Effect of 2-(4-aminophenylmethyl)-6-hydroxy-3, 4-dihydronaphthalen-1(2H)-one on all-trans and 13-cis-retinoic acid levels in plasma quantified by high perfomance liquid chromatography coupled to tandem mass spectrometry.

The effect of the titled tetralone as a retinoic acid metabolism blocking agent (RAMBA) in vivo in comparison with ketoconazole, a well known cytochrome P450 inhibitor, was studied. Development of a HPLC/MS/MS method for the quantification of retinoic acid levels extracted from rat plasma was used to demonstrate that ketoconazole and the tetralone (100 mg/kg) enhanced the endogenous plasma concentration of retinoic acid. Levels of retinoid were raised from a control value of 0.11 to 0.15 and 0.17 ng/mL after treatment with tetralone and ketoconazole respectively showing that the tetralone and ketoconazole lead to comparable effects, indicating an inhibitory activity of the tetralone on retinoic acid metabolism.

Retinoic acid metabolism inhibition by 3-azolylmethyl-1H-indoles and 2, 3 or 5-(alpha-azolylbenzyl)-1H-indoles.

Among a library of 70 azoles, 8 indole derivatives substituted in the 2-, 3- or 5- position with an azolylmethyl or alpha-azolylbenzyl chain were evaluated for retinoic acid (RA) metabolism inhibitory activity. The most active inhibitors identified in this study were 5-bromo-1-ethyl-3-methyl-2-[(phenyl)(1H-1,2,4-triazol-1-yl)methyl]-1H-indole (3) (68.9% inhibition) and 5-bromo-1-ethyl-2-[(4-fluorophenyl) (1H-1,2,4-triazol-1-yl)methyl]-3-methyl-1H-indole (6) (60.4% inhibition). At the same concentration (100 microM) ketoconazole exerted similar inhibitory effect (70% inhibition).

Inhibition of retinoic acid metabolising enzymes by 2-(4-aminophenylmethyl)-6-hydroxy-3,4-dihydronaphthalen-1(2H)-one and related compounds.

In a search for inhibitors of all-trans retinoic acid (RA)-metabolising enzymes as potential agents for the treatment of skin conditions and cancer we have examined 2-(4-aminophenylmethyl)-6-hydroxy-3,4-dihydronaphthalen-1(2H)-one (5). Compound (5) is a moderate inhibitor of RA-metabolising enzymes in mammalian cadaverous tissue microsomes and homogenates as well as RA-induced enzymes in cultured human genital fibroblasts and HaCat cells. Overall (5) was more potent than or equipotent with ketoconazole, a standard inhibitor, in the cadaverous systems but less active towards the RA-induced cell culture systems. Examination of the data suggests that RA-induction generates metabolising enzymes not present in the cadaverous systems, which are more susceptible to inhibition by ketoconazole than (5).

Some aryl substituted 2-(4-nitrophenyl)-4-oxo-4-phenylbutanoates and 3-(4-nitrophenyl)-1-phenyl-1,4-butanediols and related compounds as inhibitors of rat liver microsomal retinoic acid metabolising enzymes.

Some aryl substituted methyl 2-(4-nitrophenyl)-4-oxo-4-phenylbutanoates generally had poor to moderate inhibitory potency (4-73%) towards rat liver microsomal retinoic acid metabolising enzymes compared with ketoconazole (80%). Conversion to the corresponding 3-(4-nitrophenyl)-1-aryl-1,4-butanediols considerably increased potency (29-78%). The 4-iodophenyl analogue, (30) and the 4-iodo- (45) and 4-methoxyphenyl (46) analogues, were the most potent in both series respectively. The corresponding 5-membered lactones, in the three instances examined, were also potent (52%, 67%, 69%) as were the cis- and trans-isomers of the 5-membered tetrahydrofuran (77%, 65% respectively). Beckmann rearrangement of the oxime methyl 4-(2,4-dichlorophenyl)-4-hydroxyimino-2-(4-nitrophenyl)butanoate (54) gave the expected products (55) and (56), which were potent inhibitors (75%, 74% respectively) of the enzyme whereas the oxime was an activator.

Experiments towards the synthesis of the ergot alkaloids and related structures. Part 8. The total synthesis of 4-methyl-2,3,4,4a,5,6-hexahydrobenzo[f]quinoline-2-carbonitrile hydrochloride hemihydrate, an immediate precursor of the despyrrole analogues of lysergic acid and its amides.

Exposure of the N-methoxycarbonyl-bicyclic-keto-acid 5 (improved preparation) to the Barnick beta-keto-acid synthesis yielded an aqueous solution of the sodium salts of the beta-keto-acids 26 and 27 which on heating at 60-65 degrees C furnished the N-methoxycarbonyl-tricyclic-ketone 9 (55%) plus the hydroxy-ketone 28 which on acid treatment raised the yield of 9 to 68%. Reduction (NaBH4) of 9 yielded the alcohol 32 (94%) which was treated with thionyl chloride followed by copper (I) cyanide and sodium iodide in acetonitrile to give the tricyclic-N-methoxycarbonyl nitrile 35 whose relative configuration was obtained by X-ray analysis. Attempts to remove the N-methoxycarbonyl group from 35 were unsuccessful. Conversion of the alcohol 32 to its methoxypropyl ether 41 followed by reaction with ethereal MeLi-LiBr yielded the amino-alcohol 39 (75%) converted to the N-formyl-tricyclic alcohol 42 with formic-acetic anhydride (70%). The alcohol 42 was then converted into the N-formyl nitrile 44 via the chloride 43 as employed in the earlier synthesis of the nitrile 35. Removal of the N-formyl group from the nitrile 44 was achieved by refluxing methanolic hydrochloric acid to give the required amino-nitrile hydrochloride 46 (91%) whose structure was confirmed by X-ray analysis. Reaction of the free base with methyl iodide in ethyl acetate in the presence of calcium carbonate furnished the N-methyl base 48 isolated as its hydrochloride, hemihydrate 49 (59%). The overall yield of 49 via this eleven-step synthesis was 3.4%.

Some 3-(4-aminophenyl)pyrrolidine-2,5-diones as all-trans-retinoic acid metabolising enzyme inhibitors (RAMBAs).

A series of (+/-)-3-(4-aminophenyl) pyrrolidin-2,5-diones substituted in the 1-, 3- or 1,3-position with an aryl or long chain alkyl function are weak inhibitors of the metabolism of all-trans retinoic acid (RA) by rat liver microsomes (68-75% inhibition) compared with ketoconazole (85%). Further studies with the 1-cyclohexyl analogue (1) (IC50 = 98.8 microM, ketoconazole, 22.15 microM) showed that it was not stereoselective in its inhibition. (+/-)-(1) was not an inhibitor of pig brain microsomal enzyme (ketoconazole, IC50 = 20.9 microM), had little effect on human liver microsomal enzyme (19.3%, ketoconazole, 81.6%) or human placental microsomal enzyme (9.8%, ketoconazole 73.9%) but was a weak inhibitor of human and rat skin homogenates (52.6% and IC50 = 211.6 microM respectively; ketoconazole, 38.8% and 85.95 microM). In RA-induced cell cultures of human male genital fibroblasts and HaCat cells, (+/-)-(1) was a weak inhibitor (c. 53% at 200 microM) whereas ketoconazole showed high potency (c. 65% at 0.625 microM and 0.25 microM respectively). The nature of the induced target enzyme is discussed.