A conformationally defined 6-s-trans-retinoic acid isomer: synthesis, chemopreventive activity, and toxicity.
A conformationally defined retinoic acid analog (1) which contains a dimethylene bridge to maintain the 6-s-trans orientation for two terminal double bonds in the polyene chain was synthesized. A Reformatsky reaction 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 produced retinoic acid analogs with both 9Z- and 9Z,13Z-configurations. An I2-catalyzed isomerization of the intermediate 9Z-aldehyde yielded the all-E-aldehyde, which was olefinated as above to yield the (all-E)- and (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 ornithine decarboxylase in mouse skin. In each assay (all-E)-1 was the most active 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 proliferation of human sebaceous cells in vitro. (all-E)-1 was further evaluated for its ability to prevent the induction of mouse skin papillomas and to induce signs of vitamin A toxicity in mice. The cancer chemopreventive activity of (all-E)-1 was comparable to that of (all-E)-retinoic acid, and the toxicity was comparable to or slightly better than that of the natural vitamin.
Vaezi
M F
MF
Department of Chemistry, University of Alabama at Birmingham 35294.
Alam
M
M
Sani
B P
BP
Rogers
T S
TS
Simpson-Herren
L
L
Wille
J J
JJ
Hill
D L
DL
Doran
T I
TI
Brouillette
W J
WJ
Muccio
D D
DD
D016475:3T3 Cells; D000328:Adult; D000818:Animals; D016588:Anticarcinogenic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D002415:Cats; D005260:Female; D006801:Humans; D051379:Mice; D009955:Ornithine Decarboxylase / Q000096:biosynthesis; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014212:Tretinoin / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity
D016588:Anticarcinogenic Agents; D014212:Tretinoin; D009955:Ornithine Decarboxylase