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 : 001334 ( Main/Exploration ); précédent : 001333; suivant : 001335Synthesis 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 [États-Unis] ; Eric J. Lien [États-Unis] ; Vassilios I. Avramis [États-Unis]Source :
- Pharmaceutical Research [ 0724-8741 ] ; 1993-04-01.
English descriptors
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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></author><author><name sortKey="Lien, Eric J" sort="Lien, Eric J" uniqKey="Lien E" first="Eric J." last="Lien">Eric J. Lien</name></author><author><name sortKey="Avramis, Vassilios I" sort="Avramis, Vassilios I" uniqKey="Avramis V" first="Vassilios I." last="Avramis">Vassilios I. 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Koneru</name><affiliation wicri:level="2"><country>États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Department of Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 90033, Los Angeles</wicri:cityArea></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 wicri:level="2"><country>États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Department of Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 90033, Los Angeles</wicri:cityArea></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 wicri:level="2"><country>États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>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</wicri:cityArea></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><affiliations><list><country><li>États-Unis</li></country><region><li>Californie</li></region></list><tree><country name="États-Unis"><region name="Californie"><name sortKey="Koneru, Phanesh B" sort="Koneru, Phanesh B" uniqKey="Koneru P" first="Phanesh B." last="Koneru">Phanesh B. Koneru</name></region><name sortKey="Avramis, Vassilios I" sort="Avramis, Vassilios I" uniqKey="Avramis V" first="Vassilios I." last="Avramis">Vassilios I. Avramis</name><name sortKey="Lien, Eric J" sort="Lien, Eric J" uniqKey="Lien E" first="Eric J." last="Lien">Eric J. Lien</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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