Retinoic acid analogs with ring modifications. Synthesis and pharmacological activity

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Abstract
Analogs of retinoic acid that have their major modifications in the 5,6 double bond and 4-methylene group regions of the .beta.-cyclogeranylidene ring were synthesized as potential agents for the treatment and prevention of epithelial cancer. These modifications were intended to reduce retinoid toxicity by lowering the effective treatment dose because the major metabolic deactivation pathway would be inhibited. Ethyl (E)-3,7-dimethyl-9-(exo-2-bicyclo[2.2.1]heptyl)-2,4,6,8-nonatetraenoate (7), ethyl (E)-3,7-dimethyl-9-(2,2,6-trimethylbicyclo[4.1.0]hept-1-yl)-2,4,6,8-nonatetraenoate (18), (E)-1-(4-carbethoxyphenyl)-2-methyl-4-(2,2,6-trimethylbicyclo[4.1.0]hept-1-yl)-1,3-butadiene (28), (E)-retinoic acid-4,4,18,18,18-d5 (39), and ethyl (E)-3,7-dimethyl-9-(3,3-ethano-2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoate (47) displayed moderate to excellent activity in an assay for the inhibition of tumor promoter [12-O-tetradecanoylphorbol-13-acetate] induced mouse epidermal ornithine decarboxylase.