The human ether-a-go-go-related gene (HERG) protein forms the ion channel responsible for the rapidly acting delayed rectifier potassium current, I(Kr), and its blockade is a significant contributor ...to prolongation of the QT interval. Using descriptors which have clear physicochemical meanings and are familiar to medicinal chemists, we have carried out 2D-quantitative structure-activity relationship (2D-QSAR) studies on 104 HERG channel blockers with diverse structures collected from the literature, and we have formulated interpretable models to guide chemical-modification studies and virtual screening. Statistically significant descriptors were selected by a genetic algorithm, and the final model included the octanol/water partition coefficient, topological polar surface area, diameter, summed surface area of atoms with partial charges from -0.25 to -0.20, and an indicator variable representing the experimental conditions. The statistics were r = 0.839, r2 = 0.704, q2 = 0.671, s = 0.763, and F = 46.6. The correspondence of the molecular determinants derived from the 2D-QSAR models with the 3D structural characteristics of the putative binding site in a homology-modeled HERG channel is also discussed.
We constructed two series of Gateway binary vectors, pGWBs and R4pGWBs, possessing the bialaphos resistance gene (bar) as a selection marker for plant transformation. The reporters and tags employed ...in this system are sGFP, GUS, LUC, EYFP, ECFP, G3GFP, mRFP, TagRFP, 6xHis, FLAG, 3xHA, 4xMyc, 10xMyc, GST, T7 and TAP. Selection of Arabidopsis transformants with BASTA
®
was successfully carried out using both plate-grown and soil-grown seedlings. Transformed rice calli and suspension-cultured tobacco cells were selected on plates containing BASTA
®
or glufosinate-ammonium. These vectors are compatible with existing pGWB and R4pGWB vectors carrying kanamycin and hygromycin B resistance.
Although the Abelson (Abl) tyrosine kinase inhibitor imatinib mesylate has improved the treatment of breakpoint cluster region–Abl (Bcr-Abl)–positive leukemia, resistance is often reported in ...patients with advanced-stage disease. Although several Src inhibitors are more effective than imatinib and simultaneously inhibit Lyn, whose overexpression is associated with imatinib resistance, these inhibitors are less specific than imatinib. We have identified a specific dual Abl-Lyn inhibitor, NS-187 (elsewhere described as CNS-9), which is 25 to 55 times more potent than imatinib in vitro. NS-187 is also at least 10 times as effective as imatinib in suppressing the growth of Bcr-Abl–bearing tumors and markedly extends the survival of mice bearing such tumors. The inhibitory effect of NS-187 extends to 12 of 13 Bcr-Abl proteins with mutations in their kinase domain but not to T315I. NS-187 also inhibits Lyn without affecting the phosphorylation of Src, Blk, or Yes. These results suggest that NS-187 may be a potentially valuable novel agent to combat imatinib-resistant Philadelphia-positive (Ph+) leukemia.
Prediction of biological targets for molecules from their chemical structures is beneficial for generating focused libraries, selecting compounds for screening, and annotating biological activities ...for those compounds whose activities are unknown. We studied the ability of a probabilistic neural network (PNN), a variant of normalized radial basis function (RBF) neural networks, to predict biological activities for a set of 799 compounds having activities against seven biological targets. The compounds were taken from the MDDR database, and they were carefully selected to comprise distinct biological activities and diverse structures. The structural characteristics of compounds were represented by a set of 24 atom-type descriptors defined by 2D topological chemical structures. The modeling was done in two ways: (1). compounds having one certain activity were discriminated from those not having that activity and (2). all compounds were classified into seven biological classes. In both cases, around 90% of the compounds were correctly classified. Further validation of the modeled PNNs was done with 26 317 compounds having biological activities against various targets except for the seven targets used for modeling, and 67-98% compounds were correctly classified depending upon the targets. A PNN trains much more quickly than widely used neural networks such as a feed-forward neural network with error back-propagation. Calculation of atom-type descriptors is easy even for a large-size chemical library. Combination of PNN and atom-type descriptors thus provides a powerful way to predict biological activities from structural information.
Abstract We compared the growth-inhibitory effects and inhibition profile of the SRC family kinases (SFKs) of imatinib, dasatinib, nilotinib and INNO-406. Dasatinib exhibited the strongest potency ...against BCR–ABL with little selectivity over SFKs. Nilotinib exhibited a weaker affinity than the other inhibitors, but was highly specific for ABL and may be useful for the treatment of P-glycoprotein overexpressing leukemic cells. INNO-406 had an intermediate affinity for BCR–ABL between that of dasatinib and nilotinib, and inhibited only SFKs LCK and LYN among SFKs. Both nilotinib and INNO-406 were potent inhibitors of the dasatinib-resistant T315A, F317L and F317V BCR–ABL mutations.
Since 2012, I have been working with Japanese artists, curators and diverse participants on the use of EC Film, an academic video archive constructed in Germany in the 1950s-80s. In the first part of ...this article, we will present a series of screenings/lectures that combine EC Film, various locations, real materials and guest speakers with multiple perspectives, as well as the "Fieldwork in Films" exhibition held in Tokyo in 2019. In the second part, we will focus on the attempt to 're-enact’ music and performing arts images in EC film, and consider the ways in which we, living in the present day, can recombine and 'pass on' visual archives that capture the experiences of 'distant others'.
Stomatal development in Arabidopsis epidermis is both positively and negatively regulated by a family of Cys-rich peptides, EPIDERMAL PATTERNING FACTOR LIKEs (EPFLs). We synthesized biologically ...active synthetic EPFL5 (sEPFL5) peptide, which reduced the number of stoma in leaves and cotyledons. The sEPFL5 possesses three disulfide bonds at positions identical to those of a positive development factor, stomagen. Application of sEPFL5 had little inhibitory effect on protodermal cells entering the stomatal lineage, but did inhibit the maintenance of meristemoid activity, resulting in the differentiation of arrested meristemoids into pavement cells. This phenotype was enhanced in the too many mouths (tmm) mutant background. RNA analysis revealed that sEPFL5 application halved SPEECHLESS expression and abolished MUTE expression in tmm mutants, explaining the phenotype observed. The action of sEPFL5 was mediated by ERECTA family receptors. We propose that EPFL5 functions to establish the differentiation of stomatal lineage cells to pavement cells.
A series of novel phthalazinones were synthesized as PDE4 inhibitors. The most potent of these, with IC
50 values in the subnanomolar range, had anti-inflammatory activity in a mouse dermatitis ...model.
Inhibitors of phosphodiesterase 4 (PDE4) are an important class of anti-inflammatory drug that act by inhibiting the production of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α). We have synthesized and evaluated a series of 2-substituted phthalazinone derivatives as PDE4 inhibitors. Structure–activity relationship studies led to the identification of benzylamine-substituted phthalazinones as potent PDE4 inhibitors that also suppressed TNF-α production by whole rat blood cells. The most potent of these, when topically administered, were effective in a mouse model of dermatitis.
Abstract
Many terrestrial plants produce large quantities of alkanes for use in epicuticular wax and the pollen coat. However, their carbon chains must be long to be useful as fuel or as a ...petrochemical feedstock. Here, we focus on Nymphaea odorata, which produces relatively short alkanes in its anthers. We identified orthologs of the Arabidopsis alkane biosynthesis genes AtCER1 and AtCER3 in N. odorata and designated them NoCER1A, NoCER3A and NoCER3B. Expression analysis of NoCER1A and NoCER3A/B in Arabidopsis cer mutants revealed that the N. odorata enzymes cooperated with the Arabidopsis enzymes and that the NoCER1A produced shorter alkanes than AtCER1, regardless of which CER3 protein it interacted with. These results indicate that AtCER1 frequently uses a C30 substrate, whereas NoCER1A, NoCER3A/B and AtCER3 react with a broad range of substrate chain lengths. The incorporation of shorter alkanes disturbed the formation of wax crystals required for water-repellent activity in stems, suggesting that chain-length specificity is important for surface cleaning. Moreover, cultured tobacco cells expressing NoCER1A and NoCER3A/B effectively produced C19–C23 alkanes, indicating that the introduction of the two enzymes is sufficient to produce alkanes. Taken together, our findings suggest that these N. odorata enzymes may be useful for the biological production of alkanes of specific lengths. 3D modeling revealed that CER1s and CER3s share a similar structure that consists of N- and C-terminal domains, in which their predicted active sites are respectively located. We predicted the complex structure of both enzymes and found a cavity that connects their active sites.
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