Three heteroarotinoids containing a nitrogen atom in the first ring and a C-O linking group between the two aryl rings were synthesized and evaluated for RAR and RXR retinoid receptor transactivation, tumor cell growth inhibition, and transglutaminase (TGase) induction. Ethyl 4-(N,4,4-trimethyl-1,2,3,4-tetrahydroquinolinyl)benzoate (1) contained an N-CH(3) group and activated all retinoid receptors except for RARgamma. Inceasing the hydrophobicity around the rings with analogues ethyl 4-(N,4,4,7-tetramethyl-1,2,3, 4-tetrahydroquinolin-6-oyloxy)benzoate (2) [7-methyl group added] and ethyl 4-(4,4-dimethyl-N-isopropyl-1,2,3, 4-tetrahydroquinolin-6-oyloxy)benzoate (3) [NCH(CH(3))(2) group at C-4] increased the potency and specificity for RARalpha, RARbeta, and RXRalpha, compared to 1, but had little effect on RXRbeta and RXRgamma activation. Although 1 and 3 were unable to activate RARgamma, 2 did activate this receptor with efficacy and high potency equal to that of 9-cis-retinoic acid (9-c-RA). All three heteroarotinoids exhibited 5-8-fold greater specificities for RARbeta over RARalpha. In addition, esters 1-3 inhibited the growth of two cell lines each derived from cervix, vulvar, ovarian, and head/neck tumors with similar efficiencies to that of 9-c-RA through a mechanism independent of apoptosis. The vulvar cell lines were the most sensitive, and the ovarian lines were the least sensitive. Ester 2 was similar to 1 and 3 except that 2 was a much more potent growth inhibitor of the two vulvar cell lines, which is consistent with strong RARgamma activation by 2 (but not by 1 and 3) and the high levels of RARgamma expression in skin. All three heteroarotinoids induced production of TGase, a marker of retinoid activity in human erythroleukemic cells. Esters 2 and 3 were the more potent TGase activators than 1, in agreement with the stronger activation of the RAR receptors by 2 and 3. The biological activities of these agents, and the RARgamma potency of 2 in particular, demonstrate the promise of these compounds as pharmaceutics for cancer and skin disorders.

A total of 35 pigs were obtained by cesarean section, placed in individual sterile isolators, and randomly allotted to treatment groups. Thirty pigs received purified, isoenergetic liquid diets containing 2 or 32% butterfat (dry matter basis) and were killed at 1, 7, or 21 days of age. Five pigs were killed at 2 hours post delivery and received no diet. Twenty-one-day old pigs showed a tendency for higher weight gain and feed consumption when consuming the 32% fat diet although the differences were not significant. The rate of oxidation of [U-14C]palmitate to CO2 and acid soluble products was measured in homogenates of liver, kidney, heart, and leg muscle (biceps femoris) from pigs 0, 1, 7, and 21 days of age. The relative rates of oxidation of [U-14C]myristate, [U-14C]palmitate, and [U-14C]stearate were measured in homogenates of liver from 7-day old pigs. Palmitate oxidation was stimulated by carnitine in all four tissues and the rate of carnitine-stimulated palmitate oxidation to acid soluble products in heart and to CO2 in liver was higher in tissues from pigs consuming the 32% fat diet. The rate of palmitate oxidation increased with age in liver, kidney and leg muscle tissues and was maximum at 21 days in kidney and leg muscle and at 7 days in liver. The rate of palmitate oxidation in heart tended to decrease with animal age. In homogenates of liver from 7-day old pigs, palmitate was oxidized at a faster rate than stearate or myristate. The activities of carnitine palmitoyltransferase (CPT) (EC 2.3.1a) and succinate dehydrogenase (EC 1.3.99.1) in mitochondria isolated from liver, kidney, heart, and leg muscle did not vary considerably with age although CPT activity tended to be higher in those tissues from pigs consuming the high fat diet. Changes in the rate of palmitate oxidation with age tended to parallel changes in the level of mitochondrial protein per g of wet tissue and suggested an increased ability to utilize fat as an energy substrate during early development of the neonatal pig.

Page 3606. Under Discussion, lines 24 and 25, the reference to Table 2 is incorrect; Table 1 is the correct reference. The corrected sentence is as follows: The EC 50 value of 6 nM and the 103% efficacy of 2 (Table 1), in comparison to that of 9-c-RA, indicate that 2 may be useful as a pharmaceutical agent for disorders of the skin.

Acid catalysis (0.1 M H2S04) of (13S)-(9Z,lLE)-13-hydroperoxy-9,ll-octadecadienoic acid (1) in methanol-water (9:1) did not afford appreciable yields of anticipated products, hexanal and (Z)-12-oxo-9-dodecenoic acid, via the known Hock rearrangement of hydroperoxides. Instead, intramolecular rearrangement of the 13-hydroperoxide into 12,13-epoxides, accompanied by solvent substitution, was the primary course of reaction (all products were isolated after conversion to methyl esters). Three isomeric methyl (Z)-12,13-epoxy-11 -methoxy-9-octadecenoates were isolated in 20.2 mol % yield; methyl (llR,12fi,13S)-(Z)-12,13-epoxy-ll-methoxy-9-octadecenoate (2a) comprised 81% of the three. The stereoselectivity observed in the formation of 2a implied anchimeric assistance by the epoxide group in substitution by methanol. Kinetic evidence, as well as a 20.4 mol % yield of stereoisomers of methyl (E)-13-hydroxy-9,12-dimethoxy-10-octadecenoates, was indicative of intermediate (E)-12,13-epoxy-9-methoxy-10-octadecenoic acids. These allylic epoxides could not be isolated, presumably because they solvolyzed rapidly in the presence of acid. On the other hand, the nonallylic epoxides 2a-c solvolyzed more slowly. The following reaction mechanism is proposed: (a) a conjugate acid forms by addition of a proton to a hydroperoxy group; (b) electrophilic attack on C-12 by a partially positive-charged -oxygen of the hydroperoxy group affords