دورية أكاديمية
Beta-glucuronidase-cleavable prodrugs of O6-benzylguanine and O6-benzyl-2'-deoxyguanosine.
العنوان: | Beta-glucuronidase-cleavable prodrugs of O6-benzylguanine and O6-benzyl-2'-deoxyguanosine. |
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المؤلفون: | Wei G; Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, PO Box B, Bldg. 538, Frederick, Maryland 21702, USA., Loktionova NA, Pegg AE, Moschel RC |
المصدر: | Journal of medicinal chemistry [J Med Chem] 2005 Jan 13; Vol. 48 (1), pp. 256-61. |
نوع المنشور: | Journal Article |
اللغة: | English |
بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print Cited Medium: Print ISSN: 0022-2623 (Print) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE |
أسماء مطبوعة: | Publication: Washington Dc : American Chemical Society Original Publication: [Easton, Pa.] : American Chemical Society, [c1963- |
مواضيع طبية MeSH: | Deoxyguanosine/*analogs & derivatives , Deoxyguanosine/*metabolism , Glucuronidase/*metabolism , Guanine/*analogs & derivatives , Guanine/*metabolism , Prodrugs/*metabolism, Alkyl and Aryl Transferases/antagonists & inhibitors ; Alkyl and Aryl Transferases/drug effects ; Animals ; Antineoplastic Agents/metabolism ; Antineoplastic Agents/pharmacology ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Biochemistry/methods ; Carmustine/pharmacology ; Cattle ; Cell Death/drug effects ; Deoxyguanosine/chemical synthesis ; Deoxyguanosine/pharmacology ; Drug Stability ; Enzyme Activation/drug effects ; Escherichia coli/enzymology ; Guanine/chemical synthesis ; Guanine/pharmacology ; HT29 Cells/drug effects ; Humans ; Hydrolysis ; Kinetics ; Liver/enzymology ; Prodrugs/pharmacology |
مستخلص: | Glucuronic acid linked prodrugs of O(6)-benzylguanine and O(6)-benzyl-2'-deoxyguanosine were synthesized. The prodrugs were found to be quite stable at physiological pH and were more than 200-fold less active as inactivators of O(6)-alkylguanine-DNA alkyltransferase (alkyltransferase) than either O(6)-benzylguanine or O(6)-benzyl-2'-deoxyguanosine. Beta-glucuronidase from both Escherichia coli and bovine liver cleaved the prodrugs efficiently to release O(6)-benzylguanine and O(6)-benzyl-2'-deoxyguanosine, respectively. In combination with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), the prodrugs were not effective adjuvants for HT29 cell killing. However, as expected, incubation of these prodrugs with beta-glucuronidase in the culture medium led to much more efficient cell killing by BCNU as a result of the liberation of the more potent inactivators, O(6)-benzylguanine and O(6)-benzyl-2'-deoxyguanosine. These prodrugs may be useful for prodrug monotherapy of necrotic tumors that liberate beta-glucuronidase or for antibody-directed enzyme prodrug therapy with antibodies that can deliver beta-glucuronidase to target tumor cells. |
المشرفين على المادة: | 0 (Antineoplastic Agents) 0 (Prodrugs) 01KC87F8FE (O(6)-benzylguanine) 129732-90-7 (O(6)-benzyl-2'-deoxyguanosine) 5Z93L87A1R (Guanine) EC 2.5.- (Alkyl and Aryl Transferases) EC 3.2.1.31 (Glucuronidase) G9481N71RO (Deoxyguanosine) U68WG3173Y (Carmustine) |
تواريخ الأحداث: | Date Created: 20050107 Date Completed: 20050217 Latest Revision: 20161124 |
رمز التحديث: | 20231215 |
DOI: | 10.1021/jm0493865 |
PMID: | 15634019 |
قاعدة البيانات: | MEDLINE |
تدمد: | 0022-2623 |
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DOI: | 10.1021/jm0493865 |