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The caseinolytic protease complex ClpXP is an important house-keeping enzyme in prokaryotes charged with the removal and degradation of misfolded and aggregated proteins and performing regulatory proteolysis. Dysregulation of its function, particularly by inhibition or allosteric activation of the proteolytic core ClpP, has proven to be a promising strategy to reduce virulence and eradicate persistent bacterial infections. Here, we report a rational drug-design approach to identify macrocyclic peptides which increase proteolysis by ClpP. This work expands the understanding of ClpP dynamics and sheds light on the conformational control exerted by its binding partner, the chaperone ClpX, by means of a chemical approach. The identified macrocyclic peptide ligands may, in the future, serve as a starting point for the development of ClpP activators for antibacterial applications.

CK2 is a ubiquitous protein kinase with an anti-apoptotic role and is found to be overexpressed in multiple cancer types. To this end, the inhibition of CK2 is of great interest with regard to the development of novel anti-cancer therapeutics. ATP-site inhibition of CK2 is possible; however, this typically results in poor selectivity due to the highly conserved nature of the catalytic site amongst kinases. An alternative methodology for the modulation of CK2 activity is through allosteric inhibition. The recently identified αD site represents a promising binding site for allosteric inhibition of CK2α. The work presented herein describes the development of a series of CK2α allosteric inhibitors through iterative cycles of X-ray crystallography and enzymatic assays, in addition to both fragment growing and fragment merging design strategies. The lead fragment developed, fragment 8, exhibits a high ligand efficiency, displays no drop off in activity between enzymatic and cellular assays, and successfully engages CK2α in cells. Furthermore, X-ray crystallographic analysis provided indications towards a novel mechanism of allosteric inhibition through αD site binding. Fragments described in this paper therefore represent promising starting points for the development of highly selective allosteric CK2 inhibitors.

RAS proteins are central in the proliferation of many types of cancer, but a general approach toward the identification of pan-mutant RAS inhibitors has remained unresolved. In this work, we describe the application of a binding pharmacophore identified from analysis of known RAS binding peptides to the design of novel peptides. Using a chemically divergent approach, we generated a library of small stapled peptides from which we identified compounds with weak binding activity. Exploration of structure–activity relationships (SARs) and optimization of these early compounds led to low-micromolar binders of KRAS that block nucleotide exchange.

Aurora A kinase, a cell division regulator, is frequently overexpressed in various cancers, provoking genome instability and resistance to antimitotic chemotherapy. Localization and enzymatic activity of Aurora A are regulated by its interaction with the spindle assembly factor TPX2. We have used fragment-based, structure-guided lead discovery to develop small molecule inhibitors of the Aurora A-TPX2 protein–protein interaction (PPI). Our lead compound, CAM2602, inhibits Aurora A:TPX2 interaction, binding Aurora A with 19 nM affinity. CAM2602exhibits oral bioavailability, causes pharmacodynamic biomarker modulation, and arrests the growth of tumor xenografts. CAM2602acts by a novel mechanism compared to ATP-competitive inhibitors and is highly specific to Aurora A over Aurora B. Consistent with our finding that Aurora A overexpression drives taxane resistance, these inhibitors synergize with paclitaxel to suppress the outgrowth of pancreatic cancer cells. Our results provide a blueprint for targeting the Aurora A-TPX2 PPI for cancer therapy and suggest a promising clinical utility for this mode of action.

We introduce a novel and straightforward methodology for photoredox arylation of an indole scaffold using aryldiazonium salts under mild and metal-free conditions. Our approach enables the regioselective and chemoselective introduction of several aryl groups to the C(2) position of indoles and tryptophan, even in competition with other amino acids. This approach extends to the late-stage functionalization of peptides and lysozyme, heralding the unprecedented arylation of tryptophan residues in wild-type proteins and offering broad utility in chemical biology.

Prostate cancer is one of the leading causes of cancer-related death in men. The identification of new therapeutics to selectively target prostate cancer cells is therefore vital. Recently, the rotenoids rotenone (1) and deguelin (2) were reported to selectively kill prostate cancer cells, and the inhibition of mitochondrial complex I was established as essential to their mechanism of action. However, these hydrophobic rotenoids readily cross the blood–brain barrier and induce symptoms characteristic of Parkinson’s disease in animals. Since hydroxylated derivatives of 1and 2are more hydrophilic and less likely to readily cross the blood–brain barrier, 29 natural and unnatural hydroxylated derivatives of 1and 2were synthesized for evaluation. The inhibitory potency (IC50) of each derivative against complex I was measured, and its hydrophobicity (Slog10P) predicted. Amorphigenin (3), dalpanol (4), dihydroamorphigenin (5), and amorphigenol (6) were selected and evaluated in cell-based assays using C4-2 and C4-2B prostate cancer cells alongside control PNT2 prostate cells. These rotenoids inhibit complex I in cells, decrease oxygen consumption, and selectively inhibit the proliferation of prostate cancer cells, leaving control cells unaffected. The greatest selectivity and antiproliferative effects were observed with 3and 5. The data highlight these molecules as promising therapeutic candidates for further evaluation in prostate cancer models.

Methods that survey protein surfaces for binding hotspots can help to evaluate target tractability and guide exploration of potential ligand binding regions. Fragment Hotspot Maps builds upon interaction data mined from the CSD (Cambridge Structural Database) and exploits the idea of identifying hotspots using small chemical fragments, which is now widely used to design new drug leads. Prior to this publication, Fragment Hotspot Maps was only publicly available through a web application. To increase the accessibility of this algorithm we present the Hotspots API (application programming interface), a toolkit that offers programmatic access to the core Fragment Hotspot Maps algorithm, thereby facilitating the interpretation and application of the analysis. To demonstrate the package’s utility, we present a workflow which automatically derives protein hydrogen-bond constraints for molecular docking with GOLD. The Hotspots API is available from https://github.com/prcurran/hotspotsunder the MIT license and is dependent upon the commercial CSD Python API.

Novel divergent methodology to access sp3-rich spirocyclic fragments is reported. First, a robust modular synthesis of bis-alkene amino ester building blocks was developed. Three different carbocycles and six heterocycles were then constructed to assemble eight spirocycles. Importantly, strategic exit vectors were incorporated within each scaffold to aid fragment growth and were elaborated via chemical modifications. Finally, computational methods demonstrate higher levels of rigidity, three-dimensionality, and structural diversity of the library compared to a commercial collection.

Stapled peptides have great potential as modulators of protein–protein interactions (PPIs). However, there is a vast landscape of chemical features that can be varied for any given peptide, and identifying a set of features that maximizes cellular uptake and subsequent target engagement remains a key challenge. Herein, we present a systematic analysis of staple functionality on the peptide bioactivity landscape in cellular assays. Through application of a “toolbox” of diversified dialkynyl linkers to the stapling of MDM2-binding peptides via a double-click approach, we conducted a study of cellular uptake and p53 activation as a function of the linker. Minor changes in the linker motif and the specific pairing of linker with peptide sequence can lead to substantial differences in bioactivity, a finding which may have important design implications for peptide-based inhibitors of other PPIs. Given the complexity of the structure–activity relationships involved, the toolbox approach represents a generalizable strategy for optimization when progressing from in vitrobinding assays to cellular efficacy studies.

Operationally simple, stereocontrolled semisyntheses of the anticancer rotenoids elliptone and 12aβ-hydroxyelliptone, isolated from Derris ellipticaand Derris trifoliata, respectively, are described. Inspired by the work of Singhal, elliptone was prepared from rotenone via a dihydroxylation-oxidative cleavage, chemoselective Baeyer–Villiger oxidation, and acid-catalyzed elimination sequence. Elaboration of elliptone to 12aβ-hydroxyelliptone was achieved via a diastereoselective chromium-mediated Étard-like hydroxylation. The semisynthesis of elliptone constitutes an improvement over previous methods in terms of safety, scalability, and yield, while the first synthesis of 12aβ-hydroxyelliptone is also described.

Pseudomonas aeruginosais an opportunistic human pathogen recognized as a critical threat by the World Health Organization because of the dwindling number of effective therapies available to treat infections. Over the past decade, it has become apparent that the glyoxylate shunt plays a vital role in sustaining P. aeruginosaduring infection scenarios. The glyoxylate shunt comprises two enzymes: isocitrate lyase and malate synthase isoform G. Inactivation of these enzymes has been reported to abolish the ability of P. aeruginosato establish infection in a mammalian model system, yet we still lack the structural information to support drug design efforts. In this work, we describe the first X-ray crystal structure of P. aeruginosamalate synthase G in the apo form at 1.62 Å resolution. The enzyme is a monomer composed of four domains and is highly conserved with homologues found in other clinically relevant microorganisms. It is also dependent on Mg2+for catalysis. Metal ion binding led to a change in the intrinsic fluorescence of the protein, allowing us to quantitate its affinity for Mg2+. We also identified putative drug binding sites in malate synthase G using computational analysis and, because of the high resolution of the experimental data, were further able to characterize its hydration properties. Our data reveal two promising binding pockets in malate synthase G that may be exploited for drug design.

Early phase drug discovery is a multi‐parameter optimisation process. Finding drugable targets, discovering starting points for lead optimisation and creating novel structures with new biological properties within these constraints is challenging. As an example of a drug optimisation strategy, recent work on 5‐HT1B antagonists will be described. This is put in the context of the drugability of the target, the desired physicochemical properties of the desired molecules and approaches to compound design to create high affinity, selective molecules that are optimised to have low Central Nervous System (CNS) penetration.

A computational ligand-mapping approach to detect protein surface pockets that interact with hydrophobic moieties is presented. In this method, we incorporated benzene molecules into explicit solvent molecular dynamics simulations of various protein targets. The benzene molecules successfully identified the binding locations of hydrophobic hot-spot residues and all-hydrocarbon cross-links from known peptidic ligands. They also unveiled cryptic binding sites that are occluded by side chains and the protein backbone. Our results demonstrate that ligand-mapping molecular dynamics simulations hold immense promise to guide the rational design of peptidic modulators of protein–protein interactions, including that of stapled peptides, which show promise as an exciting new class of cell-penetrating therapeutic molecules.

An optimized procedure for the efficient preparation of 2-heptyl-3-hydroxy-4(1H)-quinolone (Pseudomonas quinolone signal or PQS) and a diverse range of structurally related 2-alkyl-4-quinolones with biological activity is presented. The two-step synthesis begins with the formation of α-chloro ketones by the coupling of a Weinreb amide (2-chloro-N-methoxy-N-methylacetamide) and an appropriate Grignard reagent. The resulting α-chloro ketones can be reacted with commercially available anthranilic acids under microwave irradiation conditions to furnish the desired 2-alkyl-4-quinolone products. As a typical example, the synthesis of PQS, a molecule involved in quorum sensing in the pathogenic bacterium Pseudomonas aeruginosa, is described in detail. The first step of this process (α-chloro ketone formation) takes ∼10 h in total to complete from commercially available bromoheptane and 2-chloro-N-methoxy-N-methylacetamide. The second step (microwave-assisted reaction with anthranilic acid) takes ∼14 h in total to complete (the reaction typically proceeds in ∼30 min, with work-up and purification requiring ∼13 h).

The natural product deoxyschizandrin has been shown to have a wide range of biological activities. In recent years the therapeutic potential of this compound against cancers has attracted significant interest. Herein we describe a concise de novo total synthesis of deoxyschizandrin based around a double organocuprate oxidation strategy. In addition, we present the results of biological studies exploring the ability of deoxyschizandrin and synthetic precursors lacking the medium ring biaryl unit to inhibit the proliferation of a human cancer cell line. These studies led to the identification of a structurally novel agent with in vitro anticancer activity.

The prevalence of the biaryl structural motif in biologically interesting and synthetically important molecules has inspired considerable interest in the development of methods for aryl–aryl bond formation. Herein we describe a novel strategy for this process involving the fluoride‐free, palladium‐catalysed cross‐coupling of readily accessible aryldisiloxanes and aryl bromides. Using a statistical‐based optimisation process, preparatively useful reaction conditions were formulated to allow the cross‐coupling of a wide range of different substrates. This methodology represents an attractive, cost‐efficient, flexible and robust alternative to the traditional transition‐metal‐catalysed routes typically used to generate molecules containing the privileged biaryl scaffold.

It is still a challenging task to discriminate adenosine‐5′‐triphosphate (ATP) from various nucleoside triphosphates, such as GTP, CTP, UTP, and TTP. The ability to distinguish ATP from adenosine diphosphate (ADP) by fluorescent signals is also urgently desired. Herein, we report two pyrene‐based zinc complexes as nucleoside polyphosphate receptors with high selectivity for ATP and ADP based on fluorescence and NMR studies. A unique pyrene–adenine–pyrene sandwich assembly was observed in the case of compound 1with ATP or ADP, resulting in the increase of monomer fluorescence intensity; whereas the other bases of nucleoside triphosphates, such as GTP, CTP, UTP, and TTP were not sandwiched, resulting in a switch in the monomer–excimer fluorescence of pyrene. The different binding patterns of various nucleobases with a pyrene–pyrene assembly make 1a highly selective fluorescent sensor for ANP (N=di, tri). In the case of compound 2, the first 0.5 equivalents of ATP induced a strong excimer emission, whilst ADP induced a large enhancement in the monomeric fluorescent peak. This fluorescence change makes 2an efficient sensor to discriminate ATP from ADP.

Traditionally a pursuit of large pharmaceutical companies, high-throughput screening assays are becoming increasingly common within academic and government laboratories. This shift has been instrumental in enabling projects that have not been commercially viable, such as chemical probe discovery and screening against high-risk targets. Once an assay has been prepared and validated, it must be fed with screening compounds. Crafting a successful collection of small molecules for screening poses a significant challenge. An optimized collection will minimize false positives while maximizing hit rates of compounds that are amenable to lead generation and optimization. Without due consideration of the relevant protein targets and the downstream screening assays, compound filtering and selection can fail to explore the great extent of chemical diversity and eschew valuable novelty. Herein, we discuss the different factors to be considered and methods that may be employed when assembling a structurally diverse compound collection for screening. Rational methods for selecting diverse chemical libraries are essential for their effective use in high-throughput screens.

Herein, a new copper‐catalysed strategy for the synthesis of rare nitrogen‐linked seven‐, eight‐ and nine‐membered biaryl ring systems is described. It is proposed that the reaction proceeds through a highly activated intramolecularly co‐ordinated copper catalyst. The process is technically simple, proceeds under relatively mild conditions, displays a broad substrate scope and forms biologically valuable products that are difficult to synthesise by other methods. We envisage that this methodology will prove useful in a wide synthetic context, with possible applications in both target‐oriented and diversity‐oriented synthesis.

Intermolecular interactions that involve aromatic rings are key processes in both chemical and biological recognition. It is common knowledge that the existence of anion–π interactions between anions and electron‐deficient (π‐acidic) aromatics indicates that electron‐rich (π‐basic) aromatics are expected to be repulsive to anions due to their electron‐donating character. Here we report the first concrete theoretical and experimental evidence of the anion–π interaction between electron‐rich alkylbenzene rings and a fluoride ion in CH3CN. The cyclophane cavity bridged with three naphthoimidazolium groups selectively complexes a fluoride ion by means of a combination of anion–π interactions and (CH)+⋅⋅⋅F−‐type ionic hydrogen bonds. 1H NMR, 19F NMR, and fluorescence spectra of 1and 2with fluoride ions are examined to show that only 2can host a fluoride ion in the cavity between two alkylbenzene rings to form a sandwich complex. In addition, the cage compounds can serve as highly selective and ratiometric fluorescent sensors for a fluoride ion. With the addition of 1 equiv of F−, a strongly increased fluorescence emission centered at 385 nm appears at the expense of the fluorescence emission of 2centered at 474 nm. Finally, isothermal titration calorimetry (ITC) experiments were performed to obtain the binding constants of the compounds 1and 2with F−as well as Gibbs free energy. The 2‐F−complex is more stable than the 1‐F−complex by 1.87 kcal mol−1, which is attributable to the stronger anion–π interaction between F−and triethylbenzene.

Background: ‘Diversity’ is often cited as a crucial consideration when generating compound collections for biological screening. However, what exactly does one mean by ‘diversity’ and why is it important? Objective: How can diversity be incorporated into compound collections and what are the theoretical and technical challenges this poses? In this editorial, we comment on various factors involved in the creation of structurally, and most crucially, functionally diverse compound libraries. Conclusions: In particular, we highlight the central role played by organic synthesis and discuss the value of diversity-driven synthetic approaches in the search for new biologically active molecules with potentially exciting and unusual biological properties.

Many Gram-negative bacteria employ a mechanism of cell–cell communication known as quorum sensing (QS). The role of QS is to enable the cells in a culture to coordinate their gene expression profile with changes in the population cell density. The best characterized mechanisms of QS employ N-acylated homoserine lactones (AHLs) as signalling molecules. These AHLs are made by enzymes known as Luxl homologs, and accumulate in the culture supernatant at a rate proportional to the increase in cell density. Once the AHL concentration exceeds a certain threshold value, these ligands bind to intracellular receptors known as LuxR homologs. The latter are transcriptional regulators, whose activity alters upon binding the AHL ligand, thereby eliciting a change in gene transcription. Over the last five years, it has become increasingly obvious that this is a rather simplistic view of AHL-dependent QS, and that in fact, there is considerable diversity in the way in which Luxl-R homologs operate. The aim of the current review is to describe these variations on the basic theme, and to show how functional genomics is revolutionizing our understanding of QS-controlled regulons.

The creation of carbon–carbon and carbon–heteroatom bonds by the oxidation of organocuprates is useful in a range of challenging contexts including the formation of biaryl bonds within medium rings, diene synthesis and the coupling of tertiary carbon centres. This tutorial reviewintroduces these applications and recent developments which have served to improve its functional group tolerance and its utility in organic synthesis.

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Chemical genetics is the study of biological systems using small molecule ‘chemical’ intervention, instead of only genetic intervention. Cell-permeable and selective small molecules can be used to perturb protein function rapidly, reversibly and conditionally with temporal and quantitative control in any biological system. This tutorial reviewhas been written to introduce this emerging field to a broad audience and focuses later on areas of biology where either it has made a significant impact, or it has the potential to do so: signalling, cytoskeleton, development, protein–protein interactions and gene transcription.

Intramolecular Diels–Alder reactionof a simple macrocyclic bis‐dihydropyridine precursor 1resulted in the formation of a complex marine alkaloid keramaphidin B, thus verifying a biosynthetic theory.

A synthetic approach to functionalised hydroisoquinoline rings, using dihydropyridinium ions as dienophiles in the Diels-Alder reaction, is described.

The high-amplitude sucking (HAS) paradigm was used to evaluate the ability of one- to four-month-old infants to discriminate two artificially synthesized disyllables (/ba bá and bá ba/) which differed solely in the location of perceived stress. One hundred and twenty infants were tested in two experiments. A modification of the HAS paradigm was developed, in which both stimuli are alternated postshift. The results of the first experiment demonstrate that young infants are able to discriminate the acoustic correlates of stress location (fundamental frequency, intensity, and duration) and that the modified HAS paradigm produces significantly stronger evidence for this discrimination than does the standard paradigm. The second experiment determined that infants can discriminate durational differences alone, without concomitant variations in the naturally correlated parameters of fundamental frequency and intensity.

Vielfalt ist Trumpf: Die Synthese einer Bibliothek naturstoffähnlicher Moleküle mit bislang unerreichter Gerüstdiversität wurde kürzlich beschrieben. Die entwickelte Methode markiert einen wichtigen Fortschritt in der Synthesechemie zur schnellen Erzeugung von strukturell diversen und komplexen Molekülen.

Building a better library: The synthesis of a library of natural‐product‐like small molecules with unprecedented scaffold diversity has been reported (see scheme; Ns=nosylate). The library represents a significant advancement in the capability of synthetic chemists to generate structurally diverse and complex small molecules in a rapid manner.

A wide range of organozinc substrates may be oxidized in the presence of catalytic copper to give carbon–carbon bonds in high yield.

A branching synthetic strategy was used to efficiently generate structurally diverse scaffolds, which span a broad area of chemical descriptor space, and their biological activity against MRSA was demonstrated.

The biomimetic synthesis of a pentacyclic alkaloid (keramaphidin B, 1), an intermediate in the biogenetic pathway to the manzamine alkaloids, has been achieved. Compound 1 was formed by an intramolecular Diels–Alder reaction of macrocycle 2 in buffer followed by reduction with NaBH4. This reaction provides the first direct expeimental evidence for the authors' biosynthetic hypothesis.

Die biomimetische Synthese eines pentacyclischen Alkaloids (Keramaphidin B, 1), eines Zwischenprodukts bei der Biogenese der Manzaminalkaloide, wurde abgeschlossen. Durch intramolekulare Diels-Alder-Reaktion des Makrocyclus 2 in Pufferlösung und nachfolgende Reduktion mit NaBH4 wurde 1 gebildet. Damit ist erstmals ein direkter experimenteller Beweis für die Biosynthesehypothese der Autoren erbracht worden.

Aryl lithium reagents formed by directed lithiation reactions undergo transmetallation with copperi salts to form organocuprates, which may be efficiently oxidized to yield ortho-substituted biaryls.

Review: 199 refs.

The efficient and stereoselective method involves the oxidation of organocuprates, generated from alkenyl bromides.

The procedure described herein offers a novel, cost‐effective, fluoride‐free, operationally simple and robust alternative for the preparation of a wide range of substituted biaryl systems.

Review: 81 refs.

A new strategy for the synthesis of rare nitrogen‐linked eight‐membered biaryl ring systems is based on the generation of a highly active intramolecular form of copper.

Review: 86 refs.

Aliphatic and aromatic vinyldisiloxanes are applied in the fluoride‐free cross‐coupling reactions with aryl iodides to afford the (E)‐products mostly exclusively.

An efficient synthesis of PQS (IVa) and several analogues is presented.

A one‐pot tandem carbocupration/oxidation of alkynyl esters provides rapid access to highly substituted symmetrical 1,3‐dienes [cf.

The preparation methods for the (E)‐ and α‐disubstituted alkenes are developed using the reaction of pentafluorodimethylsilane (I) and alkynes (II) with the proper choice of a catalyst, yielding the corresponding pentafluorodimethylvinylsilanes, and the following cross‐coupling reaction with the aryl iodides [cf.

Review: 70 refs.

Review: 74 refs.

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