Metal-catalysed C-H bond functionalisation has had a significant impact on how chemists make molecules. Translating the methodological developments to their use in the assembly of complex natural products is an important challenge for the continued advancement of chemical synthesis. In this tutorial review, we describe selected recent examples of how the metal-catalysed C-H bond functionalisation has been able to positively affect the synthesis of natural products.
Alkenes and arenes represent two classes of feedstock compounds whose union has fundamental importance to synthetic organic chemistry. We report a new approach to alkene arylation using diaryliodonium salts and Cu catalysis. Using a range of simple alkenes, we have shown that the product outcomes differ significantly from those commonly obtained by the Heck reaction. We have used these insights to develop a number of new tandem and cascade reactions that transform readily available alkenes into complex arylated products that may have broad applications in chemical synthesis.
Translocator protein (TSPO) is a biomarker of neuroinflammation, which is a hallmark of many neurodegenerative diseases and has been exploited as a positron emission tomography (PET) target. Carbon‐11‐labelled PK11195 remains the most applied agent for imaging TSPO, despite its short‐lived isotope and low brain permeability. Second‐generation radiotracers show variance in affinity amongst subjects (low‐, mixed‐, and high‐affinity binders) caused by the genetic polymorphism (rs6971) of the TSPO gene. To overcome these limitations, a new structural scaffold was explored based on the TSPO pharmacophore, and the analogue with a low‐affinity binder/high‐affinity binder (LAB/HAB) ratio similar (1.2 vs. 1.3) to that of (R)‐[11C]PK11195 was investigated. The synthesis of the reference compound was accomplished in six steps and 9 % overall yield, and the precursor was prepared in eight steps and 8 % overall yield. The chiral separation of the reference and precursor compounds was performed using supercritical fluid chromatography with >95 % ee. The absolute configuration was determined by circular dichroism. Optimisation of reaction conditions for manual radiolabelling revealed acetonitrile as a preferred solvent at 100 °C. Automation of this radiolabelling method provided R and S enantiomers in respective 21.3±16.7 and 25.6±7.1 % decay‐corrected yields and molar activities of 55.8±35.6 and 63.5±39.5 GBq μmol−1 (n=3). Injection of the racemic analogue into a healthy rat confirmed passage through the blood–brain barrier.
This review covers recent advances in decarboxylative photocatalysis applicable to the medicinal chemist. The review is not intended to be exhaustive, but instead is focussed on transformations that could be useful in the synthesis of drug-like compounds in order to highlight the utility of this methodology in the development of new pharmaceutical candidates.1 Introduction2 C–C Bond Formation3 C–N and C–O Bond Formation4 Fluorination and Trifluoromethylation5 Hydrodecarboxylation6 Protein Functionalisation7 Conclusion
Mer is a member of the TAM (Tyro3, Axl, Mer) kinase family that has been associated with cancer progression, metastasis, and drug resistance. Their essential function in immune homeostasis has prompted an interest in their role as modulators of antitumor immune response in the tumor microenvironment. Here we illustrate the outcomes of an extensive lead-generation campaign for identification of Mer inhibitors, focusing on the results from concurrent, orthogonal high-throughput screening approaches. Data mining, HT (high-throughput), and DECL (DNA-encoded chemical library) screens offered means to evaluate large numbers of compounds. We discuss campaign strategy and screening outcomes, and exemplify series resulting from prioritization of hits that were identified. Concurrent execution of HT and DECL screening successfully yielded a large number of potent, selective, and novel starting points, covering a range of selectivity profiles across the TAM family members and modes of kinase binding, and offered excellent start points for lead development.
Inhibition
of Mer and Axl kinases has been implicated as a potential
way to improve the efficacy of current immuno-oncology therapeutics
by restoring the innate immune response in the tumor microenvironment.
Highly selective dual Mer/Axl kinase inhibitors are required to validate
this hypothesis. Starting from hits from a DNA-encoded library screen,
we optimized an imidazo[1,2-a]pyridine series using
structure-based compound design to improve potency and reduce lipophilicity,
resulting in a highly selective in vivo probe compound 32. We demonstrated dose-dependent in vivo efficacy and target engagement in Mer- and Axl-dependent efficacy
models using two structurally differentiated and selective dual Mer/Axl
inhibitors. Additionally, in vivo efficacy was observed
in a preclinical MC38 immuno-oncology model in combination with anti-PD1
antibodies and ionizing radiation.
Aggregated tau protein
is a core pathology present in several neurodegenerative
diseases. Therefore, the development and application of positron emission
tomography (PET) imaging radiotracers that selectively bind to aggregated
tau in fibril form is of importance in furthering the understanding
of these disorders. While radiotracers used in human PET studies offer
invaluable insight, radiotracers that are also capable of visualizing
tau fibrils in animal models are important tools for translational
research into these diseases. Herein, we report the synthesis and
characterization of a novel library of compounds based on the phenyl/pyridinylbutadienylbenzothiazoles/benzothiazolium
(PBB3) backbone developed for this application. From this library,
we selected the compound LM229, which binds to recombinant tau fibrils
with high affinity (
K
d
= 3.6 nM) and detects
with high specificity (a) pathological 4R tau aggregates in living
cultured neurons and mouse brain sections from transgenic human P301S
tau mice, (b) truncated human 151-351 3R (SHR24) and 4R (SHR72) tau
aggregates in transgenic rat brain sections, and (c) tau neurofibrillary
tangles in brain sections from Alzheimer’s disease (3R/4R tau)
and progressive supranuclear palsy (4R tau). With LM229 also shown
to cross the blood–brain barrier
in vivo
and
its effective radiolabeling with the radioisotope carbon-11, we have
established a novel platform for PET translational studies using rodent
transgenic tau models.
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