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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.

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.

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.

Review: 199 refs.

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

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.

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