A CONFORMATIONALLY DEFINED 6-S-TRANS-RETINOIC ACID ISOMER - SYNTHESIS, CHEMOPREVENTIVE ACTIVITY, AND TOXICITY

A conformationally defined retinoic acid analog (1) which contains a d imethylene bridge to maintain the 6-s-trans orientation for two termin al double bonds in the polyene chain was synthesized. A Reformatsky re action was utilized to extend the polyene chain of the starting enone, which provided exclusively the 9Z-configuration for the intermediate aldehyde. A Horners-Emmons condensation with this aldehyde then produc ed retinoic acid analogs with both 9Z- and 9Z,13Z-configurations. An I -2-catalyzed isomerization of the intermediate 9Z-aldehyde yielded the all-E-aldehyde, which was olefinated as above to yield the (all-E)- a nd (13Z)-retinoic acid analogs of 1. Each configurational isomer of 1 was evaluated for its ability to inhibit the binding of retinoic acid to CRABP (chick skin) and to inhibit the chemical induction of ornithi ne decarboxylase in mouse skin. In each assay (all-E)-1 was the most a ctive isomer, and this activity was comparable to or better than that for (all-E)-retinoic acid. (all-E)-1 and (13Z)-1 were both shown to be equally effective as (13Z)-retinoic acid in suppressing the prolifera tion of human sebaceous cells in vitro. (all-E)-1 was further evaluate d for its ability to prevent the induction of mouse skin papillomas an d to induce signs of vitamin A toxicity in mice. The cancer chemopreve ntive activity of(all-E)-1 was comparable to that of(all-E)-retinoic a cid, and the toxicity was comparable to or slightly better than that o f the natural vitamin.