Tris and the ready production of drug-fatty acyl conjugates

Abstract

The technology described in this article utilises the common laboratory reagent tris to readily produce drug–fatty acid conjugates. Tris has structural similarities to glycerol, allowing the coupling of one to three fatty acyl groups giving compounds that mimic mono-, di-, and triglycerides. The symmetrical carbon atom of tris avoids structural isomerisation and enables large-scale production without the isolation problems generally associated with glycerol derivatives. The amine group provides an ideal attachment site for drugs. Tris is readily available, inexpensive, and approved for pharmaceutical use. We prepared representative fatty acid conjugates of an analgesic (e.g., morphine), nonsteroidal anti-inflammatory drug (e.g., indomethacin), antiviral drug (e.g., AZT), and antineoplastics (e.g., methotrexate and chlorambucil). Biological activities of these conjugates demonstrated altered properties, such as cellular uptake, delivery profiles, skin retention, and toxicity. These changes may improve the therapeutic use of some compounds. Drug Dev. Res. 46:302–308, 1999. © 1999 Wiley-Liss, Inc.