Innate immunity and its control in the pathogenesis of inflammatory rheumatic diseases

The pathogenesis of inflammatory rheumatic diseases, including rheumatoid arthritis (RA) and spondyloarthropathies (SpAs) such as reactive arthritis (ReA), is incompletely understood. ReA is a sterile joint inflammation, which may follow a distal infection caused by Gram-negative bacteria that have lipopolysaccharide (LPS) in their outer membrane. The functions of innate immunity that may affect the pathogenesis, prognosis and treatment of these diseases were studied in this thesis. When compared with healthy controls, whole blood monocytes of healthy subjects with previous ReA showed enhanced capacity to produce TNF, an essential proinflammatory cytokine, in response to adherent conditions (mimicking vascular endothelium made adherent by inflammatory signals) and non-specific protein kinase C stimulation. Also, blood neutrophils of these subjects showed high levels of CD11b, an important adhesion molecule, in response to adherence or LPS. Thus, high responsiveness of monocytes and neutrophils when encountering inflammatory stimuli may play a role in the pathogenesis of ReA. The results also suggested that the known risk allele for SpAs, HLA-B27, may be an additive contributor to the observed differences. The promoter polymorphisms TNF 308A and CD14 (gene for an LPS receptor component) 159T were found not to increase the risk of acute arthritis. However, all female patients who developed chronic SpA had 159T and none of them had 308A, possibly reflecting an interplay between hormonal and inflammatory signals in the development of chronic SpA. Among subjects with early RA, those having the polymorphic TLR4 +896G allele (causing the Asp299Gly change in TLR4, another component of LPS receptor) required a combination of disease-modifying antirheumatic drugs to achieve remission. It is known that rapid treatment response is essential in order to maintain the patients work ability. Hence, +896G might be a candidate marker for identifying the patients who need combination treatment. The production of vascular endothelial growth factor (VEGF), which strongly promotes vascular permeability and angiogenesis that takes place e.g. early in rheumatic joints, was induced by LPS and inhibited by interferon (IFN)-alpha in peripheral blood mononuclear cells. These long-living cells might provide a source of VEGF when stimulated by LPS and migrating to inflamed joints, and the effect of IFN-alpha may contribute to the clinical efficacy of this cytokine in inhibiting joint inflammation.

Facile synthesis, ex-vivo and in vitro screening of 3-sulfonamide derivative of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide (SR141716) a potent CB1 receptor antagonist

Facile synthesis of biaryl pyrazole sulfonamide derivative of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide (SR141716, 1) and an investigation of the effect of replacement of the –CO group in the compound 1 by the –SO2 group in the aminopiperidine region is reported. Primary ex-vivo pharmacological testing and in vitro screening of sulfonamide derivative 2 showed the loss of CB1 receptor antagonism.

Thymidine inhibits the incorporation of 5-fluoro-2'-deoxyuridine to DNA of mouse mammary tumour

5-Fluoro-2'-deoxyuricine is incorporated into DNA of mouse breast tumour Image . The incorporation is inhibited by thymidine. Part of the fluorodeoxyuridine is cleaved to fluorouracil and is incorporated into RNA. This incorporation is enhanced by thymidine. The result suggests that the major mechanism of action of the fluorouracil is due to its incorporation into RNA. FUra, 5-Fluorouracil; FdUR, 5-Fluoro-2'-deoxyuridine; FdUMP, 5-Fluoro-2'-deoxyuridine-5'-monophosphate.

A novel amino acid racemization in vitamin b6-amino acid schiff base copper complexes: crystal structures of aquo (5'-phosphopyridoxylidene-dl-tyrosinato) copper(II) 3.5H2O and aquo (5'-phosphopyridoxylidene-dl-phenylalaninato) copper(II) 2.5H2O

A novel racemization observed in the Vitamin B6-amino acid Schiff base complexes, aquo (5'-phosphopyridoxylidene-l-tyrosinato) copper(II) and aquo (5'-phosphopyridoxylidene-l-phenylalaninato) copper(II) is described. The racemization taking place in solution under mild acidic conditions (pH 5-6) was confirmed by CD studies and the products were characterized by single crystal X-ray diffraction. The structures of both complexes show almost parallel orientation of the aromatic side chain and the pyridoxal II-system. The activation of the αCsingle bondH group due to the intermolecular II- interaction is probably the reason for the unusual racemization observed.

Inhibition of replication of rinderpest virus by 5-fluorouracil

5-Fluorouracil (5FU), an analogue of uracil, was found to inhibit the production of infectious particles of rinderpest virus (RPV) in Vero cells (African green monkey kidney cells) by 99%, at a concentration of 1 μg/ml. The levels of individual mRNA specific for five of the virus genes were also reduced drastically, while the level of mRNA for a cellular housekeeping gene—glyceraldehyde-3-phosphate dehydrogenase (GAPDH)—was unaltered by fluorouracil treatment of infected cells. Both virus RNA and protein synthesis showed inhibition in a dose-dependent manner. The virions which budded out of 5-fluorouracil-treated cells also contained reduced amounts of virus proteins compared with virus particles from untreated cells.

Ethyl 4-(4-hydroxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carbox ylate monohydrate

In the title compound, C14H16N2O4 center dot H2O, the dihedral angles between the planes of the 4-hydroxyphenyl and ester groups with the plane of the six-membered tetrahydropyrimidine ring are 87.3 (1) and 75.9 (1)degrees, respectively. The crystal structure is stabilized by O-H center dot center dot center dot O and N-H center dot center dot center dot O hydrogen bonding between the water molecule and the organic functionalities.

Ethyl 4-(4-chlorophenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

In the title compound, C14H15ClN2O2S, the tetrahydropyrimidine ring adopts a twisted boat conformation with the carbonyl group in an s-trans conformation with respect to the C C double bond of the six-membered tetrahydropyrimidine ring. The molecular conformation is determined by an intramolecular C-H center dot center dot center dot pi interaction. The crystal structure is further stabilized by intermolecular N-H center dot center dot center dot O molecular chains and centrosymmetric N-H center dot center dot center dot S dimers.

Oxidation of bis-(2-hydroxy-1-naphthyl)methane with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. X-Ray crystal structure of a novel product

A novel compound obtained by the oxidation of the title compound with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone has been assigned structure (5) on the basis of spectral data and X-ray crystal structure analysis.

Structure of disodium deoxyuridine 5'-phosphate pentahydrate

Disodium deoxyuridine 5'-nhosDhate pentahvdrate, Na2(C9H l INEOsP). 5 H20, Call 11N208 P2-. 2Na +. 5 H20, crystallizes in the monoclinic space group P2: with a = 7.250 (4), b = 35.45 (2), c = 7.132 (4)/~, fl = 102.2 (4) °, Z = 4. The Cu Ka intensity data were collected photographically and estimated visually. The structure was obtained by the minimum-function method and difference syntheses and refined to an R of 0.089. In both molecules the uracil base has an anti conformation (2cN = 57.1 and 59.9 °) with respect to the sugar. The deoxyribose moiety of molecule B shows a typical C(l')-exo puckering, with C(I') displaced by 0.52 /k from the best plane. The furanose ring conformation of molecule A can be described as C(2')-endo,C(l')-exo. Both the molecules have an unusual trans-gauche conformation about the exocyclic C(4')-C(5') bond with (~0oo = 171.1, 172.2°; ~0oc = -64.7, -65.9°).

Trifurcated (four-center) hydrogen bond in solid state crystal structure of 5'-amino-5'-deoxyadenosine p-toluenesulfonate

The crystal structure of 5'-amino-5'-deoxyadenosine (5'-Am.dA) p-toluenesulfonate has been determined by X-ray crystallographic methods. It belongs to the orthorhombic space group P2(1)2(1)2(1) with a = 7.754(3)Angstrom, b = 8.065(1)Angstrom and c = 32.481(2)Angstrom. This nucleoside side shows a syn conformation about the glycosyl bond and C2'-endo-C3'-exo puckering for the ribose sugar. The orientation of N5' atom is gauche-trans about the exocyclic C4'-C5' bond. The amino nitrogen N5' forms a trifurcated hydrogen bond with N3, O9T and O4' atoms. Adenine bases form A.A.A triplets through hydrogen bonding between N6, N7 and N1 atoms of symmetry related nucleoside molecules.

Ethyl 4-(3-hydroxyphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate

In the molecular structure of the title compound, C21H25NO4, the dihydropyridine ring adopts a flattened boat conformation while the cyclohexenone ring is in an envelope conformation. In the crystal structure, molecules are linked into a two-dimensional network parallel to (10 (1) over bar) by N-H center dot center dot center dot O and O-H center dot center dot center dot O hydrogen bonds. The network is generated by R-4(4)(30) and R-4(4)(34) graph-set motifs.

1,1`-[4-(2-Methoxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-diyl]diethanone

In the title compound, C18H21NO3, the 1,4-dihydropyridine ring exhibits a flattened boat conformation. The methoxyphenyl ring is nearly planar [r.m.s. deviation = 0.0723 (1) angstrom] and is perpendicular to the base of the boat [dihedral angle = 88.98 (4)degrees]. Intermolecular N-H center dot center dot center dot O and C-H center dot center dot center dot O hydrogen bonds exist in the crystal structure.