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ACS Combinatorial Science

Lawrence A Stern, Cliff M Csizmar, Daniel R Woldring, Carston R Wagner, Benjamin J Hackel
Yeast surface display selections against mammalian cell monolayers have proven effective in isolating proteins with novel binding activity. Recent advances in this technique allow for recovery of clones with even micromolar binding affinity. However, no efficient method has been shown for affinity based selection in this context. This study demonstrates the effectiveness of titratable avidity reduction using dithiothreitol (DTT) to achieve this goal. A series of epidermal growth factor receptor binding fibronectin domains with a range of affinities are used to quantitatively identify the number of ligands per yeast cell that yield the strongest selectivity between strong, moderate, and weak affinities...
March 21, 2017: ACS Combinatorial Science
Liena Qin, Duc-Duy Vo, Azadeh Nakhai, C David Andersson, Mikael Elofsson
Benzofuran and 2,3-dihydrobenzofuran scaffolds are core components in a large number of biologically active natural and synthetic compounds including approved drugs. Herein, we report efficient synthetic protocols for preparation of libraries based on 3-carboxy 2-aryl benzofuran and 3-carboxy 2-aryl trans-2,3-dihydrobenzofuran scaffolds using commercially available salicylaldehydes, aryl boronic acids or halides and primary or secondary amines. The building blocks were selected to achieve variation in physicochemical properties and statistical molecular design and subsequent synthesis resulted in 54 lead-like compounds with molecular weights of 299-421 and calculated octanol/water partition coefficients of 1...
March 17, 2017: ACS Combinatorial Science
Mingi Kim, Yoon Soo Hwang, Wansang Cho, Seung Bum Park
We designed and synthesized the molecular framework of 3,5-disubstituted isoxazoles containing privileged substructures with various substituents which uniquely display polar surface area in a diverse manner. A library of 3,5-disubstituted isoxazoles were systematically prepared via 1,3-dipolar cycloaddition of alkynes with nitrile oxides prepared by two complementary synthetic routes; method A utilized a halogenating agent with a base and method B utilized a hypervalent iodine reagent. Through the biological evaluation of corresponding isoxazoles via three independent phenotypic assays, the different pattern of biological activities was shown according to the type of privileged substructure and substituent...
March 17, 2017: ACS Combinatorial Science
Jeremy A Turkett, Kevin L Bicker
Growing prevalence of antibiotic resistant bacterial infections necessitates novel antimicrobials, which could be rapidly identified from combinatorial libraries. We report the use of the Peptoid Library Agar Diffusion (PLAD) assay to screen peptoid libraries against the ESKAPE pathogens, including the optimization of assay conditions for each pathogen. Work presented here focuses on the tailoring of combinatorial peptoid library design through a detailed study of how peptoid lipophilicity relates to antibacterial potency and mammalian cell toxicity...
March 14, 2017: ACS Combinatorial Science
Alexander L Satz, Remo Hochstrasser, Ann C Petersen
To optimize future DNA encoded library design, we have attempted to quantify the library size at which signal becomes undetectable. To accomplish this we i) have calculated that percent yields of individual library members following a screen range from 0.002-1%, ii) extrapolated that ~ 1 million copies per library member are required at the outset of a screen, and iii) from this extrapolation predict that false negative rates will begin to outweigh the benefit of increased diversity at library sizes >108...
March 13, 2017: ACS Combinatorial Science
R Nishanth Rao, Barnali Maiti, Kaushik Chanda
Indole based alkaloids are well known in the literature for their diverse biological properties. Polysubstituted optically active tetrahydro-β-carboline derivatives functionalized on C-1 position are the common structural motif in most of the indole based alkaloids as well as highly marketed drug. The stereoselective Pictet-Spengler reaction is one of the currently most important synthetic techniques used for the preparation of this privilege tetrahydro-β-carboline scaffolds. Till date there are numerous research reports have been published on the synthesis of tetrahydro-β-carboline scaffold both on the solid phase as well as in solution phase...
March 9, 2017: ACS Combinatorial Science
Rita Szabó, Mónika Sebestyén, György Kóczán, Ádám Orosz, Gábor Mező, Ferenc Hudecz
Cationic macromolecular carriers can be effective carriers for small molecular compounds, drugs, epitopes, or nucleic acids. Polylysine-based polymeric branched polypeptides have been systematically studied on the level of cells and organisms as well. In the present study, we report our findings on the cellular uptake characteristics of nine structurally related polylysine-based polypeptides with cationic side chains composed of (i) single amino acid (poly[Lys(Xi)], XiK) or (ii) oligo[dl-alanine] (poly[Lys(dl-Alam)], AK) or (iii) oligo[dl-alanine] with an additional amino acid (X) at the terminal position (poly[Lys(Xi-dl-Alam)] (XAK)) or (iv) at the position next to the polylysine backbone (poly[Lys(dl-Alam-Xi)] (AXK))...
March 9, 2017: ACS Combinatorial Science
Yong Li, Jiang-Ping Meng, Jie Lei, Zhong-Zhu Chen, Dian-Yong Tang, Jin Zhu, Jin Zhang, Zhi-Gang Xu
A mild and efficient protocol was developed for the synthesis of oxazepino-isoquinolines via a one-pot Ugi four-component reaction, followed by the intramolecular addition of the resulting alcohol to an alkyne moiety under microwave irradiation conditions. Notably, this process only required one purification step, providing facile access to two series of complex and potentially interesting biologically active scaffolds.
March 8, 2017: ACS Combinatorial Science
Pravin Patil, Katarzyna Kurpiewska, Justyna Kalinowska-Tłuścik, Alexander Dömling
Ammonia in the tetrazole Ugi variation together with α-amino acid methyl ester-derived isocyanides provides tetrazolopiperidinones in good to high yields in one pot. The scope and limitations of this reaction were investigated by performing >70 reactions. The scaffold is useful to fill high-throughput screening decks and in structure-based drug design.
March 8, 2017: ACS Combinatorial Science
Julian Vastl, Tina Wang, Thi B Trinh, David A Spiegel
Solid-supported chemical libraries have proven useful for the rapid and cost-effective discovery of bioactive compounds. However, traditional on-bead screening involves time-intensive chemical characterization of hit compounds and high false positive rates. Herein, we report a new platform for encoded chemical synthesis and solid-supported screening using p-Chips, microsized silicon microtransponders capable of storing and emitting unique numerical identifiers (IDs). By encoding the structures of library members using p-Chip IDs, we can track compound identities throughout both split-and-pool synthesis and protein binding assays without destructive cleavage...
March 6, 2017: ACS Combinatorial Science
Dougal Peter Howard, Peter Marchand, Liam McCafferty, Claire J Carmalt, Ivan P Parkin, Jawwad A Darr
High-throughput continuous hydrothermal flow synthesis was used to generate a library of aluminium and gallium co-doped zinc oxide nanoparticles of specific atomic ratios. Resistivities of the materials were determined by Hall Effect measurements on heat-treated pressed discs and the results collated into a resistivity-composition map. Optimal resis-tivities of ca. 9 x 10-3 Ω cm were reproducibly achieved for several samples e.g. co-doped ZnO with 2 at% Ga and 1 at% Al. The optimum sample on balance of performance and cost was deemed to be ZnO co-doped with 3 at% Al and 1 at% Ga...
February 15, 2017: ACS Combinatorial Science
Po-Hsin Eric Yao, Sunil Kumar, Yu-Li Liu, Chiu-Ping Eikon Fang, Chia-Chen Liu, Chung-Ming Sun
Diversity-oriented synthesis of coumarin-linked benzimidazoles from N-(2-aminophenyl)-2-cyanoacetamide was achieved via a one-pot, three-step sequential reaction in excellent yields. In situ intramolecular cyclization of the cyanoacetamide afforded benzimidazoles which subsequently underwent a Knoevenagel condensation of the 2-cyanomethylbenzimidazoles with salicylaldehydes promoted by triethylamine to reach the target compounds. An important intermediate, 2-(2-imino-2H-chromen-3-yl)-1H-benzimidazole was characterized by X-ray analysis and further hydrolyzed to 2-(coumarin-3-yl)benzimidazole in acidic condition...
February 14, 2017: ACS Combinatorial Science
Eunji Kim, Myoung Chong Song, Myoun Su Kim, Ji Yoon Beom, Jin A Jung, Hang Soo Cho, Yeo Joon Yoon
Anthracyclines such as doxorubicin are effective anticancer drugs composed of a tetracyclic polyketide aglycone and one or more deoxysugar moieties, which play a critical role in their biological activity. A facile one-pot combinatorial biosynthetic system was developed for the generation of a range of glycosylated derivatives of anthracyclines. Co-cultivation of Streptomyces venezuelae mutants producing two anthracycline aglycones with eight different nucleotide deoxysugar-producing S. venezuelae mutants that co-express a substrate-flexible glycosyltransferase led to the generation of sixteen aklavinone or ε-rhodomycinone glycosides containing diverse deoxysugar moieties, seven of which are new...
February 13, 2017: ACS Combinatorial Science
Sung Hyeon Park, Chang Hyuck Choi, Seung Yong Lee, Seong Ihl Woo
Combinatorial optical screening of aprotic electrocatalysts has not yet been achieved primarily due to H(+)-associated mechanisms of fluorophore modulation. We have overcome this problem by using fluorophore metal-organic complexes. In particular, eosin Y and quinine can be coordinated with various metallic cations (e.g., Li(+), Na(+), Mg(2+), Zn(2+), and Al(3+)) in aprotic solvents, triggering changes in their fluorescent properties. These interactions have been used in a reliable screening method to determine oxygen reduction/evolution reaction activities of 100 Mn-based binary catalysts for the aprotic Li-air battery...
January 26, 2017: ACS Combinatorial Science
Shaik Karamthulla, Asim Jana, Lokman H Choudhury
A simple and novel method for the synthesis of 5,6-disubstituted pyrrolo[2,3-d]pyrimidine-2,4-diones has been reported using arylglyoxal-based three-component reactions. Under microwave heating conditions, arylglyoxal, 6-amino uracil, or its derivatives reacts with various thiols in acetic acid medium to provide a series of pyrrolo[2,3-d]pyrimidine-2,4-diones (4) having a thioether and an aryl ring in 5 and 6 positions, respectively. On the other hand reaction of arylglyoxal, amino uracil and malononitrile in place of thiols, provided corresponding 5,6-disubstituted pyrrolo[2,3-d]pyrimidine-2,4-diones (5) with selectively converting one of the -CN to -CONH2 group both in conventional (method A) and microwave heating conditions (method B)...
January 20, 2017: ACS Combinatorial Science
Deepti Goyal, Suniba Shuaib, Sukhmani Mann, Bhupesh Goyal
Alzheimer's disease (AD) is a progressive neurodegenerative disease with no clinically accepted treatment to cure or halt its progression. The worldwide effort to develop peptide-based inhibitors of amyloid-β (Aβ) aggregation can be considered an unplanned combinatorial experiment. An understanding of what has been done and achieved may advance our understanding of AD pathology and the discovery of effective therapeutic agents. We review here the history of such peptide-based inhibitors, including those based on the Aβ sequence and those not derived from that sequence, containing both natural and unnatural amino acid building blocks...
January 18, 2017: ACS Combinatorial Science
Tarak K Patra, Venkatesh Meenakshisundaram, Jui-Hsiang Hung, David S Simmons
Machine learning has the potential to dramatically accelerate high-throughput approaches to materials design, as demonstrated by successes in biomolecular design and hard materials design. However, in the search for new soft materials exhibiting properties and performance beyond those previously achieved, machine learning approaches are frequently limited by two shortcomings. First, because they are intrinsically interpolative, they are better suited to the optimization of properties within the known range of accessible behavior than to the discovery of new materials with extremal behavior...
January 9, 2017: ACS Combinatorial Science
Shrabani Panigrahi, Daniela Nunes, Tomás Calmeiro, Kasra Kardarian, Rodrigo Martins, Elvira Fortunato
A ZnO/Cu2O-based combinatorial heterojunction device library was successfully fabricated by a simple spray pyrolysis technique using ITO-coated glass as the substrate. The combinatorial approach was introduced to analyze the impact of the ZnO and Cu2O layer thicknesses on the performance of the solar cells. The thickness of the ZnO layer was varied from ∼50 to 320 nm, and the Cu2O layer was deposited orthogonal to the ZnO thickness gradient. In the case of Cu2O, the thickness varied from ∼200 to 800 nm...
January 3, 2017: ACS Combinatorial Science
Ermete Antolini
Combinatorial chemistry and high-throughput screening represent an innovative and rapid tool to prepare and evaluate a large number of new materials, saving time and expense for research and development. Considering that the activity and selectivity of catalysts depend on complex kinetic phenomena, making their development largely empirical in practice, they are prime candidates for combinatorial discovery and optimization. This review presents an overview of recent results of combinatorial screening of low-temperature fuel cell electrocatalysts for methanol oxidation...
January 3, 2017: ACS Combinatorial Science
Petra Bleckenwegner, Cezarina Cela Mardare, Christoph Cobet, Jan Philipp Kollender, Achim Walter Hassel, Andrei Ionut Mardare
Optical bandgap mapping of Nb-Ti mixed oxides anodically grown on a thin film parent metallic combinatorial library was performed via variable angle spectroscopic ellipsometry (VASE). A wide Nb-Ti compositional spread ranging from Nb-90 at.% Ti to Nb-15 at.% Ti deposited by cosputtering was used for this purpose. The Nb-Ti library was stepwise anodized at potentials up to 10 V SHE, and the anodic oxides optical properties were mapped along the Nb-Ti library with 2 at.% resolution. The surface dissimilarities along the Nb-Ti compositional gradient were minimized by tuning the deposition parameters, thus allowing a description of the mixed Nb-Ti oxides based on a single Tauc-Lorentz oscillator for data fitting...
January 3, 2017: ACS Combinatorial Science
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