Bis(bioreductive) alkylating agents: synthesis and biological activity in a nude mouse human carcinoma model

Chemical investigations leading to the construction of bis(bioreductive) alkylating agents having both conformationally restricted and mobile spacer regions are described. Two targets having the conformationally mobile ethylene spacer group, namely, 2,2'-ethylenebis[6-(hydroxymethyl)-p-benzoqui...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1983-12, Vol.26 (12), p.1679-1686
Main Authors: Witiak, Donald T, Kamat, Prabhakar L, Allison, Debra L, Liebowitz, Stephen M, Glaser, Ronald, Holliday, Jane E, Moeschberger, Melvin L, Schaller, Joseph P
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - chemical synthesis
Benzoquinones
Burkitt Lymphoma - drug therapy
Cell Line
Chemistry
Cisplatin - therapeutic use
Drug Resistance
Exact sciences and technology
Humans
Methotrexate - therapeutic use
Mice
Mice, Nude
Nasopharyngeal Neoplasms - drug therapy
Noncondensed benzenic compounds
Organic chemistry
Preparations and properties
Quinones - chemical synthesis
Quinones - therapeutic use
Tumor Stem Cell Assay
Vinblastine - therapeutic use
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Summary:Chemical investigations leading to the construction of bis(bioreductive) alkylating agents having both conformationally restricted and mobile spacer regions are described. Two targets having the conformationally mobile ethylene spacer group, namely, 2,2'-ethylenebis[6-(hydroxymethyl)-p-benzoquinone] diacetate (3b) and 2,2'-ethylenebis[6-(bromomethyl)-p-benzoquinone] (3c), were studied in vivo and in vitro using an established epithelial/Burkitt lymphoma hybrid cell line (D98/HR1) previously shown to induce carcinomas in nude mice. Inactivity of both test compounds in vitro, the relative resistance of these cells to test drugs in vitro, and the selective antitumor properties of the bis(bromomethyl) analogue in vivo lead to the proposal that this compound undergoes bioreduction to an alkylating species in the hypoxic core of the tumor, thereby exerting its action.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00366a004