The c-Jun N-terminal kinase (JNK) family includes three proteins (JNK1-3) that regulate many physiological processes, including inflammatory responses, morphogenesis, cell proliferation, differentiation, survival, and cell death. Therefore, JNK represents an attractive target for therapeutic intervention. Herein, a panel of novel tryptanthrin oxime analogs were synthesized and evaluated for JNK1-3 binding (Kd) and inhibition of cellular inflammatory responses (IC50). Several compounds exhibited submicromolar JNK binding affinity, with the most potent inhibitor being 6-(acetoxyimino)indolo[2,1-b]quinazolin-12(6H)-one (1j), which demonstrated high JNK1-3 binding affinity (Kd = 340, 490, and 180 nM for JNK1, JNK2, and JNK3, respectively) and inhibited lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/AP-1) transcription activity in THP-1Blue cells and interleukin-6 (IL-6) production in MonoMac-6 monocytic cells (IC50 = 0.8 and 1.7 μM, respectively). Compound 1j also inhibited LPS-induced production of several other proinflammatory cytokines, including IL-1α, IL-1β, granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor (TNF) in MonoMac-6 cells. Likewise, 1j inhibited LPS-induced c-Jun phosphorylation in MonoMac-6 cells, directly confirming JNK inhibition. Molecular modeling suggested modes of binding interaction of selected compounds in the JNK3 catalytic site that were in agreement with the experimental JNK3 binding data. Our results demonstrate the potential for developing anti-inflammatory drugs based on these nitrogen-containing heterocyclic systems.

The formyl peptide receptors (FPRs) are a family of G protein-coupled receptors that play an important role in host defense and inflammation (Migeotte et al., 2006;Ye et al., 2009). Three different isoforms are known in humans: FPR1, FPR2, and FPR3. FPR1, the first receptor of the family to be identified, was discovered for its ability to transduce the chemotactic effect of a formylated bacterial product, formyl-methionine-leucyl-phenylalanine (fMLF; Boulay et al., 1990). FPR1 is mainly expressed in cells of

N-formyl peptide receptors (FPRs) are G protein-coupled receptors (GPCRs) that play critical roles in inflammatory reactions, and FPR-specific interactions can possibly be used to facilitate the resolution of pathological inflammatory reactions. We here report the synthesis and biological evaluation of six pairs of chiral ureidopropanamido derivatives as potent and selective formyl peptide receptor-2 (FPR2) agonists, that were designed starting from our lead agonist (S )-3-(1H-indol-3-yl)-2-[3-(4-methoxyphenyl)ureido]-N -[[1-(5-methoxy-2-pyridinyl)cyclohexyl]methyl]propanamide ((S)-9a). The new compounds were obtained in overall yields considerably higher than (S)-9a. Various of the new compounds showed agonist properties comparable to that of (S)-9a along with higher selectivity over FPR1. Molecular modeling was used to define chiral recognition by FPR2. In vitro metabolic stability of selected compounds was also assessed to obtain preliminary insight on drug-like properties of this class of compounds.

after the operation, inflammatory phenomena in TV were noticed as well as fiber desorganization of FR frames, sharply expressed in some cases and focuses of connective tissue total destruction . Myocardium of a right ventricle near TK had signs of inflammaory destruction, which is a rheumatic disease characteristic. In a number of cases in an AV nodule the copious infiltration by lymphocytes and plasma cells, destruction of conductive myocytes were marked. OutcomesOn the basis of TV structural elements morphology it is shown that a widely applicable nowadays term < relative (functional) insufficiency of TV is not absolutely valid because organic changes of TV elements always take place at rheumatic lesion of the left parts of the heart The TCPA application allows to eliminate TI more effectively than the widely used today De Vega method. ConclusionAll existing sutural methods of TI correction are based on the A.Deloche concept, who in 1975 made supposition that the FA TV extension in the patients with npH6peTeiwu heart disease acurs unevenly the basis of a back cusp enlarges on 80 %, of the forward oneon 40 %, of the septalon 10% only. That is why the existing sutural methods of TI correction do not affect on the basis of a septal cusp. Besides, at analysing of the obtained paraffinic right auricle casts and of the area the right AV orifice there was noticed that after annuloplasty by De Vega method displacement of coaptation area of cusp and TV FR deformation take place. Nevetheless such process is not noticed after TCPA. In oar opinion this is a reason of rather often TI development or recurnng m ume iae postoperave periou. in uts connection a new sutural method of TI correction -TCPA was developed. This method consists in placing of an one-row suture on the marked by us conventional line passing on FA TI, on the upper (muscle) edge of the membranous part of an interauricle septum, passing by w a dangerous zone in the area of a forward-septal commissure and in front of the coronary sine again descending to the TV FR Besides, nowadays, on the basis of a sutural method of TI correction, offered by us, it is planned to develop a new supporting ring for expressed TI correction. This supporting ring, under condition of its industrial production, can comprise a worthy competitiveness to existing models (Carpentier ring).Thus, basing on ana cal and morphological TV FR study we marked the stitching line for new sutural and supportingring methods of TI correction.(n=5),P2>3 TV FR diameter, cm (%) 3,0±0,08 (87,2 %) 3,44±0,2 (100 %) 3,11 ±0,07 (90,4 %) p> 0,05 TV FR circumference, cm 9,5±0,23 (76,1 %) (%) 2,48± 0,5 (100 %) 10,42±0,23 (83,5 %) p < 0,05 Length of the forward cusp 3,6±0,19(64,3%) basis, cm (%) 5,6±0,19(100 %) 4,6±0,19 (82,14 %) p < 0,05 Length of the TV back cusp 1,9 ±-0,09 (76 %) basis, cm (%) 2,5 ±0,19 (100 %) 1,7±0,09 (68 %) p> 0,05 Length of the TV septal cusp 3,8 ±0,09 (88,4 %) basis, cm (%) 4,3i±0,19(100 %) 4,2±i0,09(100 %) Fulvic acids (FA) from mumie (shilajit) were fractionated by size e s chroma ...

No abstract