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ACS Combinatorial Science

Rintaro Iwata Hara, Yuta Mitsuhashi, Keita Saito, Yuske Maeda, Takeshi Wada
Peptides are still difficult to synthesize when they contain sterically hindered amino acids such as α,α-di-substituted amino acids and N-substituted amino acids. In this study, solid-phase syntheses of oligopeptides containing multiple α-aminoisobutyric acid (Aib) residues were performed in high yields by using a non-swellable resin as the solid-support and 3-nitro-1,2,4-triazol-1-yl-tris(pyrrolidin-1-yl)phosphonium hexafluorophosphate (PyNTP) as the condensing reagent.
January 17, 2018: ACS Combinatorial Science
Mladena Glavaš, Matija Gredičak, Ivanka Jeric
Multicomponent reactions represent a highly efficient approach to a broad spectrum of structurally diverse compounds starting from simple and affordable compounds. A focused library of tweezers-like compounds is prepared by employing the multicomponent Passerini reaction comprising enediyne-derived amino aldehydes. The reaction proceeds under mild conditions yielding Passerini products in good to excellent yields. Post-condensation modifications of Passerini products are demonstrated through a simple deprotection/coupling approach comprising amino functionality, furnishing enediyne cores with highly decorated arms...
January 17, 2018: ACS Combinatorial Science
Giulia Rainoldi, Fabio Begnini, Mariska De Munnik, Leonardo Lo Presti, Christophe M L Vande Velde, Romano V A Orru, Giordano Lesma, Eelco Ruijter, Alessandra Silvani
We developed two Ugi-type three-component reactions of spirooxindole-fused 3-thiazolines, isocyanides and either carboxylic acids or trimethylsilylazide, to give highly functionalized spirooxindole-fused thiazolidines. Two diverse libraries were generated using practical and robust procedures affording the products in typically good yields. The obtained thiazolidines proved to be suitable substrates for further transformations. Notably, both the Ugi-Joullié and the azido-Ugi reactions resulted highly diastereoselective, affording predominantly the trans-configured products, as confirmed by X-ray crystallographic analysis...
January 11, 2018: ACS Combinatorial Science
Nam Tran Hoang, 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 Mannich reaction between immobilized aldehydes and soluble ketones and anilines. The reaction conditions do not compromise the amplification of DNA by the PCR...
January 9, 2018: ACS Combinatorial Science
Ji-Eun Ha, Seung-Ju Yang, Young-Dae Gong
An efficient solid-phase synthetic route for construction of 1,3,4-oxadiazole and 1,3,4-thiadiazole library based on branching diversity-oriented synthesis (DOS) has been developed in this study. The core skeleton resins, 1,3,4-Oxadiazole and 1,3,4-thiadiazole, were obtained through desulfurative and dehydrative cyclizations of thiosemicarbazide resin, respectively. Various functional groups have been introduced to the core skeleton resins such as aryl, amine, amide, urea, thiourea, and an amino acid. Most of the library was purified by simple trituration without extraction, and column chromatography after cleavage of the products from solid-supported resin...
January 8, 2018: ACS Combinatorial Science
Kevin Pels, Paige Dickson, Hongchan An, Thomas Kodadek
We demonstrate that the Knoevenagel condensation can be exploited in combinatorial synthesis on the solid phase. Condensation products from such reactions were structurally characterized, and their Michael reactivity with thiol and phosphine nucleophiles is described. Cyanoacrylamides were previously reported to react reversibly with thiols, and notably, we show that dilution into low pH buffer can trap covalent adducts which are isolable via chromatography. Finally, we synthesized both traditional and DNA-encoded one-bead, one-compound libraries containing cyanoacrylamides as a source of cysteine-reactive, reversibly covalent protein ligands...
January 3, 2018: ACS Combinatorial Science
Stephen J Barigye, Matheus P Freitas, Priscila Ausina, Patricia Zancan, Mauro Sola-Penna, Juan Alberto Castillo-Garit
We have recently generalized the formerly alignment-dependent MIA-QSAR (acronym for Multivariate Image Analysis applied to Quantitative Structure Activity Relationships) method through the application of the Discrete Fourier Transform (DFT), allowing for its application to non-congruent and structurally diverse chemical compound datasets. Here, we report the first practical application of this method in the screening of molecular entities of therapeutic interest, with the human aromatase inhibitory activity as the case study...
January 3, 2018: ACS Combinatorial Science
Tulsi Ram Damase, Tanya A Miura, Christine E Parent, Peter B Allen
The low-cost Open qPCR instrument can be used for different tasks in the aptamer selection process: quantification of DNA, cyclecourse optimization, screening and final binding characterization. We have selected aptamers against whole Drosophila C virus (DCV) particles and recombinant Epidermal Growth Factor Receptor (EGFR). We performed systematic evolution of ligands by exponential enrichment (SELEX) using the Open qPCR to optimize each amplification step. The Open qPCR instrument identified the best aptamer candidate...
January 2, 2018: ACS Combinatorial Science
Pawel Ziolkowski, Matthias Wambach, Alfred Ludwig, Eckhard Mueller
In view of the variety and complexity of thermoelectric (TE) material systems, combinatorial approaches to materials development come to the fore for identifying new promising compounds. The success of this approach is related to the availability and reliability of high-throughput characterization methods for identifying interrelations between materials structures and properties within the composition spread libraries. A meaningful characterization starts with determination of the Seebeck coefficient as a major feature of TE materials...
December 21, 2017: ACS Combinatorial Science
Andrey Bogolubsky, Yurii S Moroz, Olena Savych, Sergey Pipko, Angelika Konovets, Maxim O Platonov, Oleksandr V Vasylchenko, Vasyl V Hurmach, Oleksandr O Grygorenko
An approach to the parallel synthesis of hydantoin libraries by reaction of in situ generated 2,2,2-trifluoroethylcarbamates and α-amino esters was developed. To demonstrate utility of the method, a library of 1158 hydantoins designed according to the lead-likeness criteria (MW 200…350, cLogP -1…3) was prepared. The success rate of the method was analyzed as a function of physico-chemical parameters of the products, and it was found that the method can be considered as a tool for lead-oriented synthesis...
December 11, 2017: ACS Combinatorial Science
Fahime Rahmani, Iraj Mohammadpoor-Baltork, Ahmad Reza Khosropour, Majid Moghadam, Shahram Tangestaninejad, Valiollah Mirkhani
In this article, we report an efficient synthesis of 1,3-dimethyl-5-aryl-7-(pyridine-3(2)(4)-yl)pyrimidine-2,4(1H,3H)-diones via a three-component reaction of aryl aldehydes, 1,3-dimethyl-6-aminouracil and carbonitriles in the presences of triazine diphosphonium hydrogen sulfate ionic liquid supported on functionalized nano-silica (APTADPHS-nSiO2) as a reusable catalyst under microwave irradiation and solvent-free conditions. The bis-derivatives of pyridine-pyrimidines were also efficiently prepared from dialdehydes and dinitriles...
December 7, 2017: ACS Combinatorial Science
Pravin Patil, Bhupendra Mishra, Gitanjali Sheombarsing, Katarzyna Kurpiewska, Justyna Kalinowska-Tłuścik, Alexander Dömling
Recently made accessible α-aminomethyl tetrazoles are excellent starting materials for a further Ugi MCR of high diversity, yielding substituted N-methyl-2-(((1-methyl-1H-tetrazol-5-yl)methyl)amino)acetamides in a library-2-library approach. In detail, we report scope and limitations of the 2-step reaction sequence based on >50 reactions. The target scaffold has four points of diversity and will find applications to fill screening decks for HTS and in structure-based drug design.
December 7, 2017: ACS Combinatorial Science
Santosh K Suram, Sean Fackler, Lan Zhou, Alpha T N'Diaye, Walter S Drisdell, Junko Yano, John M Gregoire
Oxynitrides with the photoelectrochemical stability of oxides and desirable band energetics of nitrides comprise a promising class of materials for solar photochemistry. Challenges in synthesizing a wide variety of oxynitride materials has limited exploration of this class of functional materials, which we address using a reactive co-sputtering combined with rapid thermal processing method to synthesize multi-cation-multi-anion libraries. We demonstrate the synthesis of a LaxTa1-xOyNz thin film composition spread library and its characterization by both traditional thin film materials characterization and custom combinatorial optical spectroscopy and X-ray Absorption Near Edge Spectroscopy (XANES) techniques, ultimately establishing structure-chemistry-property relationships...
November 27, 2017: ACS Combinatorial Science
James M Song, Arya Menon, Dylan C Mitchell, Oleta T Johnson, Amanda L Garner
Human biology is regulated by a complex network of protein-protein interactions (PPIs), and disruption of this network has been implicated in many diseases. However, the targeting of PPIs remains a challenging area for chemical probe and drug discovery. Although many methodologies have been put forth to facilitate these efforts, new technologies are still needed. Current biochemical assays for PPIs are typically limited to motif-domain and domain-domain interactions, and assays that will enable the screening of full-length protein systems, which are more biologically relevant, are sparse...
November 14, 2017: ACS Combinatorial Science
Elana Borvick, Assaf Y Anderson, Hannah-Noa Barad, Maayan Priel, David A Keller, Adam Ginsburg, Kevin J Rietwyk, Simcha Meir, Arie Zaban
Data mining tools have been known to be useful for analyzing large material data sets generated by high-throughput methods. Typically, the descriptors used for the analysis are structural descriptors, which can be difficult to obtain and to tune according to the results of the analysis. In this Research Article, we show the use of deposition process parameters as descriptors for analysis of a photovoltaics data set. To create a data set, solar cell libraries were fabricated using iron oxide as the absorber layer deposited using different deposition parameters, and the photovoltaic performance was measured...
November 9, 2017: ACS Combinatorial Science
Anne C Schneider, Daniel Fritz, Joseph K Vasquez, Sidonie B L Vollrath, Helen E Blackwell, Stefan Bräse
With microwave irradiation, the submonomer synthesis of dipeptoids on functionalized cellulose can be accelerated with good yields and purity. Optimization provided a library of 96 dipeptoids. From these, 29 compounds were found with an antibacterial activity against MRSA at a concentration of 25 μM. Large nonpolar residues, such as undecylamine and dehydroabiethylamine, are the key components engendering the observed antibacterial activity of these peptoids.
November 7, 2017: ACS Combinatorial Science
Hyo-Jeong Yoon, Seung-Ju Yang, Young-Dae Gong
2-Alkoxy/thioalkoxy benzo[d]imidazole and 2-thione benzo[d]imidazole library were constructed in solution-phase and on solid-phase, respectively. The key step in this work is reaction phase-based chemo-selective reaction of 2-mercapto benzo[d]imidazole intermediate with benzyl chloride (solution-phase) and Merrifield resin (solid-phase). In the case of solution-phase, benzyl chloride reacted with thiol group of 2-mercapto benzo[d]imidazole whereas, in the case of solid-phase, Merrifield resin was introduced at internal amine group of benzo[d]imidazole...
November 2, 2017: ACS Combinatorial Science
Hao Li, Wei Sun, Xiuli Huang, Xiao Lu, Paresma R Patel, Myunghoon Kim, Meghan J Orr, Richard M Fisher, Takeshi Q Tanaka, John C McKew, Anton Simeonov, Philip E Sanderson, Wei Zheng, Kim C Williamson, Wenwei Huang
A novel three-component, two-step, one-pot nucleophilic aromatic substitution (SNAr)-intramolecular cyclization-Suzuki coupling reaction was developed for the synthesis of benzo[h][1,6]naphthyridin-2(1H)-ones (Torins). On the basis of the new efficiently convergent synthetic route, a library of Torin analogs was synthesized. The antimalarial activities of these compounds were evaluated against asexual parasites using a growth inhibition assay and gametocytes using a viability assay.
October 27, 2017: ACS Combinatorial Science
Anastasia Lepikhina, Dmitry Dar'in, Olga Bakulina, Evgeny Chupakhin, Mikhail Krasavin
A new format for the Castagnoli-Cushman reaction of structurally diverse dicarboxylic acids, amines, and aldehydes in the presence of acetic anhydride as dehydrating agent is described. The reaction is distinctly amenable to parallel format: the combinatorial array of 180 reactions delivered 157 products of >85% purity without chromatographic purification (of this number, 143 compounds had >94% purity). The new method offers a convenient preparation of the skeletally and peripherally diverse, lead- and druglike γ- and δ-lactam carboxylic acids with high diastereoselectivity in combinatorial fashion...
October 26, 2017: ACS Combinatorial Science
Akshay A Shah, Lois K Chenard, Joseph W Tucker, Christopher J Helal
A novel parallel medicinal chemistry (PMC)-enabled synthesis of 1H-pyrazolo[3,4-d]pyrimidines employing condensation of easily accessible N-pyrazolylamides and nitriles has been developed. The presented studies describe singleton and library enablements that allowed rapid generation of molecular diversity to examine C4 and C6 vectors. This chemistry enabled access to challenging alkyl substituents, expanding the overall chemical space beyond that available via typical C(sp(2))-C(sp(2)) coupling and SNAr transformations...
October 20, 2017: ACS Combinatorial Science
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