Methyl 5′-(2-hy­droxy­phen­yl)-4′,5′,6′,7′-tetra­hydro­spiro­[2H-1-benzopyran-2,7′-1,2,4-triazolo[1,5-a]pyrimidine]-3-carboxyl­ate

There are two crystallographically independent mol­ecules in the asymmetric unit of the title compound, C21H18N4O4. The substituted benzopyran portion of one of the independent mol­ecules exhibits disorder [occupancy 0.5248 (18):0.4752 (18)], which was modelled by using two sets of atomic positions and restraints on the chemically equivalent bond lengths and angles. The central, partially saturated pyrimidine rings of both independent mol­ecules were found to assume unsymmetrical half-chair conformations. The hy­droxy­phenyl substituent occupies an equatorial position in both mol­ecules, and is rotated by 55.6 (1)° from the mean plane of the pyrimidine ring in one independent mol­ecule, and by 53.4 (1)° in the other. In the crystal, there are two types of inter­molecular hydrogen bond present: reciprocal N—H⋯N inter­actions join the two crystallographically independent mol­ecules into a dimer and O—H⋯N inter­actions link the dimers into sheets in the ab plane

(5R*,11R*)-5-Methyl-1,2-dihydro-5,11-methano-5H,11H-1,3-thia­zolo[2,3-d][1,3,5]benzoxadiazo­cine

The title compound, C13H14N2OS, crystallizes as a racemate in a non-chiral space group. It represents a conformationally restricted analogue of so-called Biginelli compounds known to exhibit multiple pharmacological activities and was selected for a single-crystal X-ray analysis in order to probe the chemical and spatial requirements of some kinds of activity. It was found that the state of hybridization of the formally aminic nitro­gen of the heterocycle is between sp 2 and sp 3 with the lone-pair electrons partially delocalized through conjugation with the sulfur atom rather than the double bond of the pyrimidine nucleus. As a result, the thia­zolo ring adopts a flat-envelope conformation and the puckering of the central pyrimidine ring is close to a half-chair. The critical phenyl ring is fixed in a pseudo-axial and perpendicular [dihedral angle 84.6 (1)°] orientation with respect to the pyrimidine ring via an oxygen bridge

rac-2-Methyl-3,4,5,6-tetra­hydro-2H-2,6-methano-1,3-benzoxazocin-4-one

The title compound, C12H13NO2, represents a conformationally restricted 2-pyridone analogue of 1,4-dihydro­pyridine-type calcium antagonists and was selected for a crystal structure determination in order to explore some aspects of drug-receptor inter­action. In the mol­ecule, two stereogenic centres are of opposite chirality, whereas a racemate occurs in the crystal. It was found that the formally aminic N atom of the heterocycle is essentially sp 2-hybridized with the lone-pair electrons partially delocalized through conjugation with the adjacent carbonyl bond. As a result, the central pyridone ring assumes an unsymmetrical half-chair conformation. The critical 4-phenyl ring is fixed in a pseudo-axial and perpendicular orientation [dihedral angle 85.8 (1)°] with respect to the pyridone ring via an oxygen bridge. In the crystal a pair of centrosymmetric N—H⋯O hydrogen bonds connect mol­ecules of opposite chirality into a dimer. The dimers are packed by hydrophobic van der Waals inter­actions

4-[(5R*,10bR*)-2-Methyl-1,10b-dihydro­pyrazolo[1,5-c][1,3]benzoxazin-5-yl]benzoic acid

In the title compound, C18H16N2O3, a potential inhibitor of the cyclo­oxygenase-2 isoenzyme, the pyrazoline ring exists in a flattened envelope conformation with one C atom deviating by 0.463 Å from the mean plane of the remaining four atoms. The puckering of the central oxazine ring is more severe, with one N atom and one C atom displaced by 0.235 (6) and 0.370 (2) Å, respectively, on opposite sides of the mean plane defined by the other four atoms; the conformation is that of a half-chair. As a result, the mol­ecule as a whole is not planar. The carboxyl group is involved in an inter­molecular O—H⋯N hydrogen bond, which links the mol­ecules into centrosymmetric dimers

Free radical scavenging activity and lipoxygenase inhibition of Mahonia aquifolium extract and isoquinoline alkaloids

Roots and stem-bark of Mahonia aquifolium (Oregon grape) (Berberidaceae) are effectively used in the treatment of skin inflammatory conditions

1-Methyl-6-nitro-1H-benzimidazole

The title compound, C8H7N3O2, a potential anti­tumour drug and an anti­oxidant agent, was studied in order to give more insight into structure–function relationships. The 1-methyl­benzimidazole unit of the mol­ecule was found to be exactly planar and the nitro group is inclined at an angle of 10.4 (2)° to the plane of the heterocycle. The bond lengths in the present derivative were analyzed in details and compared with those of the parent unsubstituted analogues in the Cambridge Structural Database. The results have shown that the additional nitro group is not involved in conjugation with the adjacent π-system and hence has no effect on the charge distribution of the heterocyclic ring

Ethyl 6-ethoxy­carbonyl­methyl-4-(2-hydroxy­phen­yl)-2-oxo-1,2,3,4-tetra­hydro­pyrimidine-5-carboxyl­ate

The title compound, C17H20N2O6, belongs to the monastrol-type of anti­cancer agents and was selected for crystal structure determination in order to confirm its mol­ecular structure and explore some aspects of its structure–activity relationships. The central tetra­hydro­pyrimidine ring has a flat-envelope conformation. The 4-hydroxy­phenyl group occupies a pseudo-axial position and is inclined at an angle of 87.7 (2)° to the mean plane of the heterocyclic ring. Of the two ethyl ester groups, one (in the 5-position) is in a coplanar and the other (in the 6-position) is in a perpendicular orientation with respect to the heterocyclic plane. There is a three-dimensional hydrogen-bonding network in which all hydrogen-bond donors and acceptors are involved

2-Methyl-1,10b-dihydro-5H-pyrazolo[1,5-c][1,3]benzoxazin-5-one

In the title compound, C11H10N2O2, a potential inhibitor of the cyclo­oxygenase-2 isoenzyme, the pyrazoline ring exists in a flat-envelope conformation while the puckering of the central oxazine ring is more severe. As a result, the mol­ecule as a whole is non-planar. The formal sp 3 pyrazoline N atom is sp 2 hybridized, with the lone-pair electrons delocalized through conjugation with the carbonyl group rather than the double bond of the pyrazoline ring

5-Amino-1-methyl-1H-benzimidazole

The structure of the title compound, C8H9N3, a potential anti­tumour drug, was determined in order to give more insight into its structure–function relationships. The benzimidazole core of the mol­ecule was found to be exactly planar, while the substituents are displaced slightly from the mol­ecular plane [C—C—N—C and C—C—C—N torsion angles of 0.8 (3) and 179.0 (1)° for the methyl and amino groups, respectively]. The bond lengths are analysed in detail and compared with those of the parent unsubstituted analogues. The results show that the lone-pair electrons on the amino N atom are involved in conjugation with the adjacent π system and hence affect the charge distribution in the heterocycle. Two inter­molecular N—H⋯N and C—H⋯N hydrogen bonds have been identified

Phosphorylation of histone deacetylase 7 by protein kinase D mediates T cell receptor–induced Nur77 expression and apoptosis

The molecular basis of thymocyte negative selection, a crucial mechanism in establishing central tolerance, is not yet resolved. Histone deacetylases (HDACs) have emerged as key transcriptional regulators in several major developmental programs. Recently, we showed that the class IIa member, HDAC7, regulates negative selection by repressing expression of Nur77, an orphan nuclear receptor involved in antigen-induced apoptosis of thymocytes. Engagement of the T cell receptor (TCR) alleviates this repression through phosphorylation-dependent nuclear exclusion of HDAC7. However, the identity of the TCR-activated kinase that phosphorylates and inactivates HDAC7 was still unknown. Here, we demonstrate that TCR-induced nuclear export of HDAC7 and Nur77 expression is mediated by activation of protein kinase D (PKD). Indeed, active PKD stimulates HDAC7 nuclear export and Nur77 expression. In contrast, inhibition of PKD prevents TCR-mediated nuclear exclusion of HDAC7 and associated Nur77 activation. Furthermore, we show that HDAC7 is an interaction partner and a substrate for PKD. We identify four serine residues in the NH2 terminus of HDAC7 as targets for PKD. More importantly, a mutant of HDAC7 specifically deficient in phosphorylation by PKD, inhibits TCR-mediated apoptosis of T cell hybridomas. These findings indicate that PKD is likely to play a key role in the signaling pathways controlling negative selection