| A unique class of duocarmycin and CC-1065 analogues subject to reductive activation. | |
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MedLine Citation:
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PMID: 18020335 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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N-Acyl O-amino phenol derivatives of CBI-TMI and CBI-indole2 are reported as prototypical members of a new class of reductively activated prodrugs of the duocarmycin and CC-1065 class of antitumor agents. The expectation being that hypoxic tumor environments, with their higher reducing capacity, carry an intrinsic higher concentration of "reducing" nucleophiles (e.g., thiols) capable of activating such derivatives (tunable N-O bond cleavage) and increasing their sensitivity to the prodrug treatment. Preliminary studies indicate the prodrugs effectively release the free drug in functional cellular assays for cytotoxic activity approaching or matching the activity of the free drug, yet remain essentially stable and unreactive to in vitro DNA alkylation conditions (<0.1-0.01% free drug release) and pH 7.0 phosphate buffer, and exhibit a robust half-life in human plasma (t1/2 = 3 h). Characterization of a representative O-(acylamino) prodrug in vivo indicates that they approach the potency and exceed the efficacy of the free drug itself (CBI-indole2), indicating that not only is the free drug effectively released from the inactive prodrug but also that they offer additional advantages related to a controlled or targeted release in vivo. |
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Authors:
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Wei Jin; John D Trzupek; Thomas J Rayl; Melinda A Broward; George A Vielhauer; Scott J Weir; Inkyu Hwang; Dale L Boger |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2007-11-17 |
Journal Detail:
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Title: Journal of the American Chemical Society Volume: 129 ISSN: 1520-5126 ISO Abbreviation: J. Am. Chem. Soc. Publication Date: 2007 Dec |
Date Detail:
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Created Date: 2007-12-06 Completed Date: 2008-02-11 Revised Date: 2010-12-03 |
Medline Journal Info:
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Nlm Unique ID: 7503056 Medline TA: J Am Chem Soc Country: United States |
Other Details:
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Languages: eng Pagination: 15391-7 Citation Subset: IM |
Affiliation:
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Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Alkylation
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drug effects Animals Antibiotics, Antineoplastic / chemistry, pharmacology* Cell Line, Tumor DNA / drug effects, metabolism Humans Indoles / chemistry, pharmacology* Inhibitory Concentration 50 Leukemia L1210 / drug therapy Mice Mice, Inbred DBA Phenols / chemistry, pharmacology Prodrugs / pharmacology* |
| Grant Support | |
ID/Acronym/Agency:
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CA41986/CA/NCI NIH HHS; R01 CA041986-20A1/CA/NCI NIH HHS; R01 CA041986-24/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antibiotics, Antineoplastic; 0/Indoles; 0/Phenols; 0/Prodrugs; 69866-21-3/CC 1065; 9007-49-2/DNA |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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