The synthesis of four quinolone natural products from the actinomycete Pseudonocardia sp. is reported. The key step involved a sp²–sp³ Suzuki–Miyaura reaction between a common boronic ester lateral chain and various functionalised quinolone cores. The quinolones slowed growth of E. coli and S. aureus by inducing extended lag phases.

Photoaffinity labelling is a useful method for studying how proteins interact with ligands and biomolecules, and can help identify and characterise new targets for the development of new therapeutics. We present the design and synthesis of a novel multifunctional benzophenone linker that serves as both a photo-crosslinking motif and a peptide stapling reagent. Using double-click stapling, we attached the benzophenone to the peptide via the staple linker, rather than by modifying the peptide sequence with a photo-crosslinking amino acid. When applied to a p53-derived peptide, the resulting photoreactive stapled peptide was able to preferentially crosslink with MDM2 in the presence of competing protein. This multifunctional linker also features an extra alkyne handle for downstream applications such as pull-down assays, and can be used to investigate the target selectivity of stapled peptides.

Peptide stapling is a method for designing macrocyclic alpha-helical inhibitors of protein–protein interactions. However, obtaining a cell-active inhibitor can require significant optimization. We report a novel stapling technique based on a double strain-promoted azide–alkyne reaction, and exploit its biocompatibility to accelerate the discovery of cell-active stapled peptides. As a proof of concept, MDM2-binding peptides were stapled in parallel, directly in cell culture medium in 96-well plates, and simultaneously evaluated in a p53 reporter assay. This in situ stapling/screening process gave an optimal candidate that showed improved proteolytic stability and nanomolar binding to MDM2 in subsequent biophysical assays. α-Helicity was confirmed by a crystal structure of the MDM2-peptide complex. This work introduces in situ stapling as a versatile biocompatible technique with many other potential high-throughput biological applications.

Peptide stapling is a method for designing macrocyclic alpha-helical inhibitors of protein–protein interactions. However, obtaining a cell-active inhibitor can require significant optimization. We report a novel stapling technique based on a double strain-promoted azide–alkyne reaction, and exploit its biocompatibility to accelerate the discovery of cell-active stapled peptides. As a proof of concept, MDM2-binding peptides were stapled in parallel, directly in cell culture medium in 96-well plates, and simultaneously evaluated in a p53 reporter assay. This in situ stapling/screening process gave an optimal candidate that showed improved proteolytic stability and nanomolar binding to MDM2 in subsequent biophysical assays. α-Helicity was confirmed by a crystal structure of the MDM2-peptide complex. This work introduces in situ stapling as a versatile biocompatible technique with many other potential high-throughput biological applications.

The 4H-quinolizin-4-one scaffold is of significant pharmaceutical interest. This heterocyclic structure is predicted to have attractive physico-chemical properties and is present in a variety of biologically active molecules. Despite these interesting characteristics, 4H-quinolizin-4-ones are largely under-represented in current small molecule screening libraries, and, therefore, this scaffold has been poorly investigated. Herein, a new strategy is reported for the syntheses of these rare and biologically interesting 4H-quinolizin-4-ones. This modular route involves the regioselective N-alkylation of 6-halo-2-pyridones followed by a Stille cross-coupling, ring-closing metathesis, and palladium-catalyzed dehydrogenation reaction sequence. This method furnishes the target compounds in good yields and allows for access to unusual substitution patterns that are difficult to achieve by using other synthetic strategies.

We investigated linear aliphatic dialkynes as a new structural class of i,i+7 linkers for the double-click stapling of p53-based peptides. The optimal combination of azido amino acids and dialkynyl linker length for MDM2 binding was determined. In a direct comparison between aliphatic and aromatic staple scaffolds, the aliphatic staples resulted in superior binding to MDM2 in vitro and superior p53-activating capability in cells when using a diazidopeptide derived from phage display. This work demonstrates that the nature of the staple scaffold is an important factor that can affect peptide bioactivity in cells.

Small-molecule modulators of biological targets play a crucial role in biology and medicine. In this context, diversity-oriented synthesis (DOS) provides strategies toward generating small molecules with a broad range of unique scaffolds, and hence three-dimensionality, to target a broad area of biological space. In this study, an organocatalysis-derived DOS library of macrocycles was synthesized by exploiting the pluripotency of aldehydes. The orthogonal combination of multiple diversity-generating organocatalytic steps with alkene metathesis enabled the synthesis of 51 distinct macrocyclic structures bearing 48 unique scaffolds in only two to four steps without the need for protecting groups. Furthermore, merging organocatalysis and alkene metathesis in a one-pot protocol facilitated the synthesis of drug-like macrocycles with natural-product-like levels of shape diversity in a single step.

Small-molecule modulators of biological targets play a crucial role in biology and medicine. In this context, diversity-oriented synthesis (DOS) provides strategies toward generating small molecules with a broad range of unique scaffolds, and hence three-dimensionality, to target a broad area of biological space. In this study, an organocatalysis-derived DOS library of macrocycles was synthesized by exploiting the pluripotency of aldehydes. The orthogonal combination of multiple diversity-generating organocatalytic steps with alkene metathesis enabled the synthesis of 51 distinct macrocyclic structures bearing 48 unique scaffolds in only two to four steps without the need for protecting groups. Furthermore, merging organocatalysis and alkene metathesis in a one-pot protocol facilitated the synthesis of drug-like macrocycles with natural-product-like levels of shape diversity in a single step.

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 Hiyama cross-coupling reaction is a powerful method for carbon–carbon bond formation. To date, the substrate scope of this reaction has predominantly been limited to sp²–sp² coupling reactions. Herein, the palladium-catalysed Hiyama type cross-coupling of vinyldisiloxanes with benzylic and allylic bromides, chlorides, tosylates and mesylates is reported. A wide variety of functional groups were tolerated, and the synthetic utility of the methodology was exemplified through the efficient total synthesis of the cytotoxic natural product bussealin A. In addition, the antiproliferative ability of bussealin A was evaluated in two cancer-cell lines.

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 1 with 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 1 a 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 2 an efficient sensor to discriminate ATP from ADP.

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 (CH)⁺⋅⋅⋅F⁻-type ionic hydrogen bonds. ¹H NMR, ¹⁹F NMR, and fluorescence spectra of 1 and 2 with fluoride ions are examined to show that only 2 can 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 2 centered at 474 nm. Finally, isothermal titration calorimetry (ITC) experiments were performed to obtain the binding constants of the compounds 1 and 2 with 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.

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.