β-Glucuronidase-Cleavable Prodrugs of O 6-Benzylguanine and O 6-Benzyl-2‘-deoxyguanosine

• Published in: Journal of medicinal chemistry Vol. 48; no. 1; pp. 256 - 261
• Main Authors: Wei, Guangping, Loktionova, Natalia A, Pegg, Anthony E, Moschel, Robert C
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 13.01.2005; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; CARMUSTINE PLUS O-6-BENZYLGUANINE; SELECTIVE CHEMOTHERAPY; BRAIN-TUMOR XENOGRAFTS; HUMAN O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE; PHASE-I TRIAL; PROGRESSIVE MALIGNANT GLIOMA; THERAPY ADEPT; DERIVATIVES; CANCER; ANTICANCER PRODRUGS
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0493865

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. β-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 β-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 β-glucuronidase or for antibody-directed enzyme prodrug therapy with antibodies that can deliver β-glucuronidase to target tumor cells.