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Dynamic combinatorial chemistry

Jalal Soubhye, Michel Gelbcke, Pierre Van Antwerpen, François Dufrasne, Mokhtaria Yasmina Boufadi, Jean Nève, Paul G Furtmüller, Christian Obinger, Karim Zouaoui Boudjeltia, Franck Meyer
The implementation of dynamic combinatorial libraries allowed the determination of highly active reversible and irreversible inhibitors of myeloperoxidase (MPO) at the nanomolar level. Docking experiments highlighted the interaction between the most active ligands and MPO, and further kinetic studies defined the mode of inhibition of these compounds. Finally, in vivo evaluation showed that one dose of irreversible inhibitors is able to suppress the activity of MPO after inducing inflammation.
February 9, 2017: ACS Medicinal Chemistry Letters
Zeynep Kanlidere, Oleg Jochim, Marta Cal, Ulf Diederichsen
Dynamic combinatorial chemistry (DCC) is an attractive method to efficiently generate libraries of molecules from simpler building blocks by reversible reactions under thermodynamic control. Here we focus on the chemical modification of DNA oligonucleotides with acyclic diol linkers and demonstrate their potential for the deoxyribonucleic acid functionalization and generation of libraries of reversibly interconverting building blocks. The syntheses of phosphoramidite building blocks derived from D-threoninol are presented in two variants with protected amino or thiol groups...
2016: Beilstein Journal of Organic Chemistry
Helen M Seifert, Karina Ramirez Trejo, Eric V Anslyn
Dynamic covalent reactions are widely used in dynamic combinatorial chemistry. Most of these reactions are run under differing reaction conditions and exhibit cross-reactivity when components of multiple reactions are present in one reaction vessel. Herein, we report the study of four dynamic covalent reactions that react reversibly under identical reaction conditions and do not exhibit any cross-reactivity. Dynamic behavior was shown via (1)H NMR based exchange experiments. Computational deconvolution of (1)H NMR spectra containing the components for more than one of the orthogonal reactions allowed for a semiquantitative analysis of the complex mixtures formed, showing that the reactions proceed independently of each other...
August 31, 2016: Journal of the American Chemical Society
Renjie Huang, Ivanhoe K H Leung
Protein-directed dynamic combinatorial chemistry is an emerging technique for efficient discovery of novel chemical structures for binding to a target protein. Typically, this method relies on a library of small molecules that react reversibly with each other to generate a combinatorial library. The components in the combinatorial library are at equilibrium with each other under thermodynamic control. When a protein is added to the equilibrium mixture, and if the protein interacts with any components of the combinatorial library, the position of the equilibrium will shift and those components that interact with the protein will be amplified, which can then be identified by a suitable biophysical technique...
July 16, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Milon Mondal, Nedyalka Radeva, Hugo Fanlo-Virgós, Sijbren Otto, Gerhard Klebe, Anna K H Hirsch
Fragment-based drug design (FBDD) affords active compounds for biological targets. While there are numerous reports on FBDD by fragment growing/optimization, fragment linking has rarely been reported. Dynamic combinatorial chemistry (DCC) has become a powerful hit-identification strategy for biological targets. We report the synergistic combination of fragment linking and DCC to identify inhibitors of the aspartic protease endothiapepsin. Based on X-ray crystal structures of endothiapepsin in complex with fragments, we designed a library of bis-acylhydrazones and used DCC to identify potent inhibitors...
August 1, 2016: Angewandte Chemie
Ping Gao, Lin Sun, Junsu Zhou, Xiao Li, Peng Zhan, Xinyong Liu
INTRODUCTION: In recent years, a variety of new synthetic methodologies and concepts have been proposed in the search for new pharmaceutical lead structures and optimization. Notably, the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry approach has drawn great attention and has become a powerful tool for the generation of privileged medicinal skeletons in the discovery of anti-HIV agents. This is due to the high degree of reliability, complete specificity (chemoselectivity and regioselectivity), mild conditions, and the biocompatibility of the reactants...
September 2016: Expert Opinion on Drug Discovery
Mee-Kyung Chung, Stephen J Lee, Marcey L Waters, Michel R Gagné
This paper reports the binding properties of tetrameric pseudo-peptide receptors for protonated cytidines. The receptors, which were isolated from a dynamic combinatorial chemistry (DCC) experiment, bind the analytes with affinities that depend on the presence or absence of excess acid, and with a stoichiometry that is both concentration and temperature dependent.
June 21, 2016: Chemical Communications: Chem Comm
A Gastón Orrillo, Andrea M Escalante, Ricardo L E Furlan
Reversibility of dithioacetal bond formation is reported under acidic mild conditions. Its utility for dynamic combinatorial chemistry was explored by combining it with orthogonal disulfide exchange. In such a setup, thiols are positioned at the intersection of both chemistries, constituting a connecting node between temporally separated networks.
May 10, 2016: Chemistry: a European Journal
John D McAnany, John P Reichert, Benjamin L Miller
Dynamic Combinatorial Chemistry (DCC) has proven to be a reliable method for identifying hit compounds for target nucleic acid (DNA and RNA) sequences. Typically, these hit compounds are subjected to a lengthy process of optimization via traditional medicinal chemistry. Here, we examine the potential of DCC to also generate and test variations on a hit compound as a method for probing the binding site of an RNA-targeted compound. Specifically, we demonstrate that addition of linker dithiols to a disulfide library containing a known binder to the HIV-1 frameshift-stimulatory RNA (a critical regulator of the HIV life cycle) can yield a mixture of new bridged structures incorporating the dithiol, depending on dithiol structure...
September 1, 2016: Bioorganic & Medicinal Chemistry
Zhao Yang, Zheng Fang, Wei He, Zhixiang Wang, Haifeng Gan, Qitao Tian, Kai Guo
The novel analysis method consisting of size-exclusion chromatography (SEC) and HRMS analysis was firstly applied in the discovery of potential inhibitors towards cancer drug targets. With vascular endothelial growth factor receptor (VEGFR-2) as a target, dynamic combinatorial libraries (DCLs) were prepared by reacting aldehydes with amines. Four sensitive binders targeted VEGFR-2 were directly isolated from the library. Antitumor activity test in vitro and inhibition experiments toward angiogenesis were also carried out...
April 1, 2016: Bioorganic & Medicinal Chemistry Letters
Yihang Wu, Linxian Li, Qing Chen, Yi Su, Pavel A Levkin, Gary Davidson
Cationic lipid-like molecules (lipidoids) are widely used for in vitro and in vivo gene delivery. Nearly all lipidoids developed to date employ double-tail or multiple-tail structures for transfection. Single-tail lipidoids are seldom considered for transfection as they have low efficiency in gene delivery. So far, there is no detailed study on the contribution to transfection efficiency of single-tail lipidoids when combined with standard double-tail lipidoids. Here, we use combinatorial chemistry to synthesize 17 double-tail and 17 single-tail lipidoids using thiol-yne and thiol-ene click chemistry, respectively...
January 11, 2016: ACS Combinatorial Science
Leticia Monjas, Anna K H Hirsch
No abstract text is available yet for this article.
2015: Future Medicinal Chemistry
Jingwei Li, Stephen A Pearson, Kevin D Fenk, J A Cowan
Halide salts of alkali and alkaline earth metals were used to probe the contributions of intramolecular salt bridge formation on the stability of glutathione-coordinated [2Fe-2S] cluster toward hydrolysis. The effect of ionic strength on cluster stability was quantitatively investigated by application of Debye-Hückel theory to the rates of hydrolysis. Results from this study demonstrate that ionic strength influences the stability of the cluster, with the rate of cluster degradation depending on the charge density, hydrated ionic radius, and hydration energy...
December 2015: Journal of Biological Inorganic Chemistry: JBIC
Nicholas K Pinkin, Amanie N Power, Marcey L Waters
Small molecule receptors are attractive potential sensors of post-translational modifications, including methylated lysine and methylated arginine. Using dynamic combinatorial chemistry (DCC), our lab previously identified a suite of receptors that bind to Kme3 with a range of affinities ranging from low micromolar to high nanomolar, each with a unique selectivity for Kme3 over the lower methylation states. To enable these receptors to have broad application as Kme3 sensors, we have developed a method for their late-stage modification, which we used to synthesize biotinylated derivatives of A2B, A2D, and A2G in a single step...
November 28, 2015: Organic & Biomolecular Chemistry
Sanna L Diemer, Morten Kristensen, Brian Rasmussen, Sophie R Beeren, Michael Pittelkow
Dynamic combinatorial chemistry has emerged as a promising tool for the discovery of complex receptors in supramolecular chemistry. At the heart of dynamic combinatorial chemistry are the reversible reactions that enable the exchange of building blocks between library members in dynamic combinatorial libraries (DCLs) ensuring thermodynamic control over the system. If more than one reversible reaction operates in a single dynamic combinatorial library, the complexity of the system increases dramatically, and so does its possible applications...
2015: International Journal of Molecular Sciences
Boshi Huang, Dongwei Kang, Peng Zhan, Xinyong Liu
INTRODUCTION: The search for additional drugs to treat HIV infection is a continuing effort due to the emergence and spread of HIV strains resistant to nearly all current drugs. The recent literature reveals that fragment-based drug design/discovery (FBDD) has become an effective alternative to conventional high-throughput screening strategies for drug discovery. AREAS COVERED: In this critical review, the authors describe the state of the art in FBDD strategies for the discovery of anti-HIV drug-like compounds...
December 2015: Expert Opinion on Drug Discovery
Sirinan Kulchat, Jean-Marie Lehn
Dynamic covalent libraries (DCLs) of quaternary ammonium cations were set up by reversible nucleophilic substitution (S(N)2' and S(N)2) exchange reactions of ammonium salts and tertiary amines. The reactions were conducted at 60 °C to generate thermodynamically and kinetically controlled mixtures of quaternary ammonium compounds and tertiary amines, and were accelerated by using iodide as a nucleophilic catalyst. Microwave irradiation was used to assist the exchange reaction between the pyridinium salts and pyridine derivatives...
November 2015: Chemistry, An Asian Journal
Wojciech Drożdż, Michał Kołodziejski, Grzegorz Markiewicz, Anna Jenczak, Artur R Stefankiewicz
We describe here the generation of new donor-acceptor disulfide architectures obtained in aqueous solution at physiological pH. The application of a dynamic combinatorial chemistry approach allowed us to generate a large number of new disulfide macrocyclic architectures together with a new type of [2]catenanes consisting of four distinct components. Up to fifteen types of structurally-distinct dynamic architectures have been generated through one-pot disulfide exchange reactions between four thiol-functionalized aqueous components...
2015: International Journal of Molecular Sciences
Vera Vasas, Chrisantha Fernando, András Szilágyi, István Zachár, Mauro Santos, Eörs Szathmáry
While it is generally agreed that some kind of replicating non-living compounds were the precursors of life, there is much debate over their possible chemical nature. Metabolism-first approaches propose that mutually catalytic sets of simple organic molecules could be capable of self-replication and rudimentary chemical evolution. In particular, the graded autocatalysis replication domain (GARD) model, depicting assemblies of amphiphilic molecules, has received considerable interest. The system propagates compositional information across generations and is suggested to be a target of natural selection...
September 21, 2015: Journal of Theoretical Biology
Marie Tani, Ryuji Kawano, Koki Kamiya, Ko Okumura
In chemistry, biology, medical sciences and pharmaceutical industries, many reactions have to be checked by transporting and mixing expensive liquids. For such purposes, microfluidics systems consisting of closed channels with external pumps have been useful. However, the usage has been limited because of high fabrication cost and need for a fixed setup. Here, we show that open-capillary channels, which can be fabricated outside a clean room on durable substrates and are washable and reusable, are considerably promising for micro-devices that function without pumps, as a result of detailed studies on the imbibition of open micro-channels...
2015: Scientific Reports
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