Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine released from T-cells and macrophages. Although a detailed understanding of the biological functions of MIF has not yet been clarified, it is known that MIF catalyzes the tautomerization of a nonphysiological molecule, D-dopachrome. Using a structure-based computer-assisted search of two databases of commercially available compounds, we have found 14 novel tautomerase inhibitors of MIF whose K(i) values are in the range of 0.038-7.4 microM. We also have determined the crystal structure of MIF complexed with the hit compound 1. It showed that the hit compound is located in the active site of MIF containing the N-terminal proline which plays an important role in the tautomerase reaction and forms several hydrogen bonds and undergoes hydrophobic interactions. A crystallographic study also revealed that there is a hydrophobic surface which consists of Pro-33, Tyr-36, Trp-108, and Phe-113 at the rim of the active site of MIF, and molecular modeling studies indicated that several more potent hit compounds have the aromatic rings which can interact with this hydrophobic surface. To our knowledge, our compounds are the most potent tautomerase inhibitors of MIF. One of these small, drug-like molecules has been cocrystallized with MIF and binds to the active site for tautomerase activity. Molecular modeling also suggests that the other hit compounds can bind in a similar fashion.
An original reaction system (the phase separative reaction system) has been designed for derivatizing native lignins to highly phenolic, functional polymers. This system is composed of a phenol derivative and concentrated acid, which are not miscible at room temperature. The key point of the lignin functionalization process, including the phase separative system, is that lignin and carbohydrates, which are totally different in structures and reactivities, are modified individually in the different phases: lignin is present in the organic phase and carbohydrates in the aqueous phase. Through the process, lignin was modified selectively at Calpha-positions of side chains, the most reactive sites, to give highly phenolic, light-colored, diphenylmethane-type materials which still retained original interunit linkages formed by the dehydrogenative polymerization during the biosynthesis. The carbohydrates were swollen, followed by partial hydrolysis and dissolution in the acid solution, resulting in the perfect decomposition of interpenetrating polymer network structures in the cell wall. Therefore, the functionalization of lignin and the separation of resulting lignin from carbohydrates were quickly achieved at room temperature, independent of wood species. This process would be a powerful tool for estimating structures and reactivities of lignins as well as the functionalization of lignins, because of the selective structural modifications.
The SUVmax of (18)F-FDG-PET reflects WHO classification of thymic epithelial tumors. High SUVmax predicts lower recurrence-free survival of the tumors.
Inhibitors of factor Xa (FXa), a crucial serine protease in the coagulation cascade, have attracted a great deal of attention as a target for developing antithrombotic agents. We previously reported findings from our optimization study of a high-throughput screening (HTS) derived lead compound 1a that resulted in the discovery of potent amidine-containing FXa inhibitors represented by compound 2. We also conducted an alternative optimization study of 1a without incorporating a strong basic amidine group, which generally has an adverse effect on the pharmacokinetic profile after oral administration. Replacement of 4-methoxybenzene with a 1,4-benzodiazepine structure and introduction of a hydroxy group at the central benzene led to the discovery of the potent and orally effective factor Xa inhibitor 14i (darexaban, YM150). Subsequent extensive study revealed a unique aspect to the pharmacokinetic profile of this compound, wherein the hydroxy moiety of 14i is rapidly transformed into its glucuronide conjugate 16 (YM-222714) as an active metabolite after oral administration and it plays a major role in expression of potent anticoagulant activity in plasma. The distinctive, potent activity of inhibitor 14i after oral dosing was explained by this unique pharmacokinetic profile and its favorable membrane permeability. Compound 14i is currently undergoing clinical development for prevention and treatment of thromboembolic diseases.
Objective-Src homology 2-containing phosphotyrosine phosphatase 2 (SHP2) is ubiquitously expressed and believed to function as part of a positive signaling pathway mediating growth factor-induced protein tyrosine phosphorylation. Proliferation of aortic vascular smooth muscle cells (SMCs) is an important contributor to atherosclerosis. We examined the effect of SHP2 expression on SMC proliferative activity. Methods and Results-SHP2 was abundant in cultured aortic SMCs, and SHP2 staining was markedly increased in the thickened aortic intima in rats with balloon-induced injury. We obtained several SMC clones by using geneticin screening. Endogenous SHP2 expression varied among individual clones. Significant positive relationships were observed between SHP2 expression and bromodeoxyuridine uptake in SMCs stimulated by FBS, platelet-derived growth factor, or insulin-like growth factor-1. In SMCs transiently transfected with SHP2, FBS stimulation significantly increased bromodeoxyuridine uptake beyond the uptake by control SMCs. Key Words: src homology 2-containing phosphotyrosine phosphatase 2 Ⅲ smooth muscle cells Ⅲ atherosclerosis A therosclerosis, the primary cause of cardiovascular disease and the cause underlying Ϸ50% of all deaths, is a process of accumulation of lipids and fibrous elements in the wall of large arteries. In the intima, monocytes differentiate into macrophages that become foam cells on subsequent exposure to modified lipoprotein. Smooth muscle cells (SMCs) migrate within the arterial wall from the media to the intima, where their proliferation contributes to intimal thickening of arteries and takes part in atherosclerosis. 1 Src homology 2-containing phosphotyrosine phosphatase 2 (SHP2, which is also abbreviated SYP, PTP1D, PTP2C, SH-PTP3, SAP-2, and SH-PTP2) is a cytoplasmic protein tyrosine phosphatase (PTPase) that contains 2 src homology (SH) 2 domains and is expressed widely throughout mammalian tissues. 2-4 SHP2 interacts with phosphorylated plateletderived growth factor (PDGF), epidermal growth factor, and erythropoietin receptors, undergoing rapid tyrosine phosphorylation on ligand stimulation. SHP2 binds to the SH2 domain of Grab2 and the p38 subunit of phosphatidylinositol-3 kinase. [5][6][7][8][9][10] The N-and C-terminal SH2 domains bind to tyrosine-phosphorylated insulin receptor substrate (IRS)-1, 11 suggesting that SHP2 is involved in positive signaling pathways serving multiple hormone receptors.
Conclusions-IncreasedWe have focused on SHP2 as a positive regulator of cell proliferation. In the present study, we examined the involvement of SHP2, which is believed to be among the most important regulators of cell proliferation, in the growth of cultured rat aortic SMCs.
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