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The anisotropic effects of the phenyl, alpha- and beta-naphthyl moieties in four series of 1,3-oxazino[4,3- a]isoquinolines on the H-1 chemical shifts of the isoquinoline protons were calculated by employing the Nucleus Independent Chemical Shift (NICS) concept and Visualized as anisotropic cones by a through-space NMR shielding grid. The signs and extents of these spatial effects on the H-1 chemical shifts of the isoquinoline protons were compared with the experimental H-1 NMR spectra. The differences between the experimental delta (H-1)/ppm values and the calculated anisotropic effects of the aromatic moieties are discussed in terms of the steric compression that occurs in the Compounds studied.
Through the reactions of 1-aminomethyl-2-naphthol and substituted 1-aminobenzyl-2-naphthols with 3,4-dihydroisoquinoline or 6,7-dimethoxy-3,4-dihydroisoquinoline under microwave conditions, naphth[1,2-e][1,3]oxazino[2,3-a]-isoquinoline derivatives were prepared in good yields. The latter reaction was extended by using 2-aminoarylmethyl-1-naphthols, leading to isomeric naphth-[2,1-e][1,3]oxazino[2,3-a] isoquinolines. Beside the detailed NMR spectroscopic and theoretical study of both stereochemistry and dynamic behaviour of these new conformational flexible heterocyclic ring systems an unexpected dynamic process between two diastereomers was observed in solution, studied by variable temperature H-1 NMR spectroscopy and the mechanism proved by theoretical DFT computations.
Cholesterol uptake and efflux are key metabolic processes associated with macrophage physiology and atherosclerosis. Peroxisome proliferator-activated receptor gamma (PPARgamma) and liver X receptor alpha (LXRalpha) have been linked to the regulation of these processes. It remains to be identified how activation of these receptors is connected and regulated by endogenous lipid molecules. We identified CYP27, a p450 enzyme, as a link between retinoid, PPARgamma, and LXR signaling. We show that the human CYP27 gene is under coupled regulation by retinoids and ligands of PPARs via a PPAR-retinoic acid receptor response element in its promoter. Induction of the enzyme's expression results in an increased level of 27-hydroxycholesterol and upregulation of LXR-mediated processes. Upregulated CYP27 activity also leads to LXR-independent elimination of CYP27 metabolites as an alternative means of cholesterol efflux. Moreover, human macrophage-rich atherosclerotic lesions have an increased level of retinoid-, PPARgamma-, and LXR- regulated gene expression and also enhanced CYP27 levels. Our findings suggest that nuclear receptor-regulated CYP27 expression is likely to be a key integrator of retinoic acid receptor-PPARgamma-LXR signaling, relying on natural ligands and contributing to lipid metabolism in macrophages
Through the reactions of 1- or 2-naphthol and 4,5-dihydro-3H-benz[c]azepine or 6,7-dihydrothieno[3,2-c]pyridine, new aminonaphthol derivatives were prepared. The syntheses were extended by using N-containing naphthol analogues such as 5-hydroxyisoquinoline and 6-hydroxyquinoline. The ring closures of the novel bifunctional compounds were also achieved, resulting in new naphth[2,1-e][1,3]oxazines, naphth[1,2-e][1,3]oxazines, isoquinolino[5,6-e][1,3]oxazines and quinolino[5,6-e][1,3]oxazines. H-1 NMR spectra of the target heterocycles 16, 20 and 21 were sufficiently resolved to indentify the present stereochemistry; therefore, beside computed structures, spatial experimental (dipolar coupling-NOE) and computed (ring current effect of the naphthyl moiety-TSNMRS) NMR studies were employed. The studied heterocycles exist exclusively as S(14b),R(N), R(14b),S(N), and S(16b)S(N) isomers, respectively. The flexible moieties of the studied compounds prefer. (C) 2016 Elsevier Ltd. All rights reserved.
Synthesis and conformational analysis of new naphth[1,2-e][1,3]oxazino[3,4-c]quinazoline derivatives
(2011)
Synthesis and conformational analysis of new naphth[1,2-e][1,3]oxazino[3,4-c]quinazoline derivatives
(2011)
A new highly functionalized aminonaphthol derivative, 1-(amino(2-aminophenyl)methyl)-2-naphthol (4), was synthesized by the reaction of 2-naphthol, 2-nitrobenzaldehyde and tert-butyl carbamate or benzyl carbamate, followed by reduction and/or removal of the protecting group. The aminonaphthol derivative thus obtained was converted in ring-closure reactions with formaldehyde. benzaldehyde and/or phosgene to the corresponding naphth[1,2-e][1,3]oxazino[3,4-c]quinazoline derivatives. The conformational analysis of some derivatives by NMR spectroscopy and accompanying molecular modelling are also reported.
Four new primary aminonaphthols (4, 5, 9 and 10) were synthesized from 1- or 2-naphthol and 1- or 2- naphthaldehyde via naphthoxazines in modified Mannich condensations. Simple ring-closure reactions of these aminonaphthols with paraformaldehyde, 4-nitrobenzaldehyde, phosgene or 4-chlorophenyl isothiocyanate led to new heterocyclic derivatives. In these transformations, either an sp2 or an sp3 carbon was inserted between the hydroxy and amino groups. The effects of substituents and the naphthyl ring on the conformation were investigated by means of NMR measurements, employing both dipolar and scalar couplings. The structures were confirmed by DFT quantum chemical calculations involving computed coupling constants, intramolecular distances between nuclei and the relative energies of the preferred conformers.
The synthesis of new phenanthr[9,10-e][1,3]oxazines was achieved by the direct coupling of 9-phenanthrol with cyclic imines in the modified aza-Friedel-Crafts reaction followed by the ring closure of the resulting bifunctional aminophenanthrols with formaldehyde. Aminophenanthrol-type Mannich bases were synthesised and transformed to phenanthr[9,10-e][1,3]oxazines via [4 + 2] cycloaddition. Detailed NMR structural analyses of the new polyheterocycles as well as conformational studies including Density Functional Theory (DFT) modelling were performed. The relative stability of ortho-quinone methides (o-QMs) was calculated, the geometries obtained were compared with the experimentally determined NMR structures, and thereby, the regioselectivity of the reactions has been assigned.
Through the cyclization of 1-(;-hydroxynaphthyl)-1,2,3,4-tetrahydroisoquinoline and 1-(;- hydroxynaphthyl)-1,2,3,4-tetrahydroisoquinoline with formaldehyde, phosgene, p-nitrobenzaldehyde or p-chlorophenyl isothiocyanate, 8-substituted 10,11-dihydro-8H,15bH-naphth[1,2-e][1,3]oxazino[4,3-a]isoquinolines (3 and 4) and 10,11- dihydro-8H,15bH-naphth[2,1-e][1,3]oxazino[4,3-a]isoquinolines (15 and 16) were prepared. Conformational analysis of both the piperidine and the 1,3-oxazine moieties of these heterocycles by NMR spectroscopy and an accompanying theoretical study revealed that these two conformationally flexible six-membered ring moieties prefer twisted chair conformers.
A new functional group, the hydroxy group, was inserted into a Betti base by reaction with salicylaldehyde, and the naphthoxazine derivatives thus obtained were converted by ring-closure reactions with formaldehyde, acetaldehyde, propionaldehyde or phosgene to the corresponding naphth[1',2':5,6][1,3]oxazino[3,2-c][1,3]benzoxazine derivatives. Further, the conformational analysis of these polycyclic compounds by NMR spectroscopy and an accompanying molecular modelling are reported; especially, both quantitative anisotropic ring current effects of the aromatic moieties in these compounds and steric substituent effects were employed to determine the stereochemistry of the naphthoxazinobenzoxazine derivatives.