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ACS Combinatorial Science

Rajendra Patil, Jagdish Chavan, Dipak S Dalal, Vaishali Sanjay Shinde, Anil Beldar
The Biginelli product, dihydropyrimidinone (DHPM) core and its derivatives are of immense biological importance. There are several methods reported as the modification in original Biginelli reaction. Among that many involves the uses of different catalysts. The advancements that have been consistently done in Biginelli reaction, intended to improve product yields, to provide less hazardous reaction conditions and easy isolation of products from reaction medium. Recently, solid phase synthetic protocol has attracted research community towards itself for better yields, less hectic steps for product purification, recyclability of solid support which forms a special economic approach for Biginelli reaction...
January 15, 2019: ACS Combinatorial Science
Petra Kralova, Sandra Benick Aacute, Miroslav Soural
The synthesis of different diketomorpholines via N-acyl-3,4-dihydro-2H-1,4-oxazine-3-carboxylic acids is reported in this article. The key intermediates were prepared using a convenient solid-phase synthesis starting from polymer-supported Ser(tBu)-OH. After subsequent sulfonylation with 4-nitrobenzenesulfonyl chloride (4-Nos-Cl), alkylation with an -bromoketone, cleavage of the 4-Nos group and acylation with an -halocarboxylic acids, acid-mediated cleavage from the resin yielded dihydrooxazine-3-carboxylic acids in high crude purities...
January 14, 2019: ACS Combinatorial Science
Syamak Farajikhah, Joan Marc Cabot, Peter C Innis, Brett Paull, Gordon G Wallace
Novel approaches that incorporate electrofluidic and microfluidic technologies are reviewed to illustrate the translation of traditional enclosed structures into open and accessible textile based platforms. Through the utilisation of on-fibre and on-textile micro-fluidics, it is possible to invert the typical enclosed capillary column or microfluidic "chip" platform, to achieve surface accessible efficient separations and fluid handling, whilst maintaining a microfluidic environment. The open fibre/textile based fluidics approach immediately provides new possibilities to interrogate, manipulate, redirect, extract, characterise and quantify solutes and target species at any point in time during such processes as on-fibre electrodriven separations...
January 14, 2019: ACS Combinatorial Science
Megan Hogan, Medhanit Bahta, Kohei Tsuji, Trung Xuan Nguyen, Scott Cherry, George T Lountos, Joseph E Tropea, Bryan Zhao, Xue Zhi Zhao, David S Waugh, Terrence R Burke, Robert G Ulrich
Chemical library screening approaches that focus exclusively on catalytic events may overlook unique effects of protein-protein interactions that can be exploited for development of specific inhibitors. Phosphotyrosyl (pTyr) residues embedded in peptide motifs comprise minimal recognition elements that determine substrate specificity of protein tyrosine phosphatases (PTPases). Using solid-phase synthesis, we incorporated aminooxy-containing amino acid residues into a 7-residue epidermal growth factor receptor (EGFR)-derived phosphotyrosine-containing peptide and subjected the peptides to on-resin oxime diversification by reacting with aldehyde-bearing drug-like functionalities...
January 10, 2019: ACS Combinatorial Science
Dominik Bernhagen, Vanessa Jungbluth, Nestor Gisbert Quilis, Jakub Dostalek, Paul B White, Kees Jalink, Peter Timmerman
We describe the identification of bicyclic RGD-peptides with high affinity and selectivity for integrin αvβ3 via high-throughput screening of partly randomized libraries. Peptide libraries (~700 different compounds) comprising the universal integrin-binding sequence Arg-Gly-Asp (RGD) in the first loop and a randomized sequence XXX (X being one of 18 canoni-cal L-amino acids) in the second loop, both enclosed by either an L- or D-Cys residue, were converted to bicyclic peptides via reaction with 1,3,5-tris(bromomethyl)benzene (T3)...
January 9, 2019: ACS Combinatorial Science
Lawrence A Stern, Patrick Lown, Alexandra C Kobe, Lotfi Abou-Elkacem, Juergen K Willmann, Benjamin J Hackel
Yeast surface display is a proven tool for the selection and evolution of ligands with novel binding activity. Selections from yeast surface display libraries against transmembrane targets are generally carried out using recombinant soluble extracellular domains. Unfortunately, these molecules may not be good models of their true, membrane-bound form for a variety of reasons. Such selection campaigns often yield ligands that bind recombinant target but not target-expressing cells or tissues. Advances in cell-based selections with yeast surface display may aid the frequency of evolving ligands that do bind true, membrane-bound antigens...
January 8, 2019: ACS Combinatorial Science
Eduardo de Pedro Beato, Julian Priego, Adrián Gironda-Martínez, Fernando González, Jesús Benavides, Jesús Blas, María Dolores Martín-Ortega, Miguel A Toledo, Jesús Ezquerra, Alicia Torrado
DNA-Encoded Library Technology (ELT) has emerged in the pharmaceutical industry as a powerful tool for hit and lead generation. Over the last 10 years, a number of DNA-compatible chemical reactions have been published and used to synthesize libraries. Among the most commonly used reactions in medicinal chemistry is the C-N bond formation and its application to DNA encoded library technology affords an alternative approach to identify high-affinity binders for biologically relevant protein targets. Herein we report a newly developed Pd promoted C-N cross coupling reactions between DNA-conjugated aryl bromides and a wide scope of aryl amines in good to excellent yields...
January 7, 2019: ACS Combinatorial Science
Zachary Cannone, Ala Shaqra, Chris Lorenc, Liza Henowitz, Santosh Keshipeddy, Victoria Lee Robinson, Adam Zweifach, Dennis L Wright, Mark Peczuh
Many small molecule natural products with antibiotic and antiproliferative activity are adorned with a carbohydrate residue as part of their molecular structure. The carbohydrate moiety can act to mediate key interactions with the target, attenuate physicochemical properties, or both. Facile incorporation of a carbohydrate group on de novo small molecules would enable these valuable properties to be leveraged in the evaluation of focused compound libraries. While there is no universal way to incorporate a sugar on small molecule libraries, techniques such as glycorandomization and neoglycorandomization have made signification headway toward this goal...
January 4, 2019: ACS Combinatorial Science
Davide Righi, Laurence Marcourt, Alexey Koval, Verena Ducret, Leonie Pellissier, Alice Mainetti, Vladimir Katanaev, Karl Perron, Jean-Luc Wolfender, Emerson Ferreira Queiroz
A generic procedure for direct bromination of polyphenol in crude plant extracts was developed in order to generate multiple 'unnatural' halogenated natural products for further bioassay evaluation. To better control the halogenation procedure, the bromination was optimized with a flavonoid standards and the reactions were monitored by HPLC-PDA coupled to the evaporative light scattering detection (ELSD). ELSD detection was successfully used for a relative yield estimation of the compounds obtained. From the halogenation of hesperitin (11), five brominated compounds were obtained...
January 4, 2019: ACS Combinatorial Science
Aparna E P, Devaky K S
This review describes the existing synthetic approaches for the solid-phase synthesis (SPS) of differently substituted and fused pyrimidine derivatives. These synthetic strategies are classified on the basis of the different synthetic routes leading to the particular type of pyrimidine heterocycle formed. The review discusses the application of a variety of polystyrene derived supports for the construction of pyrimidine rings. The effect of microwave heating on the solid-phase synthesis is also addressed in the review...
January 4, 2019: ACS Combinatorial Science
Luyan Yang, Pi Ding, Yu Luo, Jine Wang, Haiyin Lv, Wenjing Li, Yanwei Cao, Renjun Pei
In order to develop a novel light-up probe and DNAzyme, we selected aptamers for N-methyl mesoporphyrin IX (NMM), a common fluorogenic analogue of coenzyme hemin, by a modified affinity chromatography-based Systematic Evolution of Ligands by Exponential Enrichment (SELEX). Two truncated aptamers Nm1 and Nm2 with low micromolar dissociation constants (0.75 and 13.27 μM) were obtained after 11 rounds of selection and the final minimized 39-mer aptamer Nm2.1 showed 24-fold fluorescence enhancement for NMM at saturated concentration...
January 2, 2019: ACS Combinatorial Science
Patrick Mester, Christian Robben, Anna Witte, Roland Kalb, Monika Ehling-Schulz, Peter Rossmanith, Tom Grunert
Over the past decades, ionic liquids (ILs) have gained considerable attention from the scientific community due to their versatile and designable properties. As a result, there are numerous IL applications, particularly in organic synthesis, catalysis or extraction, but also as active pharmaceutical ingredients or novel antimicrobials. While considerable effort has been put into developing quantitative structure-activity relationship (QSAR) models for IL toxicity prediction, little is known about their actual mode of action...
December 31, 2018: ACS Combinatorial Science
Geetmani Singh Nongthombam, Kasmika Borah, Thingreila Muinao, Yumnam Silla, Mintu Pal, Hari Prasanna Dekaboruah, Romesh Chandra Boruah
Herein we report the synthesis of a novel class of substituted androst[17,16-b]pyridines (pyridosteroids) from the reaction of β-formyl enamides with alkynes in high yields. The optimized reaction protocol was extended to acyclic and cyclic β-formyl enamides to afford non-steroidal pyridines. Cell survival assay of all compounds were carried against prostate cancer PC-3 cells wherein 3-hydroxy-5-en-2',3'-dicarbethoxy-androst[17,16-b]pyridine showed the highest cytotoxic activity. Phase contrast microscopy and flow cytometry studies exhibited marked morphological features characteristic of apoptosis in 3-hydroxy-5-en-2',3'-dicarbethoxy-androst[17,16-b]pyridine and abiraterone treated PC-3 cells...
December 21, 2018: ACS Combinatorial Science
Josipa Suć Sajko, Vanja Ljoljić Bilić, Ivan Kosalec, Ivanka Jeric
The γ-lactam motif is often found in naturally occurring compounds with diverse biological activities. We prepared a 28-member library of N-substituted γ-lactams following a single-pot, three-component Ugi reaction comprising bifunctional building block, L-glutamic acid methyl ester. Reaction tolerates structurally diverse carbonyl and isocyanide components providing a robust access to functionalized γ-lactams. Antimicrobial susceptibility testing, including agar well diffusion assay, serial microdilution broth assay and antibiofilm activity testing, identified a potent compound with antibiofilm activity against S...
December 18, 2018: ACS Combinatorial Science
Jiannan Li, Siwei Zhao, Gaomai Yang, Ruiwu Liu, Wenwu Xiao, Paolo Disano, Kit S Lam, Tingrui Pan
In this paper, a novel inkjet printing technique, micro impact printing (MI printing), is applied for the first time to combinatorial peptide array synthesis on amine functionalized micro disc arrays through standard Fmoc chemistry. MI printing shows great advantages in combinatorial peptide array synthesis compared with other printing techniques, including 1) a disposable cartridge; 2) a small spot size (80 μm) increases array density; 3) minimal loading volume (0.6 μL) and dead volume (<0.1 μL) reduce chemical waste; and 4) multiplexability for up to 5 channels...
December 6, 2018: ACS Combinatorial Science
Marina N Semenova, Dmitry V Demchuk, Dmitry V Tsyganov, Natalia B Chernysheva, Alexander V Samet, Eugenia A Silyanova, Victor P Kislyi, Anna S Maksimenko, Alexander E Varakutin, Leonid D Konyushkin, Mikhail M Raihstat, Alex S Kiselyov, Victor V Semenov
A series of both novel and reported combretastatin analogues, including diarylpyrazoles, -isoxazoles, -1,2,3-triazoles, and -pyrroles, were synthesized via improved protocols to evaluate their antimitotic antitubulin activity using in vivo sea urchin embryo assay and a panel of human cancer cells. A systematic comparative structure-activity relationship studies of these compounds were conducted. Pyrazoles 1i and 1p, isoxazole 3a, and triazole 7b were found to be the most potent antimitotics across all tested compounds causing cleavage alteration of the sea urchin embryo at 1, 0...
November 29, 2018: ACS Combinatorial Science
Jana Pospisilova, Viktor Krchnak, Eva Schütznerová
We present the solid-phase synthesis of 1,2-dihydroquinazoline-2-carboxylate derivatives with a quaternary carbon in position 2 and their subsequent cyclization in solution into compounds with unique 3D architectures and pharmacological relevance - spiroquinazolines, namely, 1'H-spiro[pyrrolidine-3,2'-quinazolin]-2-ones and 1'H-spiro[piperidine-3,2'-quinazolin]-2-ones. Acyclic precursors were prepared from commercially available building blocks: protected amino acids (2,4-diaminobutyric acid and ornithine), 2-nitrobenzensulfonyl chlorides and α-bromoacetophenones...
November 28, 2018: ACS Combinatorial Science
Hojun Kim, Sungwook Park, Benedict Jungmin Kang, Youngdo Jung, Hyojin Lee, Kwan Hyi Lee
The heterogeneous nature of tumor cell populations suggests that quantitative analysis at the single-cell level may provide better insights into cancer biology. Specifically, detection of multiple biomarkers from a single cell offers important initial information about cellular behavior. However, conventional approaches have limitations on biomarker detections in a single cell level. Here we fabricated a polymer microwell array to capture single cells from prostate cancer cell lines and quantitatively analyzed three different cancer-related biomarker expressions, CD44, EpCAM, and PSMA without protein extraction step...
November 28, 2018: ACS Combinatorial Science
Kadalipura P Rakesh, Manukumar H Marichannegowda, Shobhith Srivastava, Xing Chen, Sihui Long, Chimatahalli S Karthik, Putswamappa Mallu, Hua-Li Qin
Staphylococcus aureus is a bacterial pathogen that can cause significant disease burden and mortality by counteracting host defenses through producing virulence factors to survive the immune responses evoked by infection. This emerging drug-resistant pathogen has led to a decline in the efficacy of traditional antimicrobial therapy. To combat these threats, precision antimicrobial therapeutics have been created to target key virulence determinants of specific pathogens. Here we review the benefits of, progresses in, and roadblocks to the development of precision antimicrobial therapeutics using combinatorial chemistry...
November 8, 2018: ACS Combinatorial Science
Ma Angeles Bonache, Silvia Moreno-Fernández, Marta Miguel, Beatriz Sabater-Muñoz, Rosario González-Muñiz
Polyphenolic compounds have attracted much interest because of their antioxidant properties and multiple applications, from food or cosmetic preservatives to free radical scavengers as therapeutic agents. Inspired by common OH substitutions in natural products, here we describe a small library of 1,2,3-triazoles disubstituted with polyphenol groups at 1,4-positions, in an attempt to correlate the number and position of hydroxyl groups in the aromatic rings with the antioxidant activity. Some compounds from this library exhibit strong radical scavenging activities in the oxygen radical absorbance capacity assay, similar to or even higher than resveratrol and other well-kwon flavonoids...
November 2, 2018: ACS Combinatorial Science
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