The Penn State Research Foundation

The United States of America, As Represented by the Secretary, Department of Health and Human Services

The United States of America As Represented by the Department of Health

Arch Development Corporation

Gary T Pauly

Anthony E Pegg

Robert C Moschel

Natalia A Loktionova

Matthew Karl Moschel, Legal Representative

M Eileen Dolan

Sahar Javanmard

Disclosed are compounds that are AGT inactivators that include a folate residue, e.g., a compound of formula (I), wherein X, X, R, and Rare as described herein. Also disclosed is a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier. Also disclosed are methods of enhancing the chemotherapeutic treatment of tumor cells and inactivating AGT in a tumor cell. The methods comprise, inter alia, administering a compound or pharmaceutically acceptable salt of formula (I). 

Inactivators of O6-alkylguanine-DNA alkyltransferase

Disclosed are prodrugs of inactivators of O-alkylguanine-DNA alkyltransferase (AGT). The prodrugs are cleavable by the &#x3b2;-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 O-benzylguanine or O-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 O-position of guanine.

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

The present invention provides a single-stranded oligodeoxyribonucleotide, which (i) comprises from about 5 to 11 bases, at least one of which is a substituted or an unsubstituted O.sup.6 -benzylguanine, and (ii) inactivates human AGT. The present invention also provides a single-stranded oligodeoxyribonucleotide, which can inactivate a mutant human AGT, which either is not inactivated by O.sup.6 -benzylguanine or is less inactivated by O.sup.6 -benzylguanine than by said single-stranded oligodeoxyribonucleotide. A phosphate of the single-stranded oligodeoxyribonucleotide can be replaced by a methylphosphonate or a phosphorothioate. The present invention also provides a composition comprising such an oligodeoxyribonucleotide. In addition, the present invention provides a method of enhancing the effect of an antineoplastic alkylating agent, which alkylates the O.sup.6 position of guanine residues in DNA, in the chemotherapeutic treatment of cancer in a mammal, which method comprises the co-administration to the mammal of a cancer-treatment effective amount of an antineoplastic alkylating agent and a chemotherapeutic treatment-enhancing amount of a present inventive oligodeoxyribonucleotide or composition thereof.

Oligodeoxyribonucleotides comprising O.sup.6 -benzylguanine and their use

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Frederick, MD, United States of America

Gary T Pauly