Prodrugs of Short-Chain Fatty Acids and Treatment Methods

Abstract

Prodrugs made up of biologically-active short-chain fatty acids or derivatives thereof conjugated to neutral or cationic amino acids capable of intracellular transport by ATB0,+ are provided. The short-chain fatty acid or derivative thereof can be attached to the amino acid through a hydroxyl group of the amino acid to form a fatty acid ester of the amino acid, or it can be attached through the amino group of the amino acid to form a fatty-acid amide of the amino acid. Serine butyrate (O-butyryl serine) is a preferred prodrug. These prodrugs are useful for treatment of colon cancer, inflammatory bowel disease, ulcerative colitis, Crohn's disease, lung cancer, cervical cancer, and cancers resulting from metastases from primary colon cancer sites. Methods of delivering biologically-active short-chain fatty acids or derivatives thereof to cells in need of these molecules and methods of treating diseases using the prodrugs of this invention are also provided.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims benefit of U.S. Provisional Application No. 60 / 644,186, filed Jan. 14, 2005, and U.S. Provisional Application No. 60 / 683,330, filed May 20, 2005, which are incorporated herein to the extent that there is no inconsistency with the present disclosure. U.S. patent application Ser. No. 10 / 467,893, first filed on Apr. 12, 2002 as Patent Cooperation Treaty Application PCT / JP02 / 03678, and published on Jul. 22, 2004 with Publication No. 2004 / 0142317 A1, is incorporated by reference herein to the extent not inconsistent herewith.BACKGROUND[0002]Colorectal cancer is the second most common cause of new cancer cases and cancer deaths in the United States, with an estimated 146,940 new cases and 56,730 deaths in 2004 (Jemal, A. et al. (2004), Cancer statistics, 2004, CA Cancer J. Clin. 54:8-29).[0003]Butyrate is a short-chain fatty-acid produced in the colon by bacterial fermentation of dietary fiber and required for colonic he...

AI Technical Summary

Benefits of technology

[0017]Because the ATB0,+ transporter's natural function is as an arginine transporter that provides the nitric oxide from arginine needed to keep blood vessels dilated where cells are rapidly proliferating, its upregulation in all types of cancers is indicated. It can thus be used to transport and target any known anticancer agent to cancer cells, thus reducing the dosage of these toxic chemicals required and reducing their damaging effects to healthy tissue. Examples of anticancer drugs that can be conjugated to amino acids for delivery to cancer cells include nucleoside drugs whose final groups can be attached to amino acids, and other anticancer drugs known to the art, e.g., 5′ fluorouracil, doxorubicin, daunorubicin, vinblastine, and cysplatin.

Problems solved by technology

Since SLC5A8, which transports butyrate from the colonic lumen into colonic epithelial cells, is downregulated in colon cancer, tributyrin, butyrate or similar tumor suppressors cannot be effectively targeted to colon cancer cells.

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