A preprocessing method for improving effectiveness of Collaborative Filtering

Collaborative filtering uses information about customers’ preferences to make personal product recommendations and is achieving widespread success in e-Commerce. However, the traditional collaborative filtering algorithms do not response accurately to customers’ needs. The quality of the recommendation needs to be improved in order to support personalized service to each customer. In this paper, we present novel method to improve the accuracy of the collaborative filtering algorithm. We borrow vector space model from information retrieval theory and use it to effectively discriminate the preference weights on the items for each customer. The proposed method achieves more accurate recommendations for customers who purchase similar types of products repeatedly. Our experimental evaluation on the well-known MovieLens data set shows that our method does result in a better accuracy

Structure-activity relationships of fluorene compounds inhibiting HCV variants

Approximately 71 million people suffer from hepatitis C virus (HCV) infection worldwide. Persistent HCV infection causes liver diseases such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma, resulting in approximately 400,000 deaths annually. Effective direct-acting antiviral agents (DAAs) have been developed and are currently used for HCV treatment targeting the following three proteins: NS3/4A proteinase that cleaves the HCV polyprotein into various functional proteins, RNA-dependent RNA polymerase (designated as NS5B), and NS5A, which is required for the formation of double membrane vesicles serving as RNA replication organelles. At least one compound inhibiting NS5A is included in current HCV treatment regimens due to the high efficacy and low toxicity of drugs targeting NS5A. Here we report fluorene compounds showing strong inhibitory effects on GT 1b and 3a of HCV. Moreover, some compounds were effective against resistance-associated variants to DAAs. The structure-activity relationships of the compounds were analyzed. Furthermore, we investigated the molecular bases of the inhibitory activities of some compounds by the molecular docking method.11Ysciescopu

Sulfur(vi) fluoride exchange as a key reaction for synthesizing biaryl sulfate core derivatives as potent hepatitis C virus NS5A inhibitors and their structure-activity relationship studies

Extremely potent, new hepatitis C virus (HCV) nonstructural 5A (NS5A) featuring substituted biaryl sulfate core structures was designed and synthesized. Based on the previously reported novel HCV NS5A inhibitors featuring biaryl sulfate core structures which exhibit two-digit picomolar half-maximal effective concentration (EC50) values against HCV genotype 1b and 2a, the new inhibitors equipped with the sulfate core structures containing diversely substituted aryl groups were explored. In this study, highly efficient, chemoselective coupling reactions between an arylsulfonyl fluoride and an aryl silyl ether, known as the sulfur(vi) fluoride exchange (SuFEx) reaction, were utilized. Among the inhibitors prepared based on the SuFEx chemistry, compounds 14, 15 and 29 exhibited two-digit picomolar EC50 values against GT-1b and single digit or sub nanomolar activities against the HCV GT-2a strain. Nonsymmetrical inhibitors containing an imidazole and amide moieties on each side of the sulfate core structures were also synthesized. In addition, a biotinylated probe targeting NS5A protein was prepared for labeling using the same synthetic methodology.11Ysciescopu

Coordinative Amphiphiles as Tunable siRNA Transporters

In this study, we developed coordinative amphiphiles for use as novel siRNA transporters. As a modification of a conventional cationic lipid structure, we replaced the cationic head with zinc(II)-dipicolylamine complex (Zn/DPA) as a phosphate directing group, and used various membrane-directing groups in the place of the hydrophobic tails. These simple amphiphiles are readily synthesized and easy to modify. The Zn/DPA head groups bind to the phosphate backbones of siRNAs, and to our surprise, they prevented the enzymatic degradation of siRNAs by RNase A. Interestingly, the Zn/DPA head itself exhibited moderate transfection efficiency, and its combination with a membrane-directing group-oleoyl (CA1), pyrenebutyryl (CA2), or biotin (CA3)-enhanced the delivery efficiency without imparting significant cytotoxicity. Notably, the uptake pathway was tunable depending on the nature of the membrane-directing group. CA1 delivered siRNAs mainly through caveolae-mediated endocytosis, and CA2 through clathrin- and caveolin-independent endocytosis; CA3 recruited siRNAs specifically into biotin receptor-positive HepG2 cells through receptor-mediated endocytosis. Thus, it appears possible to develop tunable siRNA transporters simply by changing the membrane-directing parts. These are the first examples of amphiphilic siRNA transporters accompanying coordinative interactions between the amphiphiles and siRNAs. © 2016 American Chemical Society101sciescopu

Coordinative Amphiphiles as Tunable siRNA Transporters

In this study, we developed coordinative amphiphiles for use as novel siRNA transporters. As a modification of a conventional cationic lipid structure, we replaced the cationic head with zinc(II)-dipicolylamine complex (Zn/DPA) as a phosphate directing group, and used various membrane-directing groups in the place of the hydrophobic tails. These simple amphiphiles are readily synthesized and easy to modify. The Zn/DPA head groups bind to the phosphate backbones of siRNAs, and to our surprise, they prevented the enzymatic degradation of siRNAs by RNase A. Interestingly, the Zn/DPA head itself exhibited moderate transfection efficiency, and its combination with a membrane-directing group-oleoyl (CA1), pyrenebutyryl (CA2), or biotin (CA3)-enhanced the delivery efficiency without imparting significant cytotoxicity. Notably, the uptake pathway was tunable depending on the nature of the membrane-directing group. CA1 delivered siRNAs mainly through caveolae-mediated endocytosis, and CA2 through clathrin- and caveolin-independent endocytosis; CA3 recruited siRNAs specifically into biotin receptor-positive HepG2 cells through receptor-mediated endocytosis. Thus, it appears possible to develop tunable siRNA transporters simply by changing the membrane-directing parts. These are the first examples of amphiphilic siRNA transporters accompanying coordinative interactions between the amphiphiles and siRNAs.11Nsciescopu

Identification of New <i>N</i>-methyl-piperazine Chalcones as Dual MAO-B/AChE Inhibitors

Monoamine oxidase-B (MAO-B), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) have been considered target enzymes of depression and neurodegenerative diseases, including Alzheimer’s disease (AD). In this study, seventeen N-methyl-piperazine chalcones were synthesized, and their inhibitory activities were evaluated against the target enzymes. Compound 2k (3-trifluoromethyl-4-fluorinated derivative) showed the highest selective inhibition against MAO-B with an IC50 of 0.71 μM and selectivity index (SI) of 56.34, followed by 2n (2-fluoro-5-bromophenyl derivative) (IC50 = 1.11 μM, SI = 16.04). Compounds 2k and 2n were reversible competitive MAO-B inhibitors with Ki values of 0.21 and 0.28 μM, respectively. Moreover, 2k and 2n effectively inhibited AChE with IC50 of 8.10 and 4.32 μM, which underscored their multi-target inhibitory modes. Interestingly, compound 2o elicited remarkable inhibitions over MAO-B, AChE, and BChE with IC50 of 1.19–3.87 μM. A cell-based assay of compounds 2k and 2n against Vero normal cells pointed out their low cytotoxicity. In a docking simulation, 2k showed the lowest energy for MAO-B (−11.6 kcal/mol) with four hydrogen bonds and two π-π interactions. Furthermore, in silico studies were conducted, and disclosed that 2k and 2n are expected to possess favorable pharmacokinetic properties, such as the ability to penetrate the blood–brain barrier (BBB). In view of these findings, compounds 2k and 2n could serve as promising potential candidates for the treatment of neurodegenerative diseases

New potent biaryl sulfate-based hepatitis C virus inhibitors

The discovery of a new series of potent hepatitis C virus (HCV) NS5A inhibitors containing biaryl sulfone or sulfate cores is reported. Structure-activity relationship (SAR) studies on inhibitors containing various substitution patterns of the sulfate or sulfone core structure established that m-,m&apos;- substituted biaryl sulfate core-based inhibitors containing an amide moiety (compound 20) or an imidazole moiety (compound 24) showed extremely high potency. Compound 20 demonstrated double-digit pM potencies against both genotype 1b (GT-1b) and 2a (GT-2a). Compound 24 also exhibited double-digit pM potencies against GT-1b and sub nM potencies against GT-2a. Furthermore, compounds 20 and 24 exhibited no cardiotoxicity in an hERG ligand binding assay and showed acceptable plasma stability and no mutagenic potential in the Ames test. In addition, these compounds showed distinctive additive effects in combination treatment with the NS5B targeting drug sofosbuvir (Sovaldi (R)). The results of this study showed that the compounds 20 and 24 could be effective HCV inhibitors. (C) 2016 Elsevier Masson SAS. All rights reserved.112sciescopu

Discovery of 3-((3-amino-1H-indazol-4-yl)ethynyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (AKE-72), a potent Pan-BCR-ABL inhibitor including the T315I gatekeeper resistant mutant

AbstractBCR-ABL inhibition is an effective therapeutic approach for the treatment of chronic myeloid leukaemia (CML). Herein, we report the discovery of AKE-72 (5), a diarylamide 3-aminoindazole, as a potent pan-BCR-ABL inhibitor, including the imatinib-resistant mutant T315I. A focussed array of compounds 4a, 4b, and 5 has been designed based on our previously reported indazole I to improve its BCR-ABLT315I inhibitory activity. Replacing the morpholine moiety of I with the privileged tail (4-ethylpiperazin-1-yl)methyl afforded 5 (AKE-72) with IC50 values of < 0.5 nM, and 9 nM against BCR-ABLWT and BCR-ABLT315I, respectively. Moreover, AKE-72 potently inhibited a panel of other clinically important mutants in single-digit nanomolar IC50 values. AKE-72 elicited remarkable anti-leukemic activity against K-562 cell line (GI50 < 10 nM, TGI = 154 nM). In addition, AKE-72 strongly inhibited the proliferation of Ba/F3 cells expressing native BCR-ABL or its T315I mutant. Overall, AKE-72 may serve as a promising candidate for the treatment of CML, including those harbouring T315I mutation