Search

On the reaction of 5-, 6-, 7-, and 8-nitroquinoline with potassium cyanide in methanol solution, always two kinds of compound were obtained in a moderate yield. The one was o-methoxyquinoline-carbonitrile, in which the cyano group is introduced in ortho-position to the nitro group and then the nitro group is replaced by a methoxyl group, and the other was 1-aminosoxazoloquinoline, in which the nitro group was reduced to hydroxyamino group and this hydroxyamino group was cyclized to an isoxazole ring with the cyano group introduced at ortho-position of the original nitro group. However, in the reaction of 4-nitroquinoline, 4-methoxyquinoline was obtained as a sole product.

金沢大学医薬保健研究域医学系, The liver may regulate glucose homeostasis by modulating the sensitivity/resistance of peripheral tissues to insulin, by way of the production of secretory proteins, termed hepatokines. Here, we demonstrate that selenoprotein P (SeP), a liver-derived secretory protein, causes insulin resistance. Using serial analysis of gene expression (SAGE) and DNA chip methods, we found that hepatic SeP mRNA levels correlated with insulin resistance in humans. Administration of purified SeP impaired insulin signaling and dysregulated glucose metabolism in both hepatocytes and myocytes. Conversely, both genetic deletion and RNA interference-mediated knockdown of SeP improved systemic insulin sensitivity and glucose tolerance in mice. The metabolic actions of SeP were mediated, at least partly, by inactivation of adenosine monophosphate-activated protein kinase (AMPK). In summary, these results demonstrate a role of SeP in the regulation of glucose metabolism and insulin sensitivity and suggest that SeP may be a therapeutic target for type 2 diabetes. © 2010 Elsevier Inc.

L'epoxydation de la vitamine D 3 par l'acide m-chloroperbenzoique conduit au derive epoxy-7,8 alors qu'avec l'hydroperoxyde de t-butyle on obtient le derive epoxy-5,6. On confirme la structure des epoxydes par analyse RX

A new route to the pavine skeleton was investigated starting from the readily accessible tetrahydro-6,12-methanodibenz[c,f]azocine (1,RH or Me); an efficient synthesis of a typical pavine alkaloid (±)-argemonine (6, R = OMe) from (1, R = OMe) was accomplished in 53% overall yield.

Substituted 2,5-dihydrothiophene S,S-dioxides, which are stable precursors of the corresponding buta-1,3-dienes, were prepared via reactions of 3-methylene-2,3-dihydrothiophene S,S-dioxide with electrophiles and nucleophiles; this method was applied to the synthesis of (±)-ipsenol.

A stereoselective synthesis of (E)-α-hydroxy-1,3-dienes, by thermal extrusion from adducts of 2,5-dihydrothiophene S,S-dioxide (1) with aldehydes and ketones, is presented and its extension to the synthesis of the dienone, (E)-tagetone, and of a 1,3,5-triene system, is illustrated.

The metabolism of 25-hydroxyvitamin D3 [25(OH)D3] was examined in several phagocytic cells including alveolar macrophages and myeloid leukemia cells (M1, HL-60 and U937). Phagocytic cells converted 25(OH)D3 to 10-oxo-19-nor-25-hydroxyvitamin D3 and a new metabolite. The former metabolite was dominant in shorter incubation periods (1 h), whereas the latter dominated over longer incubation periods (24 h). The new metabolite was produced from 25(OH)D3 directly but not through 10-oxo-19-nor-25-hydroxyvitamin D3. The new metabolite was unequivocally identified as 8α,25-dihydroxy-9,10-seco-4,6,10(19)-cholestatrien-3-one. These results suggest that phagocytic cells somehow promote oxidation of the triene part of vitamin D compounds.

Recent advances in the chemistry of 3- sulfolene, 2, 5- dihydrothiophene 1, 1-dioxide, are reviewed from a view point of diene synthesis. Reaction of 3- sulfolene α- carbanion generated under a variety of basic conditions with various electrophiles followed by a stereoselective desulfonylation provides a new method for synthesizing (E) -, (E, Z) -, and (E, E) -conjugated dienes with extremely high stereoselectivity. The method is applied to the syntheses of various natural products having a conjugated diene structure. 3-Sulfolenes are used as masked dienes in the syntheses of cyclic compounds including natural products via inter- and intramolecular Diels-Alder reactions. Some other developments of the chemistry of 3-sulfolenes and its benzo analogs, benzo [c] -1, 3-dihydrothiophene 2, 2-dioxides, are briefly reviewed.

A sensitive and rapid in vitro assay of 25-hydroxyvitamin D3 [25-(OH)D3]-1 alpha- and 24-hydroxylase activities was developed using rat kidney homogenates. A potent inhibitor of the enzymes in rat plasma was removed by thoroughly perfusing rats with saline. Kidney homogenates prepared from vitamin D-deficient rats preferentially produced tritiated 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3] from 25(OH) [3H]D3. Addition of 10 microliter or more of rat plasma to 3 ml of 10% kidney homogenates suppressed 1 alpha-hydroxylase activity dose-dependently. Thyroparathyroidectomy (TPTX) of vitamin D-deficient rats greatly abolished 1 alpha-hydroxylase activity. Administration of parathyroid hormone to the TPTX rats increased 1 alpha-hydroxylase activity and that of 1 alpha,25(OH)2D3 enhanced 24-hydroxylase markedly. Since this assay is technically simple, rapid and sensitive, it will be useful in studying the regulatory mechanism in the renal metabolism of 25(OH)D3 in mammals.

A novel base-induced Polonovski-type reaction is described; the regiochemistry of the Polonovski and related reactions can be examined by using 2-methoxytetrahydro-6,12-methanodibenz[c.f]azocine N-oxide (1b) as a probe.

A facile and efficient synthesis of (–)-cherylline (1) was accomplished in 46% overall yield starting from the readily accessible (12S)-(–)-3,9-dibenzyloxy-2-methoxy-tetrahydro-6,12-methanodibenz[c.f]azocine (4)viaa regiocontrolled Polonovski-type reaction as the key step.

23S,25R,26-Trihydroxyvitamin D3 and (23S,25R)-25-hydroxyvitamin D3 26,23-lactol were chemically synthesized, and the metabolism of the two compounds to (23S,25R)-25-hydroxyvitamin D3 26,23-lactone in chick kidney homogenates was studied. 23S,25R,26-trihydroxyvitamin D3 was efficiently metabolized to the lactone in kidney homogenates from vitamin D-supplemented chicks, but not from vitamin D-deficient chicks. In contrast, the (23S,25R)-25-hydroxyvitamin D3 26,23-lactol was converted to the lactone in kidney homogenates regardless of the vitamin D status of the animals used. A new metabolite was isolated in pure form from the incubation mixture of 23S,25R,26-trihydroxyvitamin D3 with kidney homogenates prepared from vitamin D-supplemented chicks. The metabolite was identified as (23S,25R)-25-hydroxyvitamin D3 26,23-lactol by its ultraviolet and mass spectra and by derivatization. The structure was confirmed by direct comparison with an authentic sample on high pressure liquid chromatography. The evidence suggests that the stereochemistries of the isolated lactol at the 23- and 25-positions are S and R, respectively.

Vitamin D compounds added to the culture medium induce differentiation of human myeloid leukemia cells (HL-60 cells) by binding to a specific cytosol receptor protein. This system provides a biologically relevant and technically simple assay to examine the relationship between molecular structure and biological activity of vitamin D compounds. Using this culture system, the biological activity of 24,24-F2-1 alpha,25(OH)2D3 and 1 alpha,25(OH)2D3-26,23-lactone was assayed. 24,24-F2-1 alpha,25(OH)2D3 was four to seven times more potent than 1 alpha,25(OH)2D3 in inducing phagocytosis and C3 rosette formation of HL-60 cells, though both compounds bound equally well to the cytosol receptor, suggesting that the defuorination at the 24-carbon position may stimulate membrane permeability of the compound. 1 alpha,25(OH)2D3-26,23-lactone, on the other hand, was only 1/200th as active as 1 alpha,25(OH)2D3. The binding affinity of the lactone for the cytosol receptor was identical with that of 1 alpha (OH)D3, suggesting that the lactone formation between the 26 and 23 positions masks the function of the 25-hydroxyl group. The binding affinity of vitamin D3 derivatives to the specific cytosol receptor of HL-60 cells was well correlated with that of intestinal cytosol protein specifically bound to 1 alpha,25(OH)2D3.

Alkylation par des iodures d'ethyle ou de butyle: etude de l'effet du substituant en 3 sur l'orientation en 2 ou en 5 de la reaction

A metabolite of 25-hydroxyvitamin D3 has been isolated in pure form from incubation mixtures containing kidney homogenates of chicks given large doses of vitamin D3. The isolation involved methanol--chloroform extraction and six steps of column chromatography. The metabolite was identified as 25-hydroxy-24-oxovitamin D3 by means of ultraviolet absorption spectrometry, mass spectrometry, infrared spectrometry, nuclear magnetic resonance spectrometry, and specific chemical reactions. Use of a sensitive in situ technique revealed that 25-hydroxy-24-oxovitamin D3 enhances intestinal calcium transport in rats approximately as effectively as 24,25-dihydroxyvitamin D3 does. In contrast, 25-hydroxy-24-oxovitamin D3 appeared to be less active than 24,25-dihydroxyvitamin D3 in chicks 24 h after intravenous injection.

The biological activity of subcutaneously injected 24,24-difluoro-25-hydroxycholecalciferol was compared with that of 25-hydroxycholecalciferol in the vitamin D-deficient growing chick. 24,24-Difluoro-25-hydroxycholecalciferol is equal to 25-hydroxycholecalciferol in the stimulation of: 1) growth, 2) intestinal calcium absorption, 3) elevation of serum calcium and serum phosphorus, 4) healing of rachitic cartilage (radiography), and 5) mineralization of rachitic bone (bone ash). The response appears to be linear in the range of 13.0 to 325 pmol daily. Since 24,24-difluorocholecaliferol cannot be 24-hydroxylated to produce either 24,25-dihydroxycholecalciferol or 1,24,25-trihydroxycholecalciferol, while it can be 1 alpha-hydroxylated to produce 24,24-difluoro-1,25-dihydroxycholecalciferol, these results demonstrate that 24-hydroxylation is not required for the known functions of cholecalciferol in the chick.

The synthesis of 25-hydroxy-24-oxovitamin D3 is described. The compound is identical in all respects with the natural product.

Singlet oxygen adducts of various vitamin D derivatives, 6,19-dihydro-6,19-epidioxyvitamin D (vitamin D endoperoxides, 2 and 2'), were chemically synthesized, and their biological activity in inducing differentiation of a human myeloid leukemia cell line (HL-60 cells) was examined. The potency of the endoperoxides derived from vitamin D derivatives possessing the 1 alpha-hydroxyl group such as 1 alpha, 25-dihydroxyvitamin D3 endoperoxides (2b and 2b') was markedly (10(-2)) diminished relative to the respective parent vitamin D compounds. In contrast, 25-hydroxyvitamin D3 endoperoxides [25-(OH)D3 endoperoxides, 2a and 2a'] and their analogues fluorinated at the 24- or 26- and 27-positions were 2.5-10 times more potent than 25-hydroxyvitamin D3 (1a) in spite of the absence of the conjugated triene structure typical of vitamin D compounds. The potency of these vitamin D endoperoxides (2 and 2'), especially those lacking the 1 alpha-hydroxyl group, in inducing differentiation of HL-60 cells was not correlated with their activity in binding to the cytosol receptor for 1 alpha, 25-dihydroxyvitamin D3 (1b). The binding efficiency to the receptor was relatively lower than the differentiating activity. To examine the action of vitamin D endoperoxides, carbon analogues of 25-(OH)D3 endoperoxides, two C-6 epimers of 25-hydroxy-6,19-dihydro-6,19-ethanovitamin D3 (6 and 6'), were synthesized. The carbon analogues (6 and 6') had no potential to induce differentiation of HL-60 cells. These results suggest that vitamin D endoperoxides (2 and 2') express their biological activity probably after being converted to some other compounds.

Chemical transformations of 1-methoxyimino-6-nitrohexa-2, 4-diene (II), resulted from the reaction of N-methoxypyridinium iodide (I) with nitromethane, were examined in relation to the nitro-aci-nitro prototropy. II reacted with diazomethane to afford methyl 1-methoxyimino-hexa-2, 4-diene-6-acinitronate (III), with acetic anhydride and with benzoyl chloride to give O-acetate and O-benzoate of 1-methoxyimino-hexa-2, 4-diene-6-hydroxamic acid (VI) respectively. The ultraviolet spectra of them were correlated to their structures.

Conjugated trienes have been synthesised readily and stereoselectively by the coupling reaction of 2-tri-n-butylstannyl-2,5-dihydrothiophene S,S-dioxides with vinyl iodides in the presence of tetrakis(triphenylphosphine)palladium(0), followed by desulphonylation.

By cochromatography, mass spectrometry, and chemical derivatization, we have shown that a metabolite isolated from the perfused rat kidney incubated with 24-(R),25-dihydroxyvitamin D3 is indistinguishable from chemically synthesized 24,25,26,27-tetranor-23-hydroxyvitamin D3. The new metabolite is also produced from 24-oxo-25-hydroxyvitamin D3 but not from 23(S),25-dihydroxyvitamin D3. Enzymes required for the synthesis of the new metabolite are absent in the vitamin D deplete animal but are induced along with the 25-hydroxyvitamin-D3 24-hydroxylase by vitamin D repletion. The pathway of 24,25-dihydroxyvitamin D3 metabolism in the perfused kidney is stimulated by pre-treatment of the rat with large doses of vitamin D3, suggesting that the pathway is a degradative one.

We synthesized 2-arachidonoylglycerol (1), an endogenous cannabinoid receptor ligand, and its metabolically stable ether-linked analogues. Compound 1 was synthesized from 1, 3-benzylideneglycerol (6) and arachidonic acid in the presence of N, N'-dicyclohexylcarbodiimide and 4-dimethylaminopyridine followed by treatment with boric acid and trimethyl borate. An ether-linked analogue of 2-arachidonoylglycerol (2) was synthesized from 6 and 5, 8, 11, 14-eicosatetraenyl iodide (9). The ether-linked analogues of 2-palmitoylglycerol (4) and 2-oleoyglycerol (5) were synthesized from 6 and hexadecyl iodide (12) and 9-octadecenyl iodide (14), respectively. We confirmed that 1 stimulates NG108-15 cells to induce rapid transient elevation of the intracellular free Ca2+ concentrations through a CB1 receptor-dependent mechanism. Noticeably, 2 exhibited appreciable agonistic activity, although its activity was significantly lower than that of 1. Compound 2 would be a useful tool in exploring the physiological significance of 1, because this compound is resistant to hydrolyzing enzymes in contrast to 1. On the other hand, the ether-linked analogues of either 4 or 5 failed to act as a CB1 receptor agonist. Compounds 4 and 5 would also be valuable as control molecules in experiments where 2 is employed.

It is known that phagocytic cells such as monocyte-macrophages and myeloid leukemia cells metabolize 25-hydroxyvitamin D3 to 10-oxo-19-nor-25-hydroxyvitamin D3. Now we have found that phagocytic cells metabolize 25-hydroxyvitamin D3 not only to 10-oxo-19-nor-25-hydroxyvitamin D3 but also to a new metabolite eluted just after 24R,25-dihydroxyvitamin D3 on straight phase high pressure liquid chromatography with a 2-propanol-hexane solvent system. The new metabolite, produced by murine myeloid leukemia cells (M1), was isolated in pure form and identified as 8,25-dihydroxy-9,10-seco-4,6,10(19)-cholestatrien-3-one on the basis of mass, ultraviolet, infrared, and proton magnetic resonance spectra. The 8 alpha-hydroxy epimer of the putative metabolite was chemically synthesized in two steps starting from 25-hydroxyvitamin D3. The spectral data and chromatographic behavior of chemically synthesized 8 alpha,25-dihydroxy-9,10-seco-4,6,10(19)-cholestatrien-3-one coincided exactly with those of the isolated metabolite, indicating that the stereochemistry of the hydroxyl group at the 8-position is alpha. On the basis of the structural characteristics of the two metabolites produced from 25-hydroxyvitamin D3 (the present metabolite and 10-oxo-19-nor-25-hydroxyvitamin D3), it is suggested that dioxygenases are involved in the production of these metabolites from 25-hydroxyvitamin D3 in phagocytic cells.

The synthesis of 25-hydroxy-24-oxovitamin D3 is described. The compound is identical in all respects with the natural product.

Triflic acid catalyzed double-cyclization reactions of N,N-dibenzyl-2-propynylamine, N-benzyl-N-phenethyl-2-propynylamine, and N-(α-benzylphenethyl)-2-propynylamine afforded 1-aza-5-methyldibenzo [c,f]bicyclo [3.3.1] nona-3,6-diene,1-aza-6-irethyldibenzo[d,q]bicyclo[4.3.1]deca-4,7-diene and 6-aza-1-methyldibenzo[b,i]bicyclo[3.3.2]nona-2,8-diene in high isolated yields, respectively.

A stereoselective synthesis of (E)-α-hydroxy-1,3-dienes, by thermal extrusion from adducts of 2,5-dihydrothiophene S,S-dioxide (1) with aldehydes and ketones, is presented and its extension to the synthesis of the dienone, (E)-tagetone, and of a 1,3,5-triene system, is illustrated.

A facile and efficient synthesis of (–)-cherylline (1) was accomplished in 46% overall yield starting from the readily accessible (12S)-(–)-3,9-dibenzyloxy-2-methoxy-tetrahydro-6,12-methanodibenz[c.f]azocine (4)viaa regiocontrolled Polonovski-type reaction as the key step.

A facile, stereoselective, and efficient synthesis of (24R)-24,25-dihydroxyvitamin D 3 , using D-glyceric acid as a chiral synthon to construct the side chain and ergosterol as a precursor of the secosteroid skeleton, is described.