Catalytic dehydrogenative cross-coupling: forming carbon-carbon bonds by oxidizing two carbon-hydrogen bonds

N-Heterocyclic Carbenes in Late Transition Metal Catalysis

Improvements in genomic and molecular methods are expanding the range of potential applications for circulating tumour DNA (ctDNA), both in a research setting and as a 'liquid biopsy' for cancer management. Proof-of-principle studies have demonstrated the translational potential of ctDNA for prognostication, molecular profiling and monitoring. The field is now in an exciting transitional period in which ctDNA analysis is beginning to be applied clinically, although there is still much to learn about the biology of cell-free DNA. This is an opportune time to appraise potential approaches to ctDNA analysis, and to consider their applications in personalized oncology and in cancer research.

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Liquid biopsies come of age: towards implementation of circulating tumour DNA

The selective oxidation of C-H bonds and the use of O(2) as a stoichiometric oxidant represent two prominent challenges in organic chemistry. Copper(II) is a versatile oxidant, capable of promoting a wide range of oxidative coupling reactions initiated by single-electron transfer (SET) from electron-rich organic molecules. Many of these reactions can be rendered catalytic in Cu by employing molecular oxygen as a stoichiometric oxidant to regenerate the active copper(II) catalyst. Meanwhile, numerous other recently reported Cu-catalyzed C-H oxidation reactions feature substrates that are electron-deficient or appear unlikely to undergo single-electron transfer to copper(II). In some of these cases, evidence has been obtained for the involvement of organocopper(III) intermediates in the reaction mechanism. Organometallic C-H oxidation reactions of this type represent important new opportunities for the field of Cu-catalyzed aerobic oxidations.

Copper-Catalyzed Aerobic Oxidative C ? H Functionalizations: Trends and Mechanistic Insights

The problem of resistance to therapy in cancer is multifaceted. Here we take a reductionist approach to define and separate the key determinants of drug resistance, which include tumour burden and growth kinetics; tumour heterogeneity; physical barriers; the immune system and the microenvironment; undruggable cancer drivers; and the many consequences of applying therapeutic pressures. We propose four general solutions to drug resistance that are based on earlier detection of tumours permitting cancer interception; adaptive monitoring during therapy; the addition of novel drugs and improved pharmacological principles that result in deeper responses; and the identification of cancer cell dependencies by high-throughput synthetic lethality screens, integration of clinico-genomic data and computational modelling. These different approaches could eventually be synthesized for each tumour at any decision point and used to inform the choice of therapy. A review of drug resistance in cancer analyses each biological determinant of resistance separately and discusses existing and new therapeutic strategies to combat the problem as a whole.

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A view on drug resistance in cancer

Malignant tumors shed DNA into the circulation. The transient half-life of circulating tumor DNA (ctDNA) may afford the opportunity to diagnose, monitor recurrence, and evaluate response to therapy solely through a non-invasive blood draw. However, detecting ctDNA against the normally occurring background of cell-free DNA derived from healthy cells has proven challenging, particularly in non-metastatic solid tumors. In this study, distinct differences in fragment length size between ctDNAs and normal cell-free DNA are defined. Human ctDNA in rat plasma derived from human glioblastoma multiforme stem-like cells in the rat brain and human hepatocellular carcinoma in the rat flank were found to have a shorter principal fragment length than the background rat cell-free DNA (134–144 bp vs. 167 bp, respectively). Subsequently, a similar shift in the fragment length of ctDNA in humans with melanoma and lung cancer was identified compared to healthy controls. Comparison of fragment lengths from cell-free DNA between a melanoma patient and healthy controls found that the BRAF V600E mutant allele occurred more commonly at a shorter fragment length than the fragment length of the wild-type allele (132–145 bp vs. 165 bp, respectively). Moreover, size-selecting for shorter cell-free DNA fragment lengths substantially increased the EGFR T790M mutant allele frequency in human lung cancer. These findings provide compelling evidence that experimental or bioinformatic isolation of a specific subset of fragment lengths from cell-free DNA may improve detection of ctDNA.

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Fragment Length of Circulating Tumor DNA

Recent advancements and challenges of palladiumII-catalyzed oxidation reactions with molecular oxygen as the sole oxidant

Mechanistic questions about the reaction of molecular oxygen with palladium in oxidase catalysis

We report a highly regioselective PdII-catalyzed reductive coupling of an alkene with an organostannane using a tandem alcohol oxidation under aerobic conditions. Both aryl- and vinylstannanes are competent coupling partners with a variety of styrene derivatives. Mechanistic experiments support a tandem alcohol oxidation/alkene functionalization process. The ability to trap a palladium hydride derived from alcohol oxidation with an alkene provides a fundamentally different approach to cross-coupling reactions.

Palladium-catalyzed reductive coupling of styrenes and organostannanes under aerobic conditions.

The Suzuki reaction, which couples an organohalide and an organoboron compound,[1] is an attractive cross-coupling reaction for use in the synthesis of natural products[2] and pharmaceuticals.[3] This utility is mainly because of the excellent functional group compatibility, ease of preparation of boronic acid derivatives, and the low toxicity of the boron byproducts.[2] The mechanistic details have been widely investigated and the reaction is thought to proceed through oxidative addition of the organohalide (R–X) to Pd0 to form R–PdII–X and then transmetalation of the organoborane (R1– B(OR)2).[1] The resulting R–PdII–R1 intermediate undergoes reductive elimination to form the product. An exogenous base is required to activate the boronic acid derivative for transmetalation, which is proposed to occur through a four-centered transition state (intermediate C, Scheme 1a).[4]

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Keith M. Gligorich

Papers

Fragment Length of Circulating Tumor DNA

Recent advancements and challenges of palladiumII-catalyzed oxidation reactions with molecular oxygen as the sole oxidant

Mechanistic questions about the reaction of molecular oxygen with palladium in oxidase catalysis

Palladium-catalyzed reductive coupling of styrenes and organostannanes under aerobic conditions.

Aerobic Alcohol Oxidation Coupled to Palladium-Catalyzed Alkene Hydroarylation with Boronic Esters†