Preparation, characterization, biological activity and metabolism of all-trans retinoyl fluoride

All-trans retinoyl fluoride was prepared by treating all-trans retinoic acid with diethylaminosulfurtrifluoride. The crystalline product, which was characterized by melting point, infrared, 1H-NMR, 19F-NMR and elementary analysis, showed lambda max at 382 nm in hexane (epsilon = 4.98 x 10(4) M-1 . cm-1) and at 392 nm in methanol (epsilon = 4.60 x 10(4) M-1 . cm-1). Its biological activity in the rat growth assay, relative to all-trans retinyl acetate, was 22% +/- 10%. Upon oral administration for 5 days to vitamin A-depleted rats, retinoyl fluoride (1020 micrograms) was rapidly metabolized to a polar metabolite fraction and, in the intestine, to an unstable retinol-like metabolite, purportedly 15-fluororetinol. Upon administering intraperitoneally smaller doses (47-94 micrograms) of [11-3H]retinoyl fluoride, which was synthesized from [11-3H]retinoic acid, radioactive retinoic acid was noted in the liver and plasma but not in the intestine. As expected, a radioactive polar fraction appeared in the intestine and liver, but radioactive retinol, retinyl ester and some common oxidation products were not detected. Of the administered radioactivity, 72% was excreted in the urine, and only 4% was found in the feces over a 7-day period. Hydrolysis of the urine gave a radioactive fraction with a polarity similar to that of retinoic acid. Retinoyl fluoride also reacts readily with glycine to yield N-retinoyl glycine. Thus, the biological activity of retinoyl fluoride can be attributed to the formation of retinoic acid, probably by way of N-retinoyl derivatives. A possible pathway for its metabolism is presented.