Synthesis and Testing of New Antileukemic Schiff Bases of N -Hydroxy- N′ - Aminoguanidine Against CCRF-CEM/0 Human Leukemia Cells in Vitro and Synergism Studies with Cytarabine (Ara-C)
Identifieur interne : 000578 ( Istex/Corpus ); précédent : 000577; suivant : 000579Synthesis and Testing of New Antileukemic Schiff Bases of N -Hydroxy- N′ - Aminoguanidine Against CCRF-CEM/0 Human Leukemia Cells in Vitro and Synergism Studies with Cytarabine (Ara-C)
Auteurs : Phanesh B. Koneru ; Eric J. Lien ; Vassilios I. AvramisSource :
- Pharmaceutical Research [ 0724-8741 ] ; 1993-04-01.
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Abstract
Abstract: A series of eight new N-hydroxy-N′-aminoguanidine (HAG) Schiff bases [ArCH = NNHC( = NH)NHOH · tosylate] was synthesized as potential antitumor agents through the inhibition of the enzyme ribonucleotide reductase (EC 1.17.4.1). Five of the HAG derivatives (LK02 through LK06) were designed to contain an orthohydroxy group on the phenyl ring of ArCH = to increase the stability of the Schiff base formed. In addition, two compounds with a substituted quinoline [LK10; ArCH = (4-hydroxy-7-trifluoromethylquinolin-3-yl)methylene] or isoquinoline (LK11; ArCH = (5-nitroisoquinolin-l-yl)methylene] moiety were synthesized through multiple-step reactions involving reduction and/or oxidation. The IC50 values of the newly synthesized HAG Schiff bases were determined against human leukemic CCRF-CEM/0 cells in culture. The IC50 values of two previously reported HAG derivatives [ATL25; ArCH = (5-nitro-isoquinolin-l-yl)methylene] and [LW02; ArCH = 2-hydroxy-3-allyl-benzylidene)] were also determined for the first time against CCRF-CEM/0 cells. Among the compounds tested, LK11 was found to be the most potent (IC50, 2.95 ± 0.1 µM) and the 4-methoxy-2-hydroxy-phenyl derivative (LK02) to be the least potent (IC50, 121 ± 16 µM). LK11 was about 15-fold more potent against CCRF-CEM/0 cells compared to the parent compound hydroxyguanidine sulfate (IC50, 46 ± 7.1 µM) and was about 32 times more potent than LK10 (IC50, 97.6 ± 0.9 µM). LK11 in combination was incubated in sequence with cytarabine (ara-C) at various molar ratios against CCRF-CEM/0 cells for 48 hr. The results were analyzed using both the isobologram and the median-effect methods. This combination at a 1:1 molar ratio was about 6-fold more potent (IC50, 0.16 µM) compared to ara-C alone (IC50, 1.05 µM) and about 18-fold more potent compared to LK11 alone (IC50, 2.95 ± 0.1 µM). In summary, the antileukemic potency of certain HAG derivatives can be improved by the presence of orthohydroxy groups of the phenyl ring, and a 1:1 molar combination of an isoquinoline HAG compound and ara-C leads to significant synergistic antileukemic activity against CCRF-CEM/0 cells in vitro.
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DOI: 10.1023/A:1018985616389
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<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title xml:lang="en">Synthesis and Testing of New Antileukemic Schiff Bases of N -Hydroxy- N′ - Aminoguanidine Against CCRF-CEM/0 Human Leukemia Cells in Vitro and Synergism Studies with Cytarabine (Ara-C)</title><author><name sortKey="Koneru, Phanesh B" sort="Koneru, Phanesh B" uniqKey="Koneru P" first="Phanesh B." last="Koneru">Phanesh B. Koneru</name><affiliation><mods:affiliation>Department of Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 90033, Los Angeles, California</mods:affiliation></affiliation></author><author><name sortKey="Lien, Eric J" sort="Lien, Eric J" uniqKey="Lien E" first="Eric J." last="Lien">Eric J. Lien</name><affiliation><mods:affiliation>Department of Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 90033, Los Angeles, California</mods:affiliation></affiliation></author><author><name sortKey="Avramis, Vassilios I" sort="Avramis, Vassilios I" uniqKey="Avramis V" first="Vassilios I." last="Avramis">Vassilios I. Avramis</name><affiliation><mods:affiliation>Children's Hospital of Los Angeles, Division of Hematology/ Oncology, USC Schools of Medicine and Pharmacy, Department of Pediatrics and Molecular Pharmacology and Toxicology, 90027, Los Angeles, California</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:F4AB6D4A3C9ECF1532D89A959CF00D74659E5E25</idno><date when="1993" year="1993">1993</date><idno type="doi">10.1023/A:1018985616389</idno><idno type="url">https://api.istex.fr/ark:/67375/1BB-711C1F74-8/fulltext.pdf</idno><idno type="wicri:Area/Istex/Corpus">000578</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">000578</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Synthesis and Testing of New Antileukemic Schiff Bases of N -Hydroxy- N′ - Aminoguanidine Against CCRF-CEM/0 Human Leukemia Cells in Vitro and Synergism Studies with Cytarabine (Ara-C)</title><author><name sortKey="Koneru, Phanesh B" sort="Koneru, Phanesh B" uniqKey="Koneru P" first="Phanesh B." last="Koneru">Phanesh B. Koneru</name><affiliation><mods:affiliation>Department of Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 90033, Los Angeles, California</mods:affiliation></affiliation></author><author><name sortKey="Lien, Eric J" sort="Lien, Eric J" uniqKey="Lien E" first="Eric J." last="Lien">Eric J. Lien</name><affiliation><mods:affiliation>Department of Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 90033, Los Angeles, California</mods:affiliation></affiliation></author><author><name sortKey="Avramis, Vassilios I" sort="Avramis, Vassilios I" uniqKey="Avramis V" first="Vassilios I." last="Avramis">Vassilios I. Avramis</name><affiliation><mods:affiliation>Children's Hospital of Los Angeles, Division of Hematology/ Oncology, USC Schools of Medicine and Pharmacy, Department of Pediatrics and Molecular Pharmacology and Toxicology, 90027, Los Angeles, California</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Pharmaceutical Research</title><title level="j" type="sub">An Official Journal of the American Association of Pharmaceutical Scientists</title><title level="j" type="abbrev">Pharm Res</title><idno type="ISSN">0724-8741</idno><idno type="eISSN">1573-904X</idno><imprint><publisher>Kluwer Academic Publishers-Plenum Publishers</publisher><pubPlace>New York</pubPlace><date type="published" when="1993-04-01">1993-04-01</date><biblScope unit="volume">10</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="515">515</biblScope><biblScope unit="page" to="520">520</biblScope></imprint><idno type="ISSN">0724-8741</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0724-8741</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Schiff bases of hydroxyaminoguanidines</term><term>antileukemic activity</term><term>cytarabine (ara-C)</term><term>isobologram</term><term>median-effect plots</term><term>synergism</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Abstract: A series of eight new N-hydroxy-N′-aminoguanidine (HAG) Schiff bases [ArCH = NNHC( = NH)NHOH · tosylate] was synthesized as potential antitumor agents through the inhibition of the enzyme ribonucleotide reductase (EC 1.17.4.1). Five of the HAG derivatives (LK02 through LK06) were designed to contain an orthohydroxy group on the phenyl ring of ArCH = to increase the stability of the Schiff base formed. In addition, two compounds with a substituted quinoline [LK10; ArCH = (4-hydroxy-7-trifluoromethylquinolin-3-yl)methylene] or isoquinoline (LK11; ArCH = (5-nitroisoquinolin-l-yl)methylene] moiety were synthesized through multiple-step reactions involving reduction and/or oxidation. The IC50 values of the newly synthesized HAG Schiff bases were determined against human leukemic CCRF-CEM/0 cells in culture. The IC50 values of two previously reported HAG derivatives [ATL25; ArCH = (5-nitro-isoquinolin-l-yl)methylene] and [LW02; ArCH = 2-hydroxy-3-allyl-benzylidene)] were also determined for the first time against CCRF-CEM/0 cells. Among the compounds tested, LK11 was found to be the most potent (IC50, 2.95 ± 0.1 µM) and the 4-methoxy-2-hydroxy-phenyl derivative (LK02) to be the least potent (IC50, 121 ± 16 µM). LK11 was about 15-fold more potent against CCRF-CEM/0 cells compared to the parent compound hydroxyguanidine sulfate (IC50, 46 ± 7.1 µM) and was about 32 times more potent than LK10 (IC50, 97.6 ± 0.9 µM). LK11 in combination was incubated in sequence with cytarabine (ara-C) at various molar ratios against CCRF-CEM/0 cells for 48 hr. The results were analyzed using both the isobologram and the median-effect methods. This combination at a 1:1 molar ratio was about 6-fold more potent (IC50, 0.16 µM) compared to ara-C alone (IC50, 1.05 µM) and about 18-fold more potent compared to LK11 alone (IC50, 2.95 ± 0.1 µM). In summary, the antileukemic potency of certain HAG derivatives can be improved by the presence of orthohydroxy groups of the phenyl ring, and a 1:1 molar combination of an isoquinoline HAG compound and ara-C leads to significant synergistic antileukemic activity against CCRF-CEM/0 cells in vitro.</div></front></TEI><istex><corpusName>springer-journals</corpusName><author><json:item><name>Phanesh B. Koneru</name><affiliations><json:string>Department of Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 90033, Los Angeles, California</json:string></affiliations></json:item><json:item><name>Eric J. Lien</name><affiliations><json:string>Department of Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 90033, Los Angeles, California</json:string></affiliations></json:item><json:item><name>Vassilios I. Avramis</name><affiliations><json:string>Children's Hospital of Los Angeles, Division of Hematology/ Oncology, USC Schools of Medicine and Pharmacy, Department of Pediatrics and Molecular Pharmacology and Toxicology, 90027, Los Angeles, California</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Schiff bases of hydroxyaminoguanidines</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>antileukemic activity</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>cytarabine (ara-C)</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>synergism</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>median-effect plots</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>isobologram</value></json:item></subject><articleId><json:string>304811</json:string><json:string>Art5</json:string></articleId><arkIstex>ark:/67375/1BB-711C1F74-8</arkIstex><language><json:string>eng</json:string></language><originalGenre><json:string>OriginalPaper</json:string></originalGenre><abstract>Abstract: A series of eight new N-hydroxy-N′-aminoguanidine (HAG) Schiff bases [ArCH = NNHC( = NH)NHOH · tosylate] was synthesized as potential antitumor agents through the inhibition of the enzyme ribonucleotide reductase (EC 1.17.4.1). Five of the HAG derivatives (LK02 through LK06) were designed to contain an orthohydroxy group on the phenyl ring of ArCH = to increase the stability of the Schiff base formed. In addition, two compounds with a substituted quinoline [LK10; ArCH = (4-hydroxy-7-trifluoromethylquinolin-3-yl)methylene] or isoquinoline (LK11; ArCH = (5-nitroisoquinolin-l-yl)methylene] moiety were synthesized through multiple-step reactions involving reduction and/or oxidation. The IC50 values of the newly synthesized HAG Schiff bases were determined against human leukemic CCRF-CEM/0 cells in culture. The IC50 values of two previously reported HAG derivatives [ATL25; ArCH = (5-nitro-isoquinolin-l-yl)methylene] and [LW02; ArCH = 2-hydroxy-3-allyl-benzylidene)] were also determined for the first time against CCRF-CEM/0 cells. Among the compounds tested, LK11 was found to be the most potent (IC50, 2.95 ± 0.1 µM) and the 4-methoxy-2-hydroxy-phenyl derivative (LK02) to be the least potent (IC50, 121 ± 16 µM). LK11 was about 15-fold more potent against CCRF-CEM/0 cells compared to the parent compound hydroxyguanidine sulfate (IC50, 46 ± 7.1 µM) and was about 32 times more potent than LK10 (IC50, 97.6 ± 0.9 µM). LK11 in combination was incubated in sequence with cytarabine (ara-C) at various molar ratios against CCRF-CEM/0 cells for 48 hr. The results were analyzed using both the isobologram and the median-effect methods. This combination at a 1:1 molar ratio was about 6-fold more potent (IC50, 0.16 µM) compared to ara-C alone (IC50, 1.05 µM) and about 18-fold more potent compared to LK11 alone (IC50, 2.95 ± 0.1 µM). In summary, the antileukemic potency of certain HAG derivatives can be improved by the presence of orthohydroxy groups of the phenyl ring, and a 1:1 molar combination of an isoquinoline HAG compound and ara-C leads to significant synergistic antileukemic activity against CCRF-CEM/0 cells in vitro.</abstract><qualityIndicators><score>5.05</score><pdfWordCount>0</pdfWordCount><pdfCharCount>0</pdfCharCount><pdfVersion>1.3</pdfVersion><pdfPageCount>6</pdfPageCount><pdfPageSize>612 x 792 pts (letter)</pdfPageSize><refBibsNative>false</refBibsNative><abstractWordCount>319</abstractWordCount><abstractCharCount>2151</abstractCharCount><keywordCount>6</keywordCount></qualityIndicators><title>Synthesis and Testing of New Antileukemic Schiff Bases of N -Hydroxy- N′ - Aminoguanidine Against CCRF-CEM/0 Human Leukemia Cells in Vitro and Synergism Studies with Cytarabine (Ara-C)</title><pmid><json:string>8483833</json:string></pmid><genre><json:string>research-article</json:string></genre><host><title>Pharmaceutical Research</title><language><json:string>unknown</json:string></language><publicationDate>1993</publicationDate><copyrightDate>1993</copyrightDate><issn><json:string>0724-8741</json:string></issn><eissn><json:string>1573-904X</json:string></eissn><journalId><json:string>11095</json:string></journalId><volume>10</volume><issue>4</issue><pages><first>515</first><last>520</last></pages><genre><json:string>journal</json:string></genre><subject><json:item><value>Pharmacology/Toxicology</value></json:item><json:item><value>Pharmacy</value></json:item><json:item><value>Biochemistry, general</value></json:item><json:item><value>Medical Law</value></json:item><json:item><value>Biomedical Engineering</value></json:item></subject></host><namedEntities><unitex><date></date><geogName></geogName><orgName></orgName><orgName_funder></orgName_funder><orgName_provider></orgName_provider><persName></persName><placeName></placeName><ref_url></ref_url><ref_bibl></ref_bibl><bibl></bibl></unitex></namedEntities><ark><json:string>ark:/67375/1BB-711C1F74-8</json:string></ark><categories><wos><json:string>1 - 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Aminoguanidine Against CCRF-CEM/0 Human Leukemia Cells in Vitro and Synergism Studies with Cytarabine (Ara-C)</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher scheme="https://scientific-publisher.data.istex.fr">Kluwer Academic Publishers-Plenum Publishers</publisher><pubPlace>New York</pubPlace><availability><licence><p>Plenum Publishing Corporation, 1993</p></licence><p scheme="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-3XSW68JL-F">springer</p></availability><date>1993</date></publicationStmt><notesStmt><note type="research-article" scheme="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</note><note type="journal" scheme="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Synthesis and Testing of New Antileukemic Schiff Bases of N -Hydroxy- N′ - Aminoguanidine Against CCRF-CEM/0 Human Leukemia Cells in Vitro and Synergism Studies with Cytarabine (Ara-C)</title><author xml:id="author-0000"><persName><forename type="first">Phanesh</forename><surname>Koneru</surname></persName><affiliation>Department of Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 90033, Los Angeles, California</affiliation></author><author xml:id="author-0001"><persName><forename type="first">Eric</forename><surname>Lien</surname></persName><affiliation>Department of Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 90033, Los Angeles, California</affiliation></author><author xml:id="author-0002"><persName><forename type="first">Vassilios</forename><surname>Avramis</surname></persName><affiliation>Children's Hospital of Los Angeles, Division of Hematology/ Oncology, USC Schools of Medicine and Pharmacy, Department of Pediatrics and Molecular Pharmacology and Toxicology, 90027, Los Angeles, California</affiliation></author><idno type="istex">F4AB6D4A3C9ECF1532D89A959CF00D74659E5E25</idno><idno type="ark">ark:/67375/1BB-711C1F74-8</idno><idno type="DOI">10.1023/A:1018985616389</idno><idno type="article-id">304811</idno><idno type="article-id">Art5</idno></analytic><monogr><title level="j">Pharmaceutical Research</title><title level="j" type="sub">An Official Journal of the American Association of Pharmaceutical Scientists</title><title level="j" type="abbrev">Pharm Res</title><idno type="pISSN">0724-8741</idno><idno type="eISSN">1573-904X</idno><idno type="journal-ID">true</idno><idno type="issue-article-count">29</idno><idno type="volume-issue-count">12</idno><imprint><publisher>Kluwer Academic Publishers-Plenum Publishers</publisher><pubPlace>New York</pubPlace><date type="published" when="1993-04-01"></date><biblScope unit="volume">10</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="515">515</biblScope><biblScope unit="page" to="520">520</biblScope></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>1993</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Abstract: A series of eight new N-hydroxy-N′-aminoguanidine (HAG) Schiff bases [ArCH = NNHC( = NH)NHOH · tosylate] was synthesized as potential antitumor agents through the inhibition of the enzyme ribonucleotide reductase (EC 1.17.4.1). Five of the HAG derivatives (LK02 through LK06) were designed to contain an orthohydroxy group on the phenyl ring of ArCH = to increase the stability of the Schiff base formed. In addition, two compounds with a substituted quinoline [LK10; ArCH = (4-hydroxy-7-trifluoromethylquinolin-3-yl)methylene] or isoquinoline (LK11; ArCH = (5-nitroisoquinolin-l-yl)methylene] moiety were synthesized through multiple-step reactions involving reduction and/or oxidation. The IC50 values of the newly synthesized HAG Schiff bases were determined against human leukemic CCRF-CEM/0 cells in culture. The IC50 values of two previously reported HAG derivatives [ATL25; ArCH = (5-nitro-isoquinolin-l-yl)methylene] and [LW02; ArCH = 2-hydroxy-3-allyl-benzylidene)] were also determined for the first time against CCRF-CEM/0 cells. Among the compounds tested, LK11 was found to be the most potent (IC50, 2.95 ± 0.1 µM) and the 4-methoxy-2-hydroxy-phenyl derivative (LK02) to be the least potent (IC50, 121 ± 16 µM). LK11 was about 15-fold more potent against CCRF-CEM/0 cells compared to the parent compound hydroxyguanidine sulfate (IC50, 46 ± 7.1 µM) and was about 32 times more potent than LK10 (IC50, 97.6 ± 0.9 µM). LK11 in combination was incubated in sequence with cytarabine (ara-C) at various molar ratios against CCRF-CEM/0 cells for 48 hr. The results were analyzed using both the isobologram and the median-effect methods. This combination at a 1:1 molar ratio was about 6-fold more potent (IC50, 0.16 µM) compared to ara-C alone (IC50, 1.05 µM) and about 18-fold more potent compared to LK11 alone (IC50, 2.95 ± 0.1 µM). In summary, the antileukemic potency of certain HAG derivatives can be improved by the presence of orthohydroxy groups of the phenyl ring, and a 1:1 molar combination of an isoquinoline HAG compound and ara-C leads to significant synergistic antileukemic activity against CCRF-CEM/0 cells in vitro.</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><item><term>Schiff bases of hydroxyaminoguanidines</term></item><item><term>antileukemic activity</term></item><item><term>cytarabine (ara-C)</term></item><item><term>synergism</term></item><item><term>median-effect plots</term></item><item><term>isobologram</term></item></list></keywords></textClass><textClass><keywords scheme="Journal Subject"><list><head>Biomedicine</head><item><term>Pharmacology/Toxicology</term></item><item><term>Pharmacy</term></item><item><term>Biochemistry, general</term></item><item><term>Medical Law</term></item><item><term>Biomedical Engineering</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="1993-04-01">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/ark:/67375/1BB-711C1F74-8/fulltext.txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus springer-journals not found" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="UTF-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//Springer-Verlag//DTD A++ V2.4//EN" URI="http://devel.springer.de/A++/V2.4/DTD/A++V2.4.dtd" name="istex:docType"></istex:docType><istex:document><Publisher><PublisherInfo><PublisherName>Kluwer Academic Publishers-Plenum Publishers</PublisherName><PublisherLocation>New York</PublisherLocation></PublisherInfo><Journal><JournalInfo JournalProductType="ArchiveJournal" NumberingStyle="Unnumbered"><JournalID>11095</JournalID><JournalPrintISSN>0724-8741</JournalPrintISSN><JournalElectronicISSN>1573-904X</JournalElectronicISSN><JournalTitle>Pharmaceutical Research</JournalTitle><JournalSubTitle>An Official Journal of the American Association of Pharmaceutical Scientists</JournalSubTitle><JournalAbbreviatedTitle>Pharm Res</JournalAbbreviatedTitle><JournalSubjectGroup><JournalSubject Type="Primary">Biomedicine</JournalSubject><JournalSubject Type="Secondary">Pharmacology/Toxicology</JournalSubject><JournalSubject Type="Secondary">Pharmacy</JournalSubject><JournalSubject Type="Secondary">Biochemistry, general</JournalSubject><JournalSubject Type="Secondary">Medical Law</JournalSubject><JournalSubject Type="Secondary">Biomedical Engineering</JournalSubject></JournalSubjectGroup></JournalInfo><Volume><VolumeInfo VolumeType="Regular" TocLevels="0"><VolumeIDStart>10</VolumeIDStart><VolumeIDEnd>10</VolumeIDEnd><VolumeIssueCount>12</VolumeIssueCount></VolumeInfo><Issue IssueType="Regular"><IssueInfo TocLevels="0"><IssueIDStart>4</IssueIDStart><IssueIDEnd>4</IssueIDEnd><IssueArticleCount>29</IssueArticleCount><IssueHistory><CoverDate><Year>1993</Year><Month>4</Month></CoverDate></IssueHistory><IssueCopyright><CopyrightHolderName>Plenum Publishing Corporation</CopyrightHolderName><CopyrightYear>1993</CopyrightYear></IssueCopyright></IssueInfo><Article ID="Art5"><ArticleInfo Language="En" ArticleType="OriginalPaper" NumberingStyle="Unnumbered" TocLevels="0" ContainsESM="No"><ArticleID>304811</ArticleID><ArticleDOI>10.1023/A:1018985616389</ArticleDOI><ArticleSequenceNumber>5</ArticleSequenceNumber><ArticleTitle Language="En">Synthesis and Testing of New Antileukemic Schiff Bases of <Emphasis Type="Italic">N</Emphasis>-Hydroxy-<Emphasis Type="Italic">N′</Emphasis> - Aminoguanidine Against CCRF-CEM/0 Human Leukemia Cells <Emphasis Type="Italic">in Vitro</Emphasis> and Synergism Studies with Cytarabine (Ara-C)</ArticleTitle><ArticleFirstPage>515</ArticleFirstPage><ArticleLastPage>520</ArticleLastPage><ArticleHistory><RegistrationDate><Year>2004</Year><Month>8</Month><Day>26</Day></RegistrationDate></ArticleHistory><ArticleCopyright><CopyrightHolderName>Plenum Publishing Corporation</CopyrightHolderName><CopyrightYear>1993</CopyrightYear></ArticleCopyright><ArticleGrants Type="Regular"><MetadataGrant Grant="OpenAccess"></MetadataGrant><AbstractGrant Grant="OpenAccess"></AbstractGrant><BodyPDFGrant Grant="Restricted"></BodyPDFGrant><BodyHTMLGrant Grant="Restricted"></BodyHTMLGrant><BibliographyGrant Grant="Restricted"></BibliographyGrant><ESMGrant Grant="Restricted"></ESMGrant></ArticleGrants><ArticleContext><JournalID>11095</JournalID><VolumeIDStart>10</VolumeIDStart><VolumeIDEnd>10</VolumeIDEnd><IssueIDStart>4</IssueIDStart><IssueIDEnd>4</IssueIDEnd></ArticleContext></ArticleInfo><ArticleHeader><AuthorGroup><Author AffiliationIDS="Aff1"><AuthorName DisplayOrder="Western"><GivenName>Phanesh</GivenName><GivenName>B.</GivenName><FamilyName>Koneru</FamilyName></AuthorName></Author><Author AffiliationIDS="Aff1"><AuthorName DisplayOrder="Western"><GivenName>Eric</GivenName><GivenName>J.</GivenName><FamilyName>Lien</FamilyName></AuthorName></Author><Author AffiliationIDS="Aff2"><AuthorName DisplayOrder="Western"><GivenName>Vassilios</GivenName><GivenName>I.</GivenName><FamilyName>Avramis</FamilyName></AuthorName></Author><Affiliation ID="Aff1"><OrgDivision>Department of Pharmaceutical Sciences, School of Pharmacy</OrgDivision><OrgName>University of Southern California</OrgName><OrgAddress><City>Los Angeles</City><State>California</State><Postcode>90033</Postcode></OrgAddress></Affiliation><Affiliation ID="Aff2"><OrgName>Children's Hospital of Los Angeles, Division of Hematology/ Oncology, USC Schools of Medicine and Pharmacy, Department of Pediatrics and Molecular Pharmacology and Toxicology</OrgName><OrgAddress><City>Los Angeles</City><State>California</State><Postcode>90027</Postcode></OrgAddress></Affiliation></AuthorGroup><Abstract ID="Abs1" Language="En"><Heading>Abstract</Heading><Para>A series of eight new <Emphasis Type="Italic">N</Emphasis>-hydroxy-<Emphasis Type="Italic">N′</Emphasis>-aminoguanidine (HAG) Schiff bases [ArCH = NNHC( = NH)NHOH · tosylate] was synthesized as potential antitumor agents through the inhibition of the enzyme ribonucleotide reductase (EC 1.17.4.1). Five of the HAG derivatives (LK02 through LK06) were designed to contain an orthohydroxy group on the phenyl ring of ArCH = to increase the stability of the Schiff base formed. In addition, two compounds with a substituted quinoline [LK10; ArCH = (4-hydroxy-7-trifluoromethylquinolin-3-yl)methylene] or isoquinoline (LK11; ArCH = (5-nitroisoquinolin-l-yl)methylene] moiety were synthesized through multiple-step reactions involving reduction and/or oxidation. The IC<Subscript>50</Subscript> values of the newly synthesized HAG Schiff bases were determined against human leukemic CCRF-CEM/0 cells in culture. The IC<Subscript>50</Subscript> values of two previously reported HAG derivatives [ATL25; ArCH = (5-nitro-isoquinolin-l-yl)methylene] and [LW02; ArCH = 2-hydroxy-3-allyl-benzylidene)] were also determined for the first time against CCRF-CEM/0 cells. Among the compounds tested, LK11 was found to be the most potent (IC<Subscript>50</Subscript>, 2.95 ± 0.1 µ<Emphasis Type="Italic">M</Emphasis>) and the 4-methoxy-2-hydroxy-phenyl derivative (LK02) to be the least potent (IC<Subscript>50</Subscript>, 121 ± 16 µ<Emphasis Type="Italic">M</Emphasis>). LK11 was about 15-fold more potent against CCRF-CEM/0 cells compared to the parent compound hydroxyguanidine sulfate (IC<Subscript>50</Subscript>, 46 ± 7.1 µ<Emphasis Type="Italic">M</Emphasis>) and was about 32 times more potent than LK10 (IC<Subscript>50</Subscript>, 97.6 ± 0.9 µ<Emphasis Type="Italic">M</Emphasis>). LK11 in combination was incubated in sequence with cytarabine (ara-C) at various molar ratios against CCRF-CEM/0 cells for 48 hr. The results were analyzed using both the isobologram and the median-effect methods. This combination at a 1:1 molar ratio was about 6-fold more potent (IC<Subscript>50</Subscript>, 0.16 µ<Emphasis Type="Italic">M</Emphasis>) compared to ara-C alone (IC<Subscript>50</Subscript>, 1.05 µ<Emphasis Type="Italic">M</Emphasis>) and about 18-fold more potent compared to LK11 alone (IC<Subscript>50</Subscript>, 2.95 ± 0.1 µ<Emphasis Type="Italic">M</Emphasis>). In summary, the antileukemic potency of certain HAG derivatives can be improved by the presence of orthohydroxy groups of the phenyl ring, and a 1:1 molar combination of an isoquinoline HAG compound and ara-C leads to significant synergistic antileukemic activity against CCRF-CEM/0 cells <Emphasis Type="Italic">in vitro</Emphasis>.</Para></Abstract><KeywordGroup Language="En"><Keyword>Schiff bases of hydroxyaminoguanidines</Keyword><Keyword>antileukemic activity</Keyword><Keyword>cytarabine (ara-C)</Keyword><Keyword>synergism</Keyword><Keyword>median-effect plots</Keyword><Keyword>isobologram</Keyword></KeywordGroup></ArticleHeader><NoBody></NoBody></Article></Issue></Volume></Journal></Publisher></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Synthesis and Testing of New Antileukemic Schiff Bases of N -Hydroxy- N′ - Aminoguanidine Against CCRF-CEM/0 Human Leukemia Cells in Vitro and Synergism Studies with Cytarabine (Ara-C)</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Synthesis and Testing of New Antileukemic Schiff Bases of N -Hydroxy- N′ - Aminoguanidine Against CCRF-CEM/0 Human Leukemia Cells in Vitro and Synergism Studies with Cytarabine (Ara-C)</title></titleInfo><name type="personal"><namePart type="given">Phanesh</namePart><namePart type="given">B.</namePart><namePart type="family">Koneru</namePart><affiliation>Department of Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 90033, Los Angeles, California</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Eric</namePart><namePart type="given">J.</namePart><namePart type="family">Lien</namePart><affiliation>Department of Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 90033, Los Angeles, California</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Vassilios</namePart><namePart type="given">I.</namePart><namePart type="family">Avramis</namePart><affiliation>Children's Hospital of Los Angeles, Division of Hematology/ Oncology, USC Schools of Medicine and Pharmacy, Department of Pediatrics and Molecular Pharmacology and Toxicology, 90027, Los Angeles, California</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="OriginalPaper" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</genre><originInfo><publisher>Kluwer Academic Publishers-Plenum Publishers</publisher><place><placeTerm type="text">New York</placeTerm></place><dateIssued encoding="w3cdtf">1993-04-01</dateIssued><copyrightDate encoding="w3cdtf">1993</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><abstract lang="en">Abstract: A series of eight new N-hydroxy-N′-aminoguanidine (HAG) Schiff bases [ArCH = NNHC( = NH)NHOH · tosylate] was synthesized as potential antitumor agents through the inhibition of the enzyme ribonucleotide reductase (EC 1.17.4.1). Five of the HAG derivatives (LK02 through LK06) were designed to contain an orthohydroxy group on the phenyl ring of ArCH = to increase the stability of the Schiff base formed. In addition, two compounds with a substituted quinoline [LK10; ArCH = (4-hydroxy-7-trifluoromethylquinolin-3-yl)methylene] or isoquinoline (LK11; ArCH = (5-nitroisoquinolin-l-yl)methylene] moiety were synthesized through multiple-step reactions involving reduction and/or oxidation. The IC50 values of the newly synthesized HAG Schiff bases were determined against human leukemic CCRF-CEM/0 cells in culture. The IC50 values of two previously reported HAG derivatives [ATL25; ArCH = (5-nitro-isoquinolin-l-yl)methylene] and [LW02; ArCH = 2-hydroxy-3-allyl-benzylidene)] were also determined for the first time against CCRF-CEM/0 cells. Among the compounds tested, LK11 was found to be the most potent (IC50, 2.95 ± 0.1 µM) and the 4-methoxy-2-hydroxy-phenyl derivative (LK02) to be the least potent (IC50, 121 ± 16 µM). LK11 was about 15-fold more potent against CCRF-CEM/0 cells compared to the parent compound hydroxyguanidine sulfate (IC50, 46 ± 7.1 µM) and was about 32 times more potent than LK10 (IC50, 97.6 ± 0.9 µM). LK11 in combination was incubated in sequence with cytarabine (ara-C) at various molar ratios against CCRF-CEM/0 cells for 48 hr. The results were analyzed using both the isobologram and the median-effect methods. This combination at a 1:1 molar ratio was about 6-fold more potent (IC50, 0.16 µM) compared to ara-C alone (IC50, 1.05 µM) and about 18-fold more potent compared to LK11 alone (IC50, 2.95 ± 0.1 µM). In summary, the antileukemic potency of certain HAG derivatives can be improved by the presence of orthohydroxy groups of the phenyl ring, and a 1:1 molar combination of an isoquinoline HAG compound and ara-C leads to significant synergistic antileukemic activity against CCRF-CEM/0 cells in vitro.</abstract><subject lang="en"><topic>Schiff bases of hydroxyaminoguanidines</topic><topic>antileukemic activity</topic><topic>cytarabine (ara-C)</topic><topic>synergism</topic><topic>median-effect plots</topic><topic>isobologram</topic></subject><relatedItem type="host"><titleInfo><title>Pharmaceutical Research</title><subTitle>An Official Journal of the American Association of Pharmaceutical Scientists</subTitle></titleInfo><titleInfo type="abbreviated"><title>Pharm Res</title></titleInfo><genre type="journal" authority="ISTEX" authorityURI="https://publication-type.data.istex.fr" valueURI="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</genre><originInfo><publisher>Springer</publisher><dateIssued encoding="w3cdtf">1993-04-01</dateIssued><copyrightDate encoding="w3cdtf">1993</copyrightDate></originInfo><subject><genre>Biomedicine</genre><topic>Pharmacology/Toxicology</topic><topic>Pharmacy</topic><topic>Biochemistry, general</topic><topic>Medical Law</topic><topic>Biomedical Engineering</topic></subject><identifier type="ISSN">0724-8741</identifier><identifier type="eISSN">1573-904X</identifier><identifier type="JournalID">11095</identifier><identifier type="IssueArticleCount">29</identifier><identifier type="VolumeIssueCount">12</identifier><part><date>1993</date><detail type="volume"><number>10</number><caption>vol.</caption></detail><detail type="issue"><number>4</number><caption>no.</caption></detail><extent unit="pages"><start>515</start><end>520</end></extent></part><recordInfo><recordOrigin>Plenum Publishing Corporation, 1993</recordOrigin></recordInfo></relatedItem><identifier type="istex">F4AB6D4A3C9ECF1532D89A959CF00D74659E5E25</identifier><identifier type="ark">ark:/67375/1BB-711C1F74-8</identifier><identifier type="DOI">10.1023/A:1018985616389</identifier><identifier type="ArticleID">304811</identifier><identifier type="ArticleID">Art5</identifier><accessCondition type="use and reproduction" contentType="copyright">Plenum Publishing Corporation, 1993</accessCondition><recordInfo><recordContentSource authority="ISTEX" authorityURI="https://loaded-corpus.data.istex.fr" valueURI="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-3XSW68JL-F">springer</recordContentSource><recordOrigin>Plenum Publishing Corporation, 1993</recordOrigin></recordInfo></mods><json:item><extension>json</extension><original>false</original><mimetype>application/json</mimetype><uri>https://api.istex.fr/ark:/67375/1BB-711C1F74-8/record.json</uri></json:item></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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