976aa81a09047752acfa2cb4ec4a03685dea9c33</citedby><cites>FETCH-LOGICAL-c4275-e36446e3ed8c1c6f87f09a4c2976aa81a09047752acfa2cb4ec4a03685dea9c33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1021%2Fjs960120y$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1021%2Fjs960120y$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,777,781,1412,27905,27906,45555,45556</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=3237497$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8897269$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Revelle, Larry K.</creatorcontrib><creatorcontrib>d'Avignon, D. André</creatorcontrib><creatorcontrib>Wilson, Joe A.</creatorcontrib><title>3-[(Phenylacetyl)amino]-2,6-piperidinedione Hydrolysis Studies with Improved Synthesis and Characterization of Hydrolysates</title><title>Journal of pharmaceutical sciences</title><addtitle>J. Pharm. Sci</addtitle><description>In an attempt to clarify ambiguities in earlier reports on the preclinical chemistry of Antineoplaston A10 (3-[(phenylacetyl)amino]-2,6-piperidinedione; PAP), we detail herein hydrolysis studies with improved synthesis and characterization of PAP hydrolysis products, (phenylacetyl)-glutamine (PAG), (phenylacetyl)isoglutamine (PAIG), and (phenylacetyl)-glutamic acid (PAGA). Flash chromatography proved superior to extraction in the isolation of synthetic standards and hydrolysates. Synthesis of PAIG directly from commercial isoglutamine showed consistently better yields than the previously reported method. The 1H and 13C NMR and HPLC–MS data from the synthesized standards matched the data from the isolated PAP hydrolysates formed under acid and alkaline degradation conditions. Multiple quantum coherence NMR methods (HMQC and HMBC) and HPLC–MS–MS methods were applied to provide unambiguous structural assignments for key isomers PAG and PAIG. Previous PAP hydrolysis studies are shown to be reproducible, and the structures of hydrolysis products are elucidated in detail.</description><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Benzeneacetamides</subject><subject>Biological and medical sciences</subject><subject>Chromatography, High Pressure Liquid</subject><subject>General aspects</subject><subject>Glutamic Acid - analogs & derivatives</subject><subject>Glutamic Acid - chemical synthesis</subject><subject>Glutamic Acid - chemistry</subject><subject>Glutamine - analogs & derivatives</subject><subject>Glutamine - chemical synthesis</subject><subject>Glutamine - chemistry</subject><subject>Hydrolysis</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Mass Spectrometry</subject><subject>Medical sciences</subject><subject>Pharmacology. 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André</creator><creator>Wilson, Joe A.</creator><general>Elsevier Inc</general><general>John Wiley & Sons, Inc</general><general>Wiley</general><general>American Pharmaceutical Association</general><scope>BSCLL</scope><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>7X8</scope></search><sort><creationdate>199610</creationdate><title>3-[(Phenylacetyl)amino]-2,6-piperidinedione Hydrolysis Studies with Improved Synthesis and Characterization of Hydrolysates</title><author>Revelle, Larry K. ; d'Avignon, D. André ; Wilson, Joe A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4275-e36446e3ed8c1c6f87f09a4c2976aa81a09047752acfa2cb4ec4a03685dea9c33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1996</creationdate><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Benzeneacetamides</topic><topic>Biological and medical sciences</topic><topic>Chromatography, High Pressure Liquid</topic><topic>General aspects</topic><topic>Glutamic Acid - analogs & derivatives</topic><topic>Glutamic Acid - chemical synthesis</topic><topic>Glutamic Acid - chemistry</topic><topic>Glutamine - analogs & derivatives</topic><topic>Glutamine - chemical synthesis</topic><topic>Glutamine - chemistry</topic><topic>Hydrolysis</topic><topic>Magnetic Resonance Spectroscopy</topic><topic>Mass Spectrometry</topic><topic>Medical sciences</topic><topic>Pharmacology. Drug treatments</topic><topic>Piperidones - chemistry</topic><topic>Reference Standards</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Revelle, Larry K.</creatorcontrib><creatorcontrib>d'Avignon, D. André</creatorcontrib><creatorcontrib>Wilson, Joe A.</creatorcontrib><collection>Istex</collection><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>MEDLINE - Academic</collection><jtitle>Journal of pharmaceutical sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Revelle, Larry K.</au><au>d'Avignon, D. André</au><au>Wilson, Joe A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>3-[(Phenylacetyl)amino]-2,6-piperidinedione Hydrolysis Studies with Improved Synthesis and Characterization of Hydrolysates</atitle><jtitle>Journal of pharmaceutical sciences</jtitle><addtitle>J. Pharm. Sci</addtitle><date>1996-10</date><risdate>1996</risdate><volume>85</volume><issue>10</issue><spage>1049</spage><epage>1052</epage><pages>1049-1052</pages><issn>0022-3549</issn><eissn>1520-6017</eissn><coden>JPMSAE</coden><abstract>In an attempt to clarify ambiguities in earlier reports on the preclinical chemistry of Antineoplaston A10 (3-[(phenylacetyl)amino]-2,6-piperidinedione; PAP), we detail herein hydrolysis studies with improved synthesis and characterization of PAP hydrolysis products, (phenylacetyl)-glutamine (PAG), (phenylacetyl)isoglutamine (PAIG), and (phenylacetyl)-glutamic acid (PAGA). Flash chromatography proved superior to extraction in the isolation of synthetic standards and hydrolysates. Synthesis of PAIG directly from commercial isoglutamine showed consistently better yields than the previously reported method. The 1H and 13C NMR and HPLC–MS data from the synthesized standards matched the data from the isolated PAP hydrolysates formed under acid and alkaline degradation conditions. Multiple quantum coherence NMR methods (HMQC and HMBC) and HPLC–MS–MS methods were applied to provide unambiguous structural assignments for key isomers PAG and PAIG. Previous PAP hydrolysis studies are shown to be reproducible, and the structures of hydrolysis products are elucidated in detail.</abstract><cop>New York</cop><pub>Elsevier Inc</pub><pmid>8897269</pmid><doi>10.1021/js960120y</doi><tpages>4</tpages></addata></record> |
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| ispartof | Journal of pharmaceutical sciences, 1996-10, Vol.85 (10), p.1049-1052 |
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| source | MEDLINE; Wiley Online Library Journals Frontfile Complete; Alma/SFX Local Collection |
| subjects | Antineoplastic agents Antineoplastic Agents - chemistry Benzeneacetamides Biological and medical sciences Chromatography, High Pressure Liquid General aspects Glutamic Acid - analogs & derivatives Glutamic Acid - chemical synthesis Glutamic Acid - chemistry Glutamine - analogs & derivatives Glutamine - chemical synthesis Glutamine - chemistry Hydrolysis Magnetic Resonance Spectroscopy Mass Spectrometry Medical sciences Pharmacology. Drug treatments Piperidones - chemistry Reference Standards |
| title | 3-[(Phenylacetyl)amino]-2,6-piperidinedione Hydrolysis Studies with Improved Synthesis and Characterization of Hydrolysates |
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