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ACS Combinatorial Science

Yanbing Han, Bethany E Matthews, Dennice M Roberts, Kevin Talley, Sage Bauers, Craig L Perkins, Qun Zhang, Andriy Zakutayev
High throughput synthesis and characterization methods can significantly accelerate the rate of experimental research. For physical vapor deposition (PVD), high throughput synthesis methods include combinatorial sputtering with intentional gradients of metal/metalloid composition, temperature, and thickness across the substrate. However, many other synthesis parameters still remain out of reach for combinatorial methods. In this paper, we extend combinatorial sputtering parameters to include gradients of gaseous elements in thin films...
May 17, 2018: ACS Combinatorial Science
Naveen Kumar Singh, Babina Chakma, Priyamvada Jain, Pranab Goswami
A novel 90 mer long ssDNA aptamer (NG3) covering a 40 mer random region targeting Plasmodium falciparum glutamate dehydrogenase (PfGDH) was developed through systematic evolution of ligands by exponential enrichment (SELEX) technique. The binding affinity of the aptamer to PfGDH discerned by circular dichroism (CD) was 0.5 ± 0.04 μM. The specificity of the aptamer towards the target was confirmed by gel electrophoresis and CD studies. The presence of two quadruplex forming regions, two big and four small stem loop structures with a δG of -7...
May 3, 2018: ACS Combinatorial Science
Jonas Odgaard Petersen, Katrine Englund Christensen, Mathias Thor Nielsen, Kim Thollund Mortensen, Vitaly Komnatnyy, Thomas Eiland Nielsen, Katrine Qvortrup
Fluorescence labeling of proteins and peptides is fundamental for the study of biological systems, as it can provide detailed visualization of complex molecular mechanisms. This approach has been crucial for our understanding of molecular dynamics and led to the development of new potent drugs. Nowadays, the most common approach to fluorescence labeling compresses introduction of carbo- and heterocyclic molecules to the nucleophilic side chain of lysine, serine, threonine and cysteine in the peptide sequence of interest...
May 2, 2018: ACS Combinatorial Science
Luxi Chen, Chao Long, Jonghae Youn, Jiyong Lee
We describe a "phenotypic cell-binding screen" by which therapeutic candidate targeting cancer cells of a particular phenotype can be isolated without knowledge of drug target(s). Chemical library beads are incubated with cancer cells of the phenotype of interest in the presence of cancer cells lacking the phenotype of interest, and then the beads bound to only cancer cells of the phenotype of interest are selected as hits. We have applied this screening strategy in discovering a novel compound (LC129-8) targeting triple-negative breast cancer (TNBC)...
May 2, 2018: ACS Combinatorial Science
Hannah-Noa Barad, David A Keller, Kevin J Rietwyk, Adam Ginsburg, Shay Tirosh, Simcha Meir, Assaf Y Anderson, Arie Zaban
In this work, we describe the formation of a reduced bandgap CeNiO3 phase, which, to our knowledge, has not been previously reported, and we show how it is utilized as an absorber layer in a photovoltaic cell. The CeNiO3 phase is prepared by a combinatorial materials science approach, where a library containing a continuous compositional spread of Ce x Ni1- x O y is formed by pulsed laser deposition (PLD); a method that has not been used in the past to form Ce-Ni-O materials. The library displays a reduced bandgap throughout, calculated to be 1...
May 2, 2018: ACS Combinatorial Science
Mark L G Borst, Cécile M J Ouairy, Sander C Fokkema, Alessandro Cecchi, Jessica M C A Kerckhoffs, Vincent L de Boer, Peter J van den Boogaard, Rutger F Bus, Rijko Ebens, Rob van der Hulst, Joop Knol, Rob Libbers, Zhou M Lion, Bart W Settels, Ellen de Wever, Khaled A Attia, Piet-Jan Sinnema, Jesse M de Gooijer, Karen Harkema, Marieke Hazewinkel, Susan Snijder, Kees Pouwer
The design and synthesis of three novel and original polycyclic scaffolds containing sulfoximines is presented in this work, showing that sulfoximines represent a real opportunity for the discovery of new drug candidates. Additionally, the structures present at least two points of diversification and contain a high level of sp3-character, hence being very interesting 3D-scaffolds. The compounds synthesized were added to the compound collection of the European Lead Factory.
May 1, 2018: ACS Combinatorial Science
Aizhan Abdildinova, Young-Dae Gong
Solid-phase organic synthesis is a powerful tool in the synthesis of small organic molecules and building of libraries of compounds for drug discovery. Heterocyclic compounds as well are important components of the drug discovery field and serve as a core for hundreds of marketed drugs. In particular, oxadiazole and thiadiazole cores are compounds of great interest, due to their comprehensive biological activities and structural features. Therefore, a plethora of oxadiazole and thiadiazole synthesis methodologies have been reported to date, including solution and solid-phase synthesis methodologies...
May 1, 2018: ACS Combinatorial Science
Golnaz Parhizkar, Ahmad Reza Khosropour, Iraj Mohammadpoor-Baltork, Elahehnaz Parhizkar, Hadi Amiri Rudbari
A versatile and straightforward synthetic strategy for the construction of new four-membered 1,3-diazinones is described. The procedure is based on CsF-catalyzed microwave-assisted ring transformation reaction of arylidene azlactones with amidines. Moreover, this technique provides diversified trans-N-(6-oxo-1,4,5,6-tetrahydropyrimidin-5-yl)benzamides with good antimicrobial activity.
April 24, 2018: ACS Combinatorial Science
Yun Ding, Jing Chai, Paolo A Centrella, Chenaimwoyo Gondo, Jennifer L DeLorey, Matthew A Clark
Encoded library technology (ELT) is an effective approach to the discovery of novel small-molecule ligands for biologi-cal targets. A key factor for the success of the technology is the chemical diversity of the libraries. Here we report the development of DNA-conjugated benzimidazoles. Using 4-fluoro-3-nitrobenzoic acid as a key synthon, we synthesized a 320 million-member DNA-encoded benzimidazole library using Fmoc-protected amino acids, amines and aldehydes as diversity elements. Affinity selection of the library led to the discovery of a novel, potent and specific antagonist of the NK3 receptor...
April 12, 2018: ACS Combinatorial Science
Daniel C Schmitt, Nootaree Niljianskul, Neal W Sach, John I Trujillo
A modular, two-pot assembly of 7-arylpyrazolo[1,5- a]pyrimidones from aryl/heteroaryl halides and aminopyrazoles in library format was developed. Sonogashira coupling of aryl bromides with triethyl orthopropiolate, followed by in situ orthoester hydrolysis, provides access to β-aryl ynoates, which undergo regioselective cyclocondensation with aminopyrazoles. The ability to vary the C7 vector of 7-arylpyrazolo[1,5- a]pyrimidones in two steps using readily available (hetero)aryl halides significantly enhances synthetic access to this challenging vector...
April 6, 2018: ACS Combinatorial Science
Jie Lei, Zhi-Gang Xu, Dianyong Tang, Yong Li, Jia Xu, Hong-Yu Li, Jin Zhu, Zhong-Zhu Chen
Under the acidic conditions, substituted furans were constructed from γ alkynyl ketones through corresponding allene intermediates in one-pot. The methodolgy was also tailored to a series of the Ugi reaction products for the synthesis of 6-methylpyrazin-2(1H)-one derivatives. The current method offered significant advantages for the combinatorial applications of these chemcial scaffolds.
April 5, 2018: ACS Combinatorial Science
Jonathan T Goodman, Adam Mullis, Lucas Dunshee, Akash Mitra, Balaji Narasimhan
The development of high throughput techniques and combinatorial libraries can facilitate rapid synthesis and screening of biomaterial-based nano-carriers for drug and vaccine delivery. This study describes an high throughput method using an automated robot for synthesizing polyanhydride nanoparticles encapsulating proteins. Polyanhydrides are a class of safe and biodegradable polymers that have been widely used as drug and vaccine delivery vehicles. The robot contains a multiplexed homogenizer and has the capacity to handle parallel streams of monomer or polymer solutions to synthesize polymers and/or nanoparticles...
April 4, 2018: ACS Combinatorial Science
Keitou Shu, Thomas Kodadek
One-bead-one-compound (OBOC) libraries constructed by solid-phase split-and-pool synthesis are a valuable source of protein ligands. Most OBOC libraries are comprised of oligoamides, particularly peptides, peptoids and peptoid-inspired molecules. Further diversification of the chemical space covered by OBOC libraries is desirable. Towards this end, we report here the efficient proline-catalyzed asymmetric aldol reaction between immobilized aldehydes and soluble ketones. These reaction conditions do not compromise the amplification of DNA by the polymerase chain reaction...
March 26, 2018: ACS Combinatorial Science
Hyun-Jeong Ryu, Seung-Ju Yang, Gee-Hyung Lee, Young-Dae Gong
A 2-amido benzo[d]imidazole library has been constructed on solid-phase synthesis. The key step of this solid-phase synthesis involves the preparation of polymer-bound 2-amino benzo[d]imidazole resin through desulfurative cyclization of thiourea resin by using DMC and DIPEA in DCM, and the resin is then functionalized by acylation at the 2-amine position, to afford 2-amido benzo[d]imidazole resin. In the case of 2-amido benzo[d]imidazole resin having p-I, and m-NO2, the resin was further functionalized by Suzuki/Sonogashira-coupling (p-I), and was reduced to primary amine (m-NO2), followed by acylation...
March 20, 2018: ACS Combinatorial Science
Rachel Coleman, Darci J Trader
To attenuate an over-abundance of cellular protein, it has been hypothesized that the 20S core particle (20S CP) of the proteasome can be chemically stimulated to degrade proteins into non-toxic peptides more quickly. Screening for small molecule 20S CP stimulators is typically performed with a reporter peptide composed of four amino acids and a coumarin group that is released upon proteasome-mediated hydrolysis to generate a fluorescent signal. Screening with this small reporter can lead to false negatives because the reporter peptide is rapidly turned-over without stimulation...
March 19, 2018: ACS Combinatorial Science
Woo-Ri Shin, Simranjeet Singh Sekhon, Sung-Keun Rhee, Jung Ho Ko, Ji-Young Ahn, Jiho Min, Yang-Hoon Kim
Aptamer-based paper strip sensor for detecting Vibrio fischeri was developed. Our method was based on the aptamer sandwich assay between whole live cells, V. fischeri and DNA aptamer probes. Following 9 rounds of Cell-SELEX and one of the negative-SELEX, V. fischeri Cell Aptamer (VFCA)-02 and -03 were isolated, with the former showing approximately 10-fold greater avidity (in the sub-nanomolar range) for the target cells when arrayed on a surface. The colorimetric response of a paper sensor based on VFCA-02 was linear in the range of 4 × 101 to 4 × 105 CFU/mL of target cell by using scanning reader...
March 19, 2018: ACS Combinatorial Science
Po-Chia Chen, Pawel Masiewicz, Vladimir Rybin, Dmitri Svergun, Janosch Hennig
We present a screening protocol utilizing small-angle X-ray scattering (SAXS) to obtain structural information on biomolecular interactions independent of prior knowledge, so as to complement affinity-based screening and provide leads for further exploration. This protocol categorizes ligand titrations by computing pairwise agreement between curves, and separately estimates affinities by quantifying complex formation as a departure from the linear sum properties of solution SAXS. The protocol is validated by sparse sequence search around the native poly uridine RNA motifs of the two-RRM domain Sex-lethal protein (Sxl)...
April 9, 2018: ACS Combinatorial Science
Hajo Meyer, Michael Meischein, Alfred Ludwig
A high-throughput method is presented for the efficient assessment of the formation and stability of nanoparticle suspensions in ionic liquids which differ in their cations and anions. As a proof of principle, Ag was sputtered on a cavity array filled with 9 different ionic liquids. Not all nanoparticle ionic liquid combinations form a stable suspension with separated nanoparticles. Directly after synthesis, the formation of nonagglomerated nanoparticle suspensions with sizes from 4 to 9 nm is observed by transmission electron microscopy as well as different time dependencies of the suspension stabilities...
April 9, 2018: ACS Combinatorial Science
Xiao Wang, Detlef Rogalla, Alfred Ludwig
The mechanical stress change of VO2 film substrate combinations during their reversible phase transformation makes them promising for applications in micro/nanoactuators. V1- x W x O2 thin film libraries were fabricated by reactive combinatorial cosputtering to investigate the effects of the addition of W on mechanical and other transformation properties. High-throughput characterization methods were used to systematically determine the composition spread, crystalline structure, surface topography, as well as the temperature-dependent phase transformation properties, that is, the hysteresis curves of the resistance and stress change...
April 9, 2018: ACS Combinatorial Science
I Ayelen Ramallo, Victoria L Alonso, Federico Rua, Esteban Serra, Ricardo L E Furlan
A set of chemically engineered extracts enriched in compounds including N-N and N-O fragments in their structures was prepared. Bromodomain binding screening and bioguided fractionation led to the identification of one oxime hit that interacts with TcBDF3 with affinity in the submicromolar range and that shows interesting antiparasitic properties against the different life cycle stages of T. cruzi.
April 9, 2018: ACS Combinatorial Science
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