Terminal bifunctional retinoids. Synthesis and evaluations related to cancer chemopreventive activity.

Retinoids that have two functional groups at the side-chain terminus have been synthesized. The two terminal functional groups are combinations of the carboxyl, carbethoxy, and N-(ethylamino)carbonyl groups. The synthesis route is based on the sodium amide catalyzed condensation of (E,E)-beta-ionylideneacetaldehyde with diethyl isopropylidenemalonate. Ethyl 14-carboxyretinoate (6), the initial bifunctional analogue, undergoes isomerization in unbuffered aqueous ethanol and reaches a state of equilibrium with ethyl 14-carboxy-13-cis-retinoate. Both of the possible amide-esters and amide-acids were obtained. The structures of the isomeric bifunctional analogues were established by studies of nuclear Overhauser effects. The bifunctional analogues induce differentiation of mouse embryonal carcinoma cells, and those analogues that have a free carboxyl group bind to cellular retinoic acid binding protein.