Risk Prediction Method for Anticholinergic Action Using Auto-quantitative Structure-Activity Relationship and Docking Study with Molecular Operating Environment.

Lower urinary tract symptoms (LUTS) induced by anticholinergic drug action impair the QOL of patients and are associated with a poor prognosis. Therefore, it is expedient to develop methods of predicting the anticholinergic side effects of drugs, which we aimed to achieve in this study using a quantitative structure-activity relationship (QSAR) and docking study with molecular operations environment (MOE; Molecular Simulation Informatics Systems [MOLSIS], Inc.) In the QSAR simulation, the QSAR model built using the partial least squares regression (PLS) and genetic algorithm-multiple linear regression (GA-MLR) methods showed remarkable coefficient of determination (R2) and XR2 values. In the docking study, a specific relationship was identified between the adjusted docking score (-S) and bioactivity (pKi) values. In conclusion, the methods developed could be useful for in silico risk assessment of LUTS, and plans are potentially applicable to numerous drugs with anticholinergic activity that induce serious side effects, limiting their use.

Sulfatides inhibit adhesion, migration, and invasion of murine melanoma B16F10 cell line in vitro.

Endogenous sulfatide, such as 3-sulfated galactosylceramide (3-sulfatide) has been reported to be involved in neuronal development and regulation of tumor cell metastasis. Recently, a new 6-sulfated glucosylceramide (6-sulfatide) has been isolated from the ascidian, Ciona intestinalis. To determine the antitumor function of the new sulfatide, we examined the effects of synthetic 6-sulfatide and 3-sulfatide on the metastatic features of a murine melanoma cell line, B16F10. Both sulfatides significantly inhibited the adhesion of melanoma cells onto fibronectin-coated tissue plates and, the motility and invasion of the cells, with 6-sulfatide showing stronger inhibitory activities. In addition, both sulfatides inhibited α(5)-, and ß(1)- but not α(v)- or ß(3)-integrin expression. Furthermore, these sulfatides inhibited the activation of focal adhesion kinase, Akt, and extracellular signal-regulated kinase signaling pathways, which are thought to be important for cell migration and invasion. Therefore, these sulfatides may serve as promising drug candidates for the treatment of cancer metastasis.

Synthetic studies on glycosphingolipids from protostomia phyla: synthesis of glycosphingolipids and related carbohydrate moieties from the parasite Schistosoma mansoni.

Stereocontrolled syntheses of three neutral glycosphingolipids and six oligosaccharide derivatives found from the parasite Schistosoma mansoni have been accomplished. A pentasaccharide glycosphingolipid ß-D-Galp-(1→4)-[α-L-Fucp-(1→3)]-ß-D-GlcpNAc-(1→3)-ß-D-GalpNAc-(1→4)-ß-D-Glcp-(1↔1)-Cer (1), two hexasaccharide glycosphingolipids α-L-Fucp-(1→3)-ß-D-Galp-(1→4)-[α-L-Fucp-(1→3)]-ß-D-GlcpNAc-(1→3)-ß-D-GalpNAc-(1→4)-ß-D-Glcp-(1↔1)-Cer (2) and ß-D-Galp-(1→4)-[α-L-Fucp-(1→3)]-ß-D-GlcpNAc-(1→3)-ß-D-GlcpNAc-(1→3)-ß-D-GalpNAc-(1→4)-ß-D-Glcp-(1↔1)-Cer (3), together with their non-reducing end tri- and tetrasaccharides, ß-D-Galp-(1→4)-[α-L-Fucp-(1→3)]-ß-D-GlcpNAcOR (4) and α-L-Fucp-(1→3)-ß-D-Galp-(1→4)-[α-L-Fucp-(1→3)]-ß-D-GlcpNAcOR (5), were synthesized by block synthesis. Moreover, non-reducing end oligosaccharides of schistosomal glycosphingolipids, ß-D-GalpNAc-(1→4)-[α-L-Fucp-(1→3)]-ß-D-GlcpNAcOR (6), α-L-Fucp-(1→3)-ß-D-GalpNAc-(1→4)-[α-L-Fucp-(1→3)]-ß-D-GlcpNAcOR (7), α-L-Fucp-(1→3)-ß-D-GalpNAc-(1→4)-[α-L-Fucp-(1→2)-α-L-Fucp-(1→3)]-ß-D-GlcpNAcOR (8) and α-L-Fucp-(1→3)-ß-D-GalpNAc-(1→4)-[α-L-Fucp-(1→2)-α-L-Fucp-(1→2)-α-L-Fucp-(1→3)]-ß-D-GlcpNAcOR (9) [R=2-(trimethylsilyl)ethyl], were synthesized as probes to explore their diagnostic potential to detect schistosomiasis from patients' sera.

Synthetic studies on glycosphingolipids from protostomia phyla: synthesis of glycosphingolipids from the parasite Schistosoma mansoni.

Synthetic access to three neutral glycosphingolipids from the parasite Schistosoma mansoni adult worm has been achieved. These structures differ significantly from those of other parasites and exhibit a unique structural motif termed "schisto-core" consisting of GalNAcbeta1-->4Glcbeta1-->sequence. We have synthesized glycosphingolipids, beta-D-GalNAcp-(1-->4)-beta-D-Glcp-(1-->1)Cer (1), beta-D-GlcNAcp-(1-->3)-beta-D-GalNAcp-(1-->4)-beta-D-Glcp-(1-->1)Cer (2) and beta-D-Galp-(1-->4)-beta-D-GlcNAcp-(1-->3)-beta-D-GalNAcp-(1-->4)-beta-D-Glcp-(1-->1)Cer (3).