Click Here for Better Chemistry.
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ABSTRACT:
SUBMITTER: Zeglis BM
PROVIDER: S-EPMC10501737 | biostudies-literature | 2022 Dec
REPOSITORIES: biostudies-literature
Publications
Click Here for Better Chemistry.
Zeglis Brian M BM Lewis Jason S JS
The New England journal of medicine 20221130 24
Similar Datasets
Project description:The success of targeted therapies hinges on our ability to understand the molecular and cellular mechanism of action of these agents. Here we modify various BET bromodomain inhibitors, an exemplar novel targeted therapy, to create functionally conserved compounds that are amenable to click-chemistry and can be used as molecular probes in vitro and in vivo. Using click-proteomics and click-sequencing we provide new mechanistic insights to explain the gene regulatory function of BRD4 and the transcriptional changes invoked by BET inhibitors. In mouse models of acute leukaemia, we use high resolution microscopy and flow cytometry to highlight the underappreciated heterogeneity of drug activity within tumour cells located in different tissue compartments. We also demonstrate the differential distribution and effects of the drug in normal and malignant cells in vivo. These data provide critical insights that reveal the cellular and molecular details for the efficacy and limitations of these agents. This study provides a framework for the pre-clinical assessment of other conventional and targeted therapies.
2017-07-13 | GSE88748 | GEO
Project description:The success of targeted therapies hinges on our ability to understand the molecular and cellular mechanism of action of these agents. Here we modify various BET bromodomain inhibitors, an exemplar novel targeted therapy, to create functionally conserved compounds that are amenable to click-chemistry and can be used as molecular probes in vitro and in vivo. Using click-proteomics and click-sequencing we provide new mechanistic insights to explain the gene regulatory function of BRD4 and the transcriptional changes invoked by BET inhibitors. In mouse models of acute leukaemia, we use high resolution microscopy and flow cytometry to highlight the underappreciated heterogeneity of drug activity within tumour cells located in different tissue compartments. We also demonstrate the differential distribution and effects of the drug in normal and malignant cells in vivo. These data provide critical insights that reveal the cellular and molecular details for the efficacy and limitations of these agents. This study provides a framework for the pre-clinical assessment of other conventional and targeted therapies.
2017-07-13 | GSE88749 | GEO
Project description:Academic researchers and many in industry often lack the financial resources available to scientists working in "big pharma." High costs include those associated with high-throughput screening and chemical synthesis. In order to address these challenges, many researchers have in part turned to alternate methodologies. Virtual screening, for example, often substitutes for high-throughput screening, and click chemistry ensures that chemical synthesis is fast, cheap, and comparatively easy. Though both in silico screening and click chemistry seek to make drug discovery more feasible, it is not yet routine to couple these two methodologies. We here present a novel computer algorithm, called AutoClickChem, capable of performing many click-chemistry reactions in silico. AutoClickChem can be used to produce large combinatorial libraries of compound models for use in virtual screens. As the compounds of these libraries are constructed according to the reactions of click chemistry, they can be easily synthesized for subsequent testing in biochemical assays. Additionally, in silico modeling of click-chemistry products may prove useful in rational drug design and drug optimization. AutoClickChem is based on the pymolecule toolbox, a framework that may facilitate the development of future python-based programs that require the manipulation of molecular models. Both the pymolecule toolbox and AutoClickChem are released under the GNU General Public License version 3 and are available for download from http://autoclickchem.ucsd.edu.
| S-EPMC3305364 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2017-07-13 | GSE88751 | GEO
Project description:The advent of click chemistry has had a profound influence on almost all branches of chemical science. This is particularly true of radiochemistry and the synthesis of agents for positron emission tomography (PET), single photon emission computed tomography (SPECT), and targeted radiotherapy. The selectivity, ease, rapidity, and modularity of click ligations make them nearly ideally suited for the construction of radiotracers, a process that often involves working with biomolecules in aqueous conditions with inexorably decaying radioisotopes. In the following pages, our goal is to provide a broad overview of the first 10 years of research at the intersection of click chemistry and radiochemistry. The discussion will focus on four areas that we believe underscore the critical advantages provided by click chemistry: (i) the use of prosthetic groups for radiolabeling reactions, (ii) the creation of coordination scaffolds for radiometals, (iii) the site-specific radiolabeling of proteins and peptides, and (iv) the development of strategies for in vivo pretargeting. Particular emphasis will be placed on the four most prevalent click reactions-the Cu-catalyzed azide-alkyne cycloaddition (CuAAC), the strain-promoted azide-alkyne cycloaddition (SPAAC), the inverse electron demand Diels-Alder reaction (IEDDA), and the Staudinger ligation-although less well-known click ligations will be discussed as well. Ultimately, it is our hope that this review will not only serve to educate readers but will also act as a springboard, inspiring synthetic chemists and radiochemists alike to harness click chemistry in even more innovative and ambitious ways as we embark upon the second decade of this fruitful collaboration.
| S-EPMC5193009 | biostudies-other
Project description:Click chemistry has been established rapidly as one of the most valuable methods for the chemical transformation of complex molecules. Due to the rapid rates, clean conversions to the products, and compatibility of the reagents and reaction conditions even in complex settings, it has found applications in many molecule-oriented disciplines. From the vast landscape of click reactions, approaches have emerged in the past decade centered around oxidative processes to generate in situ highly reactive synthons from dormant functionalities. These approaches have led to some of the fastest click reactions know to date. Here, we review the various methods that can be used for such oxidation-induced "one-pot" click chemistry for the transformation of small molecules, materials, and biomolecules. A comprehensive overview is provided of oxidation conditions that induce a click reaction, and oxidation conditions are orthogonal to other click reactions so that sequential "click-oxidation-click" derivatization of molecules can be performed in one pot. Our review of the relevant literature shows that this strategy is emerging as a powerful approach for the preparation of high-performance materials and the generation of complex biomolecules. As such, we expect that oxidation-induced "one-pot" click chemistry will widen in scope substantially in the forthcoming years.
| S-EPMC8227495 | biostudies-literature
Project description:The copper-catalyzed azide alkyne cycloaddition is employed to modify phosphatidylcholine precursors with sn-2 acyl chains containing terminal alkyne or azide groups. Although the reactions are conducted as biphasic dispersions, the yields are essentially quantitative. Bolaamphiphiles are formed by simply clicking together two phosphatidylcholine alkyne precursors to a central bisazide scaffold. The chemistry introduces polar 1,4-triazole units into the lipophilic region of the bilayer membrane, and the bolaamphiphiles do not form stable vesicles. [structure: see text].
| S-EPMC2851100 | biostudies-literature
Project description:Histone deacetylase inhibitors (HDACi) are a relatively new class of chemotherapy agents. Herein, we report a click-chemistry based approach to the synthesis of HDACi. Fourteen agents were synthesized from the combination of two alkyne and seven azido precursors. The inhibition of HDAC1 and HDAC8 was then determined by in vitro enzymatic assays, after which the cytotoxicity was evaluated in the NCI human cancer cell line screen. A lead compound 5 g (NSC746457) was discovered that inhibited HDAC1 at an IC(50) value of 104 +/- 30 nM and proved quite potent in the cancer cell line screen with GI(50) values ranging from 3.92 microM to 10 nM. Thus, this click HDACi design has provided a new chemical scaffold that has not only revealed a lead compound, but one which is easily amendable to further structural modifications given the modular nature of this approach.
| S-EPMC3441833 | biostudies-literature
Project description:Click chemistry is perhaps the most powerful synthetic toolbox that can efficiently access the molecular diversity and unique functions of complex natural products up to now. It enables the ready synthesis of diverse sets of natural product derivatives either for the optimization of their drawbacks or for the construction of natural product-like drug screening libraries. This paper showcases the state-of-the-art development of click chemistry in natural product modification and summarizes the pharmacological activities of the active derivatives as well as the mechanism of action. The aim of this paper is to gain a deep understanding of the fruitful achievements and to provide perspectives, trends, and directions regarding further research in natural product medicinal chemistry.
| S-EPMC8635925 | biostudies-literature
Project description: Not available
| S-EPMC3210829 | biostudies-literature