James Sanderson

Selectivity snapshots with PALs: Photoaffinity probes were designed to target the cyclin‐dependent kinase family, and found to competitively enrich CDKs from cell lysates. Subsequently, a biochemical photoaffinity displacement assay was developed to measure compound potency.

Abstract

The CDK family plays a crucial role in the control of the cell cycle. Dysregulation and mutation of the CDKs has been implicated in cancer and the CDKs have been investigated extensively as potential therapeutic targets. Selective inhibition of specific isoforms of the CDKs is crucial to achieve therapeutic effect while minimising toxicity. We present a group of photoaffinity probes designed to bind to the family of CDKs. The site of crosslinking of the optimised probe, as well as its ability to enrich members of the CDK family from cell lysates, was investigated. In a proof of concept study, we subsequently developed a photoaffinity probe‐based competition assay to profile CDK inhibitors. We anticipate that this approach will be widely applicable to the study of small molecule binding to protein families of interest.

A radical hybrid: The dicarbofunctionalization of vinylB(pin) was achieved through the use of a nickel‐based chiral catalyst. The reaction employs alkyl halide and organozinc reagents and can be accomplished with good levels of enantioselectivity in an intra‐ or intermolecular fashion.

Abstract

A hybrid transition‐metal/radical process is described that results in the addition of organozinc reagents and alkyl halides across alkenyl boron reagents in an enantioselective catalytic fashion. The reaction can be accomplished both intermolecularly and intramolecularly, providing useful product yields and high enantioselectivities in both manifolds.

Use of abundant feedstock pronucleophiles in catalytic carbonyl reductive coupling enhances efficiency in target‐oriented synthesis. For such reactions, equally inexpensive reductants are desired or, ideally, corresponding hydrogen autotransfer processes may be enacted wherein alcohols serve dually as reductant and carbonyl proelectrophile. These concepts allow reactions that traditionally require preformed organometallic reagents to be conducted catalytically in a byproduct‐free manner from inexpensive π‐unsaturated precursors.

Abstract

Use of abundant feedstock pronucleophiles in catalytic carbonyl reductive coupling enhances efficiency in target‐oriented synthesis. For such reactions, equally inexpensive reductants are desired or, ideally, corresponding hydrogen autotransfer processes may be enacted wherein alcohols serve dually as reductant and carbonyl proelectrophile. As described in this Minireview, these concepts allow reactions that traditionally require preformed organometallic reagents to be conducted catalytically in a byproduct‐free manner from inexpensive π‐unsaturated precursors.

Goldilocks and the sensitivity screen: This work introduces a standardized, systematic, and user‐friendly tool to gain valuable information on the sensitivity of a reaction, with the aim of enhancing reproducibility and supporting troubleshooting.

Abstract

A systematic, user‐friendly assessment tool that delivers a clear overview of the sensitivity of reactions to key parameters is highly desirable. Herein, the development of such a method is described. The intuitive, standardized presentation of the results in a radar diagram enables the sensitivity of a protocol to be rapidly assessed. This method was applied to five different visible‐light‐mediated photochemical reactions, and the results were correlated to the underlying mechanism. Ultimately, we believe that this assessment will help to increase the uptake of new synthetic methods and their reproducibility.

Keep calm and carry on (doing kinetics): Two different kinetic analysis methods, based on variable time normalization analysis (VTNA), are described for studying reactions with catalyst deactivation and activation processes. The cases studied are a hydroformylation reaction catalyzed by a supramolecular rhodium complex and an aminocatalytic Michael reaction.

Abstract

Progress reaction profiles are affected by both catalyst activation and deactivation processes occurring alongside the main reaction. These processes complicate the kinetic analysis of reactions, often directing researchers toward incorrect conclusions. We report the application of two kinetic treatments, based on variable time normalization analysis, to reactions involving catalyst activation and deactivation processes. The first kinetic treatment allows the removal of induction periods or the effect of rate perturbations associated with catalyst deactivation from kinetic profiles when the quantity of active catalyst can be measured. The second treatment allows the estimation of the activation or deactivation profile of the catalyst when the order of the reactants for the main reaction is known. Both treatments facilitate kinetic analysis of reactions suffering catalyst activation or deactivation processes.

Making light of catalysis: In contrast to classical reactions catalyzed by Pd complexes in the ground state, which mostly proceed through two‐electron redox processes, the mechanisms of the methods based on the photoexcitation of Pd usually operate through transfer of a single electron. This Minireview highlights the recent progress in this rapidly emerging area of Pd catalysis induced by visible light.

Abstract

Palladium catalysis induced by visible light is an emerging field of catalysis. In contrast to classical reactions catalyzed by Pd complexes in the ground state, which mostly proceed through two‐electron redox processes, the mechanisms of these new methods based on photoexcited Pd complexes usually operate through transfer of a single electron. Such processes lead to putative hybrid Pd/radical species, which exhibit both radical and classical Pd‐type reactivity. This Minireview highlights the recent progress in this rapidly growing area.

Nature, Published online: 27 May 2019; doi:10.1038/d41586-019-01596-7

Only a few types of natural amino-acid residue are used directly by enzymes to catalyse reactions. The incorporation of an unnatural residue into an enzyme shows how the catalytic repertoire of enzymes can be enlarged.

Fluorinated drugs: This Review outlines 17 fluorine‐containing drugs approved by the food and drug administration (FDA) in 2018. These newly developed fluorinated pharmaceuticals are recommended for the treatment of various diseases, including cancer, HIV, malarial and smallpox infections.

Abstract

Over the last two decades, fluorine substitution has become one of the essential structural traits in modern pharmaceuticals. Thus, about half of the most successful drugs (blockbuster drugs) contain fluorine atoms. In this review, we profile 17 fluorine‐containing drugs approved by the food and drug administration (FDA) in 2018. The newly approved pharmaceuticals feature several types of aromatic F and CF₃, as well as aliphatic (CF₂) substitution, offering advances in the treatment of various diseases, including cancer, HIV, malarial and smallpox infections.

Starting from scratch: How close are we to the vision of fully automated de novo drug design? The field is more than 20 years old now and in this Minireview the progress is surveyed and the state‐of‐the‐art is assessed with reference to experimentally validated test cases from the literature. Also included is a look ahead to predict some of the possibilities and limitations of drug design using machine intelligence.

Abstract

Medicinal chemistry and, in particular, drug design have often been perceived as more of an art than a science. The many unknowns of human disease and the sheer complexity of chemical space render decision making in medicinal chemistry exceptionally demanding. Computational models can assist the medicinal chemist in this endeavour. Provided here is an overview of recent examples of automated de novo molecular design, a discussion of the concepts and computational approaches involved, and the daring prediction of some of the possibilities and limitations of drug design using machine intelligence.

Abstract

A polystyrene‐cross‐linking bisphosphine ligand PS‐DPPBz was used for Ni‐catalyzed cross‐coupling with organolithiums. A bench‐stable precatalyst [NiCl₂(PS‐DPPBz)] enabled efficient coupling reactions between aryl chlorides and alkyllithiums. The heterogeneous Ni system showed good reusability.

Abstract

The first B(C₆F₅)₃‐catalyzed deoxygenative reduction of amides into the corresponding amines with readily accessible and stable ammonia borane (AB) as a reducing agent under mild reaction conditions is reported. This metal‐free protocol provides facile access to a wide range of structurally diverse amine products in good to excellent yields, and various functional groups including those that are reduction‐sensitive were well tolerated. This new method is also applicable to chiral amide substrates without erosion of the enantiomeric purity. The role of BF₃ ⋅ OEt₂ co‐catalyst in this reaction is to activate the amide carbonyl group via the in situ formation of an amide‐boron adduct.

The front cover picture, provided by Lijin Xu and co‐workers, illustrates the first B(C₆F₅)₃‐catalyzed reduction of amides into the corresponding amines with readily accessible and stable ammonia borane under mild reaction conditions. The role of BF₃⋅OEt₂ co‐catalyst is to activate the amide carbonyl group via the in situ formation of an amide‐boron adduct. This metal‐free protocol provides facile access to various amines in good to excellent yields with high functional group tolerance. Details of this work can be found in the full paper on pages 2301–2308 (Y. Pan, Z. Luo, J. Han, X. Xu, C. Chen, H. Zhao, L. Xu, Q. Fan, J. Xiao, Adv. Synth. Catal. 2019, 361, 2301–2308; DOI: https://doi.org/10.1002/adsc.20180144710.1002/adsc.201801447).

Abstract

Biocatalysis over the past few years has matured into an essential tool for modern, cost effective and sustainable pharmaceutical manufacturing. While some reaction classes are well established, and may even be the option of first intent, other more recently discovered enzyme classes are being rapidly developed both in academia and industry. Notwithstanding this, there are further promising enzymes that require further investment and investigation to allow their future industrial use. We here outline GSK's perspective on the current status of biocatalysis for pharmaceutical manufacturing and provide our views on areas of significant potential.

Nature, Published online: 17 May 2019; doi:10.1038/d41586-019-01572-1

Neuroscientist Blaine Roberts explains how partnering with companies, or a consortium of companies, can bring significant benefits to researchers — from funding and training to expanding professional networks.

The merger of Ni and photoredox catalysis enables a CO₂ insertion at remote sp³ C−H sites under visible‐light irradiation and in the absence of metal reductants. The salient features of this method are the mild conditions and a site‐selectivity pattern that can be modulated by subtle modifications of the ligand backbone, offering an unrecognized opportunity in the metallaphotoredox arena and a complementary reactivity mode to existing functionalization techniques at remote sp³ C−H sites.

Abstract

A photoinduced carboxylation of alkyl halides with CO₂ at remote sp³ C−H sites enabled by the merger of photoredox and Ni catalysis is described. This protocol features a predictable reactivity and site selectivity that can be modulated by the ligand backbone. Preliminary studies reinforce a rationale based on a dynamic displacement of the catalyst throughout the alkyl side chain.

A shape‐diverse fragment set was designed and collated to assess experimentally the added value of increased three dimensionality in fragment‐based ligand discovery.

Abstract

Historically, chemists have explored chemical space in a highly uneven and unsystematic manner. As an example, the shape diversity of existing fragment sets does not generally reflect that of all theoretically possible fragments. To assess experimentally the added value of increased three dimensionality, a shape‐diverse fragment set was designed and collated. The set was assembled by both using commercially available fragments and harnessing unified synthetic approaches to sp³‐rich molecular scaffolds. The resulting set of 80 fragments was highly three‐dimensional, and its shape diversity was significantly enriched by twenty synthesised fragments. The fragment set was screened by high‐throughput protein crystallography against Aurora‐A kinase, revealing four hits that targeted the binding site of allosteric regulators. In the longer term, it is envisaged that the fragment set could be screened against a range of functionally diverse proteins, allowing the added value of more shape‐diverse screening collections to be more fully assessed.

Publication date: 9 August 2019

Source: Tetrahedron, Volume 75, Issue 32

Author(s): Bryan T. Ingoglia, Corin C. Wagen, Stephen L. Buchwald

Graphical abstract