Synthesis and biological evaluation of the mimics of cis ligand for CD22

Yuki Sugamuna,Naoko Matsubara,Yuki Iwayama,Akiharu Ueki,Akihiro Imamura,Hiromune Ando,Takeshi Tsubata,Hideharu Ishida,Makoto Kiso 한국당과학회 2012 한국당과학회 학술대회 Vol.2012 No.1

CD22 (siglec-2) is an accessory molecule of the B-cell receptor complex (BCR) that exertsnegative effects on receptor signaling. It is also well-documented that CD22 is a regulatoryprotein that sets a threshold for immune responses. The carbohydrate ligand recognized byCD22 is the sequence Neuα(2,6)Galβ(1,4)GlcNAc found on both neighboringglycoconjugate of the same cell (cis ligand) and on other cells that interact with B cells (transligands). Recently, we have reported that the C-9 amido derivative of sialic acid (GSC718;9-(4’-hydroxy-4-biphenyl)acetamido-9-deoxy-Neu5Gc-OBn) show a potent affinity andselectivity for CD22 than other siglecs such as MAG [1]. Moreover, the compoundpromoted the proliferation of B cells in vitro. As next step of our investigation, we intend toreinforce the promoting activity of GSC718 for B cell growth by chemical modification.Herein, we report the efficient synthesis of GSC718 analogs which have varied aglyconmoieties. To achieve the comprehensive synthesis of GSC718 analogs having varied aglycons, wereexamined every synthetic process to obtain a fine target compound. In case of thesialoside synthesis, the most time-consuming and troublesome process is thechromatographic separation of α-sialoside from other byproducts such as β−isomer, 2,3-enederivative etc. after glycosylation reaction with aglycon part. To improve this process, weemployed 1,5-lactam formation as the key step for separation because the lactam formation isknown to proceed only in α-sialoside [2]. At the beginning of the synthesis of targetmolecules, we synthesized a suitably modified sialic acid donor in good yields. Then, thesialyl donor was reacted with various 2-substituted-ethanols to give the mixtures of α- and β-glycosides and 2,3-ene derivative, which were subsequently advanced to 1,5-lactamformation. As we anticipated, 1,5-lactamized α-sialosides became isolable from themixtures due to its different polarity from the other byproducts. Finally, the obtained 1,5-lactamized silaosides were successfully converted into target structures via reaction sequenceincluding C9-midification with biphenyl amide group, lactam opening and globaldeprotection. The synthesized analogs were advanced to biological assay using B cells. In this poster presentation, we will also discuss the structure-activity relationships of thesynthesized analogs. [1] H. H. M. Abdu-Allah et al, Bioorg. Med. Chem. Lett. 2011, 19, 1966-1971. [2] H. Tanaka et al, Tetrahedron Lett. 2009, 50, 4478-4481.

ORiginal Article : A Novel, Fully Covered Laser-Cut Nitinol Stent with Antimigration Properties for Nonresectable Distal Malignant Biliary Obstruction: A Multicenter Feasibility Study

( Hiroyuki Isayama ),( Kazumichi Kawakubo ),( Yousuke Nakai ),( Kouta Inoue ),( Chimyon Gon ),( Saburo Matsubara ),( Hirofumi Kogure ),( Yukiko Ito ),( Takeshi Tsujino ),( Suguru Mizuno ),( Tsuyoshi H The Editorial Office of Gut and Liver 2013 Gut and Liver Vol.7 No.6

Background/Aims: Stent migration occurs frequently, but the prevention of complications resulting from covered self-expandable metal stents (C-SEMSs) remains unresolved. We prospectively assessed a newly developed C-SEMS, a modi-fied covered Zeo stent (m-CZS), in terms of its antimigration effect. Methods: Between February 2010 and January 2011, an m-CZS was inserted into 42 patients (31 initial drainage cases and 11 reintervention cases) at a tertiary referral center and three affiliated hospitals. The laser-cut stent was flared for 1.5 cm at both ends, with a 1 cm raised bank located 1 cm in from each flared end. The main outcome of this study was the rate of stent migration, and second-ary outcomes were the rate of recurrent biliary obstruction (RBO), the time to RBO, the frequencies of complications, and overall survival. Results: Of the 31 patients with initial drainage, stent migration occurred in four (12.9%, 95% con-fidence interval, 5.1% to 29.0%), with a mean time of 131 days. RBO occurred in 18 (58%), with a median time to RBO of 107 days. Following previous C-SEMS migration, seven of 10 patients (70%) did not experience m-CZS migration until death. Conclusions: m-CZSs with antimigration properties ef-fectively, although not completely, prevented stent migration after stent insertion. (Gut Liver 2013;7:725-730)

Transcription Factor 7-Like 2 (TCF7L2) Regulates Activin Receptor-Like Kinase 1 (ALK1)/Smad1 Pathway for Development of Diabetic Nephropathy

Araoka, Toshikazu,Abe, Hideharu,Tominaga, Tatsuya,Mima, Akira,Matsubara, Takeshi,Murakami, Taichi,Kishi, Seiji,Nagai, Kojiro,Doi, Toshio Korean Society for Molecular and Cellular Biology 2010 Molecules and cells Vol.30 No.3

Smad1 has previously been shown to play a key role in the development of diabetic nephropathy (DN), by increasing synthesis of extracellular matrix. However, the regulatory mechanism of Smad1 in DN is still unclear. This study aims to elucidate molecular interactions between activin receptor-like kinase 1 (ALK1)/Smad1 signaling pathway and transcription factor 7-like 2 (TCF7L2) in the progression of DN in vitro and in vivo. The expressions of TCF7L2 and ALK1 were induced by advanced glycation end products (AGEs) in parallel with Smad1, phosphorylated Smad1 (pSmad1), and alpha-smooth muscle actin (${\alpha}$-SMA) through TGF-${\beta}$1 in cultured mesangial cells. Constitutively active ALK1 increased pSmad1 and ${\alpha}$-SMA expressions. The binding of TCF7L2 to ALK1 promoter was confirmed by chromatin immunoprecipitation assay. Furthermore, TCF7L2 induced promoter activity of ALK1. AGEs and TGF-${\beta}$1 induced a marked increase in TCF7L2 expression in parallel with ALK1. Overexpression of TCF7L2 increased the expressions of ALK1 and Smad1. Inversely, TCF7L2 knockdown by siRNA suppressed ${\alpha}$-SMA expression as well as ALK1 and Smad1. The iNOS transgenic mice (iNOS-Tgm), which developed diabetic glomerulosclerosis resembling human diabetic nephropathy, exhibited markedly increased expressions of ALK1, TCF7L2, Smad1, pSmad1, and ${\alpha}$-SMA in glomeruli in association with mesangial matrix expansion. These results provide a new evidence that the TCF7L2/ALK1/Smad1 pathway plays a key role in the development of DN.

Transcription Factor 7-Like 2 (TCF7L2) Regulates Activin Receptor-Like Kinase 1 (ALK1)/Smad1 Pathway for Development of Diabetic Nephropathy

Toshikazu Araoka,Hideharu Abe,Tatsuya Tominaga,Akira Mima,Takeshi Matsubara,Taichi Murakami,Seiji Kishi,Kojiro Nagai,Toshio Doi 한국분자세포생물학회 2010 Molecules and cells Vol.30 No.3

Smad1 has previously been shown to play a key role in the development of diabetic nephropathy (DN), by increasing synthesis of extracellular matrix. However, the regulatory mechanism of Smad1 in DN is still unclear. This study aims to elucidate molecular interactions between activin receptor-like kinase 1 (ALK1)/Smad1 signaling pathway and transcription factor 7-like 2 (TCF7L2) in the progression of DN in vitro and in vivo. The expressions of TCF7L2and ALK1 were induced by advanced glycation end products (AGEs) in parallel with Smad1, phosphorylated Smad1 (pSmad1), and alpha-smooth muscle actin (α-SMA)through TGF-β1 in cultured mesangial cells. Constitutively active ALK1 increased pSmad1 and α-SMA expressions. The binding of TCF7L2 to ALK1 promoter was confirmed by chromatin immunoprecipitation assay. Furthermore,TCF7L2 induced promoter activity of ALK1. AGEs and TGF-β1 induced a marked increase in TCF7L2 expression in parallel with ALK1. Overexpression of TCF7L2 increased the expressions of ALK1 and Smad1. Inversely, TCF7L2knockdown by siRNA suppressed α-SMA expression as well as ALK1 and Smad1. The iNOS transgenic mice (iNOS-Tgm), which developed diabetic glomerulosclerosis resembling human diabetic nephropathy, exhibited markedly increased expressions of ALK1, TCF7L2, Smad1,pSmad1, and α-SMA in glomeruli in association with mesangial matrix expansion. These results provide a new evidence that the TCF7L2/ALK1/Smad1 pathway plays a key role in the development of DN.