Abstract

Cultures of the human colorectal carcinoma line, HT29, were used to assess the susceptibility to glucuronidation of the cytostatic, immunosuppressive drug mycophenolic acid (MPA) and 19 of its analogs. Removal of the metabolically vulnerable 7-hydroxyl group or its replacement by a fluorine atom, amino group, or nitrile group resulted in compounds that were completely resistant to metabolism, but that had substantially lower antiproliferative potency against the EMT6 carcinoma line that is unable to glucuronidate MPA. In compounds retaining the 7-hydroxy function replacement of the lactone moiety of the phthalane ring of MPA by either a cyclopentanone or a 6-membered lactam afforded some protection against metabolism, but also partially or completely suppressed antiproliferative activity. Some lipophilic substituents at position 2 of the hexenoic side chain in analogs with the 7-hydroxy function resulted in increased metabolism, whereas several substituents with increased steric bulk in this position (including benzyl, p-hydroxyphenyl, trifluoroacetamidophenyl,S-methyl, and methoxymethyl) markedly inhibited metabolism. The last three of these derivatives also maintained or exceeded the antiproliferative potency of MPA. We suggest that cultures of human colorectal carcinoma cells lines may provide a rapid and convenient means of assessing the susceptibility of novel synthetic compounds to both phase I and phase II metabolic conversions.