title: Beta-glucuronidase-cleavable prodrugs of O6-benzylguanine and O6-benzyl-2'-deoxyguanosine.
abstract: 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.
authors.affiliation: Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, PO Box B, Bldg. 538, Frederick, Maryland 21702, USA.
authors.forename: Guangping
authors.initials: G
authors.lastname: Wei
authors.forename: Natalia A
authors.initials: NA
authors.lastname: Loktionova
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Pegg
authors.forename: Robert C
authors.initials: RC
authors.lastname: Moschel
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001671:Biochemistry / Q000379:methods; D002330:Carmustine / Q000494:pharmacology; D002417:Cattle; D016923:Cell Death / Q000187:drug effects; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D004355:Drug Stability; D004789:Enzyme Activation / Q000187:drug effects; D004926:Escherichia coli / Q000201:enzymology; D005966:Glucuronidase / Q000378:metabolism*; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D019073:HT29 Cells / Q000187:drug effects; D006801:Humans; D006868:Hydrolysis; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D011355:Prodrugs / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D011355:Prodrugs; C064976:O(6)-benzylguanine; C088636:O(6)-benzyl-2'-deoxyguanosine; D006147:Guanine; D019883:Alkyl and Aryl Transferases; D005966:Glucuronidase; D003849:Deoxyguanosine; D002330:Carmustine