Browse
Submit Data
Databases
API
Help

Dataset Information

15 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Flash chemistry enables high productivity metalation-substitution of 5-alkyltetrazoles† † Electronic supplementary information (ESI) available. CCDC 2088099. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d1sc04176b

ABSTRACT: Tetrazoles play a prominent role in medicinal chemistry due to their role as carboxylate bioisosteres but have largely been overlooked as C–H functionalisation substrates. We herein report the development of a high-yielding and general procedure for the heterobenzylic C–H functionalisation of 5-alkyltetrazoles in up to 97% yield under batch conditions using a metalation/electrophilic trapping strategy. Through the use of thermal imaging to identify potentially unsafe exotherms, a continuous flow procedure using a flash chemistry strategy has also been developed, allowing products to be accessed in up to 95% yield. This enabled an extremely high productivity rate of 141 g h−1 to be achieved on an entry-level flow system. We report a α-metalation-substitution of readily deprotected 5-alkyltetrazoles under batch and continuous flow conditions. In flow, thermal imaging enabled identification of an unsafe exotherm and optimisation of a productivity rate of 141 g h−1.

SUBMITTER: Wong J

PROVIDER: S-EPMC8528014 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Metalation: nature's challenge in bioinorganic chemistry.

Project description:The association of proteins with metals, metalation, is challenging because the tightest binding metals are rarely the correct ones. Inside cells, correct metalation is enabled by controlled bioavailability plus extra mechanisms for tricky combinations such as iron and manganese.

| S-EPMC7239837 | biostudies-literature

Organomagnesium Based Flash Chemistry: Continuous Flow Generation and Utilization of Halomethylmagnesium Intermediates.

Project description:The generation of highly unstable chloromethylmagnesium chloride in a continuous flow reactor and its reaction with aldehydes and ketones is reported. With this strategy, chlorohydrins and epoxides were synthesized within a total residence time of only 2.6 s. The outcome of the reaction can be tuned by simply using either a basic or an acidic quench. Very good to excellent isolated yields, up to 97%, have been obtained for most cases (30 examples).

| S-EPMC7586391 | biostudies-literature

Click chemistry enables comprehensive preclinical evaluation of targeted epigenetic therapies

Project description:This SuperSeries is composed of the SubSeries listed below.

2017-07-13 | GSE88751 | GEO

Reactive polymer enables efficient in vivo bioorthogonal chemistry.

Project description:There has been intense interest in the development of selective bioorthogonal reactions or "click" chemistry that can proceed in live animals. Until now however, most reactions still require vast surpluses of reactants because of steep temporal and spatial concentration gradients. Using computational modeling and design of pharmacokinetically optimized reactants, we have developed a predictable method for efficient in vivo click reactions. Specifically, we show that polymer modified tetrazines (PMT) are a key enabler for in vivo bioorthogonal chemistry based on the very fast and catalyst-free [4 + 2] tetrazine/trans-cyclooctene cycloaddition. Using fluorescent PMT for cellular resolution and (18)F labeled PMT for whole animal imaging, we show that cancer cell epitopes can be easily reacted in vivo. This generic strategy should help guide the design of future chemistries and find widespread use for different in vivo bioorthogonal applications, particularly in the biomedical sciences.

| S-EPMC3324005 | biostudies-literature

Click chemistry enables preclinical evaluation of targeted epigenetic therapies.

Project description:The success of new therapies hinges on our ability to understand their molecular and cellular mechanisms of action. We modified BET bromodomain inhibitors, an epigenetic-based therapy, to create functionally conserved compounds that are amenable to click chemistry and can be used as molecular probes in vitro and in vivo. We used click proteomics and click sequencing to explore the gene regulatory function of BRD4 (bromodomain containing protein 4) and the transcriptional changes induced by BET inhibitors. In our studies of mouse models of acute leukemia, we used high-resolution microscopy and flow cytometry to highlight the heterogeneity of drug activity within tumor cells located in different tissue compartments. We also demonstrate the differential distribution and effects of BET inhibitors in normal and malignant cells in vivo. This study provides a potential framework for the preclinical assessment of a wide range of drugs.

| S-EPMC5865750 | biostudies-literature

Click chemistry enables comprehensive preclinical evaluation of targeted epigenetic therapies [RNA-seq]

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 | GSE88750 | GEO

Charge-transfer-directed radical substitution enables para-selective C-H functionalization.

Project description:Efficient C-H functionalization requires selectivity for specific C-H bonds. Progress has been made for directed aromatic substitution reactions to achieve ortho and meta selectivity, but a general strategy for para-selective C-H functionalization has remained elusive. Herein we introduce a previously unappreciated concept that enables nearly complete para selectivity. We propose that radicals with high electron affinity elicit arene-to-radical charge transfer in the transition state of radical addition, which is the factor primarily responsible for high positional selectivity. We demonstrate with a simple theoretical tool that the selectivity is predictable and show the utility of the concept through a direct synthesis of aryl piperazines. Our results contradict the notion, widely held by organic chemists, that radical aromatic substitution reactions are inherently unselective. The concept of radical substitution directed by charge transfer could serve as the basis for the development of new, highly selective C-H functionalization reactions.

| S-EPMC4957710 | biostudies-literature

The Effects of Research & Development Funding on Scientific Productivity: Academic Chemistry, 1990-2009.

Project description:This article examines the relationship between Research & Development (R&D) funding and the production of knowledge by academic chemists. Using articles published, either raw counts or adjusted for quality, we find a strong, positive causal effect of funding on knowledge production. This effect is similar across subsets of universities, suggesting a relatively efficient allocation of R&D funds. Finally, we document a rapid acceleration in the rate at which chemical knowledge was produced in the late 1990s and early 2000s relative to the financial and human resources devoted to its production.

| S-EPMC4570780 | biostudies-literature

FLASH assembly of TALENs for high-throughput genome editing.

Project description:Engineered transcription activator–like effector nucleases (TALENs) have shown promise as facile and broadly applicable genome editing tools. However, no publicly available high-throughput method for constructing TALENs has been published, and large-scale assessments of the success rate and targeting range of the technology remain lacking. Here we describe the fast ligation-based automatable solid-phase high-throughput (FLASH) system, a rapid and cost-effective method for large-scale assembly of TALENs. We tested 48 FLASH-assembled TALEN pairs in a human cell–based EGFP reporter system and found that all 48 possessed efficient gene-modification activities. We also used FLASH to assemble TALENs for 96 endogenous human genes implicated in cancer and/or epigenetic regulation and found that 84 pairs were able to efficiently introduce targeted alterations. Our results establish the robustness of TALEN technology and demonstrate that FLASH facilitates high-throughput genome editing at a scale not currently possible with other genome modification technologies.

| S-EPMC3558947 | biostudies-literature

Click chemistry enables comprehensive preclinical evaluation of targeted epigenetic therapies [Click-Seq 2]

2017-07-13 | GSE88749 | GEO