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Predicate | Object |
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
1
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pubmed:dateCreated |
1987-2-24
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pubmed:abstractText |
Chromophore modification of the anthracenediones related to mitoxantrone in an attempt to provide agents with diminished or no cardiotoxicity has resulted in a novel class of DNA binders, the anthrapyrazoles. Their synthesis was carried out by a two-stage condensation sequence starting from requisite 1,4- or 1,5-dichloro-9,10-anthracenedione precursors. Reaction with a monoalkylhydrazine gave a chloroanthrapyrazole intermediate whose subsequent condensation with primary or secondary alkylamines provided the target "two-armed" anthrapyrazoles. A-ring 7,10-dihydroxy anthrapyrazoles were derived from amine condensation with intermediate 5-chloro-7,10-dihydroxyanthrapyrazoles or, alternatively, from intermediate 5-chloro-7,10-bis(benzyloxy)anthrapyrazoles followed by hydrogenolysis of the benzyl protecting groups to provide the target compounds. Potent in vitro activity was demonstrated against murine L1210 leukemia in vitro (IC50 = 10(-7)-10(-8) M) as well as against P388 leukemia in vivo over a wide range of structural variants. In general, activity against the P388 line was maximized by basic side chains at N-2 and C-5, two to three carbon spacers between proximal and distal nitrogens of the side chain, and A-ring hydroxylation. Besides having curative activity against the P388 line, the more active compounds were curative against murine B-16 melanoma in vivo. On the basis of their exceptional in vivo anticancer activity, A-ring dihydroxy compounds 71 and 74 reported in this study have been selected for development toward clinical trials.
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pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Anthracenes,
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Indicators and Reagents,
http://linkedlifedata.com/resource/pubmed/chemical/Mitoxantrone,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrazoles
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pubmed:status |
MEDLINE
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pubmed:month |
Jan
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pubmed:issn |
0022-2623
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:volume |
30
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
121-31
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pubmed:dateRevised |
2006-11-15
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pubmed:meshHeading |
pubmed-meshheading:3806589-Animals,
pubmed-meshheading:3806589-Anthracenes,
pubmed-meshheading:3806589-Antineoplastic Agents,
pubmed-meshheading:3806589-Drug Evaluation, Preclinical,
pubmed-meshheading:3806589-Indicators and Reagents,
pubmed-meshheading:3806589-Leukemia, Experimental,
pubmed-meshheading:3806589-Leukemia L1210,
pubmed-meshheading:3806589-Leukemia P388,
pubmed-meshheading:3806589-Magnetic Resonance Spectroscopy,
pubmed-meshheading:3806589-Mice,
pubmed-meshheading:3806589-Mitoxantrone,
pubmed-meshheading:3806589-Pyrazoles,
pubmed-meshheading:3806589-Spectrophotometry,
pubmed-meshheading:3806589-Structure-Activity Relationship
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pubmed:year |
1987
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pubmed:articleTitle |
Anthrapyrazole anticancer agents. Synthesis and structure-activity relationships against murine leukemias.
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pubmed:publicationType |
Journal Article,
Comparative Study
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