Cancer chemopreventive 3-substituted-4-oxoretinoic acids

The introduction of substituents at position 3 of methyl 4-oxoretinoate can be effected in good yields by alkylating the lithium dienolate. A second substituent can be introduced also, but the resulting 3,3-disubstituted-4-oxoretinoates were isolated in lower yields. Evidence was obtained for a slower rate of alkylation at the alpha-position (carbon 14) of the ester group. Some of these 4-oxoretinoic acid analogues showed high activity in assays in vivo for the inhibition of ornithine decarboxylase activity and carcinogen-induced papillomas in mouse skin.