O6-alkylguanine-DNA alkyltransferase inactivators and beta-glucuronidase cleavable prodrugs

US7825096B2 · kind B2 · utility

Assignees

• The United States of America, as represented by the Department of Health and Human Services · US
• The Penn State Research Foundation · US

Inventors

• Robert C. Moschel · Frederick, US
• Natalia Loktionova · Hershey, US
• Anthony E. Pegg · Hershey, US
• Gary Pauly · Frederick, US

Key dates

• Filing date: Mar 7, 2007
• Grant date: Nov 2, 2010
• Expiry date: Mar 23, 2029

Classification

• Technology area (CPC A): Human Necessities
• CPC primary: A61P35/00
• WIPO field: Organic fine chemistry
• WIPO sector: Chemistry

Abstract

Disclosed are prodrugs of inactivators of O6-alkylguanine-DNA alkyltransferase (AGT). The prodrugs are cleavable by the β-glucuronidase enzyme, which is either administered to the patient or produced by necrotic tumor cells. The prodrugs are represented by the formula A-B-C, wherein A is a glucuronosyl residue linked through its 1-oxygen to the phenyl ring of B; B is a benzyloxycarbonyl group, optionally ring-substituted with one or more electron withdrawing groups; and C is an inactivator of AGT, e.g., a substituted or unsubstituted O6-benzylguanine or O6-benzyl-2′-deoxyguanosine. Also disclosed are additional inactivators of AGT, pharmaceutical compositions comprising an inactivator or prodrug and a pharmaceutically acceptable carrier, and a method of use of the inactivator or prodrug in enhancing the chemotherapeutic treatment of tumor cells in a mammal, e.g., a human, with an antineoplastic alkylating agent that causes cytotoxic lesions at the O6-position of guanine.