Cyclooxygenase-2 isozyme is a promising anti-inflammatory drug target, and overexpression of this enzyme is also associated with several cancers and neurodegenerative diseases. The amino-acid sequence and structural similarity between inducible cyclooxygenase-2 and housekeeping cyclooxygenase-1 isoforms present a significant challenge to design selective cyclooxygenase-2 inhibitors. Herein, we describe the use of the cyclooxygenase-2 active site as a reaction vessel for the in situ generation of its own highly specific inhibitors. Multi-component competitive-binding studies confirmed that the cyclooxygenase-2 isozyme can judiciously select most appropriate chemical building blocks from a pool of chemicals to build its own highly potent inhibitor. Herein, with the use of kinetic target-guided synthesis, also termed as in situ click chemistry, we describe the discovery of two highly potent and selective cyclooxygenase-2 isozyme inhibitors. The in vivo anti-inflammatory activity of these two novel small molecules is significantly higher than that of widely used selective cyclooxygenase-2 inhibitors. Traditional inflammation and pain relief drugs target both cyclooxygenase 1 and 2 (COX-1 and COX-2), causing severe side effects. Here, the authors use in situ click chemistry to develop COX-2 specific inhibitors with high in vivo anti-inflammatory activity.

/pdf/in-situ-click-chemistry-generation-of-cyclooxygenase-2-zyy8rhnlnx.pdf

In situ click chemistry generation of cyclooxygenase-2 inhibitors

The role of fluorine in drug design and development is expanding rapidly as we learn more about the unique properties associated with this unusual element and how to deploy it with greater sophistication. The judicious introduction of fluorine into a molecule can productively influence conformation, pKa, intrinsic potency, membrane permeability, metabolic pathways, and pharmacokinetic properties. In addition, 18F has been established as a useful positron emitting isotope for use with in vivo imaging technology that potentially has extensive application in drug discovery and development, often limited only by convenient synthetic accessibility to labeled compounds. The wide ranging applications of fluorine in drug design are providing a strong stimulus for the development of new synthetic methodologies that allow more facile access to a wide range of fluorinated compounds. In this review, we provide an update on the effects of the strategic incorporation of fluorine in drug molecules and applications in po...

Applications of Fluorine in Medicinal Chemistry

Single cell transcriptomics (scRNA-seq) has transformed our ability to discover and annotate cell types and states, but deep biological understanding requires more than a taxonomic listing of clusters. As new methods arise to measure distinct cellular modalities, including high-dimensional immunophenotypes, chromatin accessibility, and spatial positioning, a key analytical challenge is to integrate these datasets into a harmonized atlas that can be used to better understand cellular identity and function. Here, we develop a computational strategy to "anchor" diverse datasets together, enabling us to integrate and compare single cell measurements not only across scRNA-seq technologies, but different modalities as well. After demonstrating substantial improvement over existing methods for data integration, we anchor scRNA-seq experiments with scATAC-seq datasets to explore chromatin differences in closely related interneuron subsets, and project single cell protein measurements onto a human bone marrow atlas to annotate and characterize lymphocyte populations. Lastly, we demonstrate how anchoring can harmonize in-situ gene expression and scRNA-seq datasets, allowing for the transcriptome-wide imputation of spatial gene expression patterns, and the identification of spatial relationships between mapped cell types in the visual cortex. Our work presents a strategy for comprehensive integration of single cell data, including the assembly of harmonized references, and the transfer of information across datasets. Availability: Installation instructions, documentation, and tutorials are available at: https://www.satijalab.org/seurat

https://biorxiv.org/content/biorxiv/early/2018/11/02/460147.full-text.pdf

Comprehensive integration of single cell data

Click Chemistry for Drug Development and Diverse Chemical–Biology Applications

From bench to bedside

Radiolabeled peptides have been the subject of intense research efforts for targeted diagnostic imaging and radiotherapy over the last 20 years. Peptides offer several advantages for receptor imaging and targeted radiotherapy. The low molecular weight of peptides allows for rapid clearance from the blood and non-target tissue, which results in favorable target-to-non-target ratios. Moreover, peptides usually display good tissue penetration and they are generally non-immunogenic. A major drawback is their potential low metabolic stability. The majority of currently used radiolabeled peptides for targeted molecular imaging and therapy of cancer is labeled with various radiometals like 99mTc, 68Ga, and 177Lu. However, over the last decade an increasing number of 18F-labeled peptides have been reported. Despite of obvious advantages of 18F like its ease of production in large quantities at high specific activity, the low β+ energy (0.64 MeV) and the favorable half-life (109.8 min), 18F-labeling of peptides remains a special challenge. The first part of this review will provide a brief overview on chemical strategies for peptide labeling with 18F. A second part will discuss recent technological advances for 18F-labeling of peptides with special focus on microfluidic technology, automation, and kit-like preparation of 18F-labeled peptides.

https://www.mdpi.com/1420-3049/19/12/20536/pdf

18F-Labeled Peptides: The Future Is Bright.

Click chemistry has received considerable attention as powerful modular synthesis approach, which has found numerous ap- plications in many areas of modern organic chemistry, drug discovery and material science. Recently, click chemistry, and in particular the copper-mediated 1,3-dipolar (3+2) cycloaddition between azides and alkynes, has also entered the field of radiopharmaceutical sci- ences. This review addresses the recent developments of click chemistry for the synthesis of various radiotracers for molecular imaging purposes. Click chemistry-based radiotracers that will be covered include peptides and small organic molecules containing the short-lived positron emitter fluorine-18, and the gamma-emitters technetium-99m, indium-111, and iodine-125. Current biomedical research is revealing the fundamental mo- lecular processes of life and diseases. The understanding of how molecular components of living cells are organized, how they inter- act, how they move and how they are formed and eliminated within the life cycle of an organism represents an integrative approach, which requires the direct observation of biochemical and physio- logical processes at the molecular level in vivo. The molecular processes of life can be studied and visualized at various levels of resolution by means of in vivo imaging techniques (1-3). Molecular imaging techniques span the electromagnetic spectrum from ultra- sonic to gamma-ray frequencies. In this line, especially magnetic resonance imaging (MRI), optical imaging and nuclear imaging are emerging as key molecular imaging techniques. Nuclear imaging techniques are based on the application and detection of decaying radioisotopes. In most cases, the radioiso- topes are combined with biologically active compounds to form radiolabeled probes capable of imaging specific biochemical and physiological events in vivo. The radiolabed probe is administered to follow a metabolic pathway connected with the pathophysiology of disease processes. The detection of the emitted radiation can either be performed by positron emission tomography (PET) or single photon computered tomography (SPECT) (2-4). PET and SPECT have extensively been used for noninvasive diagnosis, stag- ing and therapy control of diseases at the molecular level. Both techniques have found numerous applications in the field of clinical oncology, cardiology and neurology. Moreover, especially PET has also been recognized and applied as a valuable research tool in the process of drug development and evaluation. The success of radiotracer-based molecular imaging techniques like PET and SPECT stems mainly from the availability of suitable radiolabed probes, also referred to as radiotracers. The design and synthesis of radiotracers as molecular probes is subject of radio- pharmaceutical chemistry. Today's radiopharmaceutical chemistry has evolved into a complex chemical science, combining recent advances in synthetic organic and inorganic chemistry with devel- opments and achievements in the field of molecular biology. The development of radiotracers for molecular imaging purposes has to address important questions on target selection and target validation while considering the special requirements encountered in ra- diotracer synthesis such as choice of the appropriate radionuclide and suitable labeling position.

Recent Applications of Click Chemistry for the Synthesis of Radiotracers for Molecular Imaging

The use of radiopharmaceuticals for molecular imaging of biochemical and physiological processes in vivo has evolved into an important diagnostic tool in modern nuclear medicine and medical research. Positron emission tomography (PET) is currently the most sophisticated molecular imaging methodology, mainly due to the unrivalled high sensitivity which allows for the studying of biochemistry in vivo on the molecular level. The most frequently used radionuclides for PET have relatively short half-lives (e.g. 11C: 20.4 min; 18F: 109.8 min) which may limit both the synthesis procedures and the time frame of PET studies. Iodine-124 (124I, t1/2 = 4.2 d) is an alternative long-lived PET radionuclide attracting increasing interest for long term clinical and small animal PET studies. The present review gives a survey on the use of 124I as promising PET radionuclide for molecular imaging. The first part describes the production of 124I. The second part covers basic radiochemistry with 124I focused on the synthesis of 124I-labeled compounds for molecular imaging purposes. The review concludes with a summary and an outlook on the future prospective of using the long-lived positron emitter 124I in the field of organic PET chemistry and molecular imaging.

https://www.mdpi.com/1420-3049/15/4/2686/pdf

Frank Wuest

Papers

In situ click chemistry generation of cyclooxygenase-2 inhibitors

18F-Labeled Peptides: The Future Is Bright.

Recent Applications of Click Chemistry for the Synthesis of Radiotracers for Molecular Imaging

Iodine-124: A Promising Positron Emitter for Organic PET Chemistry

Labeling of low-density lipoproteins using the 18F-labeled thiol-reactive reagent N-[6-(4-[18F]fluorobenzylidene)aminooxyhexyl]maleimide.