HUMAN COLORECTAL-CARCINOMA CELLS IN-VITRO AS A MEANS TO ASSESS THE METABOLISM OF ANALOGS OF MYCOPHENOLIC-ACID

Cultures of the human colorectal carcinoma line, HT29, were used to as sess the susceptibility to glucuronidation of the cytostatic, immunosu ppressive 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 substantial ly lower antiproliferative potency against the EMT6 carcinoma line tha t is unable to glucuronidate MPA. In compounds retaining the 7-hydroxy function replacement of the lactone moiety of the phthalane ring of M PA by either a cyclopentanone or a 6-membered lactam afforded some pro tection against metabolism, but also partially or completely suppresse d antiproliferative activity, Some lipophilic substituents at position 2 of the hexenoic side chain in analogs with the 7-hydroxy function r esulted in increased metabolism, whereas several substituents with inc reased steric bulk in this position (including benzyl, p-hydroxyphenyl , trifluoroacetamidophenyl,S-methyl, and methoxymethyl) markedly inhib ited metabolism. The last three of these derivatives also maintained o r exceeded the antiproliferative potency of MPA. We suggest that cultu res of human colorectal carcinoma cells lines may provide a rapid and convenient means of assessing the susceptibility of novel synthetic co mpounds to both phase I and phase II metabolic conversions.