Diversely Functionalised Cytochalasins through Mutasynthesis and Semi-Synthesis

Mutasynthesis of pyrichalasin H from Magnaporthe grisea NI980 yielded a series of unprecedented 4′-substituted cytochalasin analogues in titres as high as the wild-type system (≈60 mg L⁻¹). Halogenated, O-alkyl, O-allyl and O-propargyl examples were formed, as well as a 4′-azido analogue. 4′-O-Propargyl and 4′-azido analogues reacted smoothly in Huisgen cycloaddition reactions, whereas p-Br and p-I compounds reacted in Pd-catalysed cross-coupling reactions. A series of examples of biotin-linked, dye-linked and dimeric cytochalasins was rapidly created. In vitro and in vivo bioassays of these compounds showed that the 4′-halogenated and azido derivatives retained their cytotoxicity and antifungal activities; but a unique 4′-amino analogue was inactive. Attachment of larger substituents attenuated the bioactivities. In vivo actin-binding studies with adherent mammalian cells showed that actin remains the likely intracellular target. Dye-linked compounds revealed visualisation of intracellular actin structures even in the absence of phalloidin, thus constituting a potential new class of actin-visualisation tools with filament-barbed end-binding specificity.     

Discovery of Homobivalent Bitopic Ligands of the Cannabinoid CB2 Receptor**

Single chemical entities with potential to simultaneously interact with two binding sites are emerging strategies in medicinal chemistry. We have designed, synthesized and functionally characterized the first bitopic ligands for the CB₂ receptor. These compounds selectively target CB₂ versus CB₁ receptors. Their binding mode was studied by molecular dynamic simulations and site-directed mutagenesis.     

Pandemic-Driven Development of a Medical-Grade,Economic and Decentralized Applicable Polyolefin Filament for Additive Fused Filament Fabrication

A polyolefin with certified biocompatibility according to USP class VI was used by our group as feedstock for filament-based 3D printing to meet the highest medical standards in order to print personal protective equipment for our university hospital during the ongoing pandemic. Besides the chemical resistance and durability, as well as the ability to withstand steam sterilization, this polypropylene (PP) copolymer is characterized by its high purity, as achieved by highly efficient and selective catalytic polymerization. As the PP copolymer is suited to be printed with all common printers in fused filament fabrication (FFF), it offers an eco-friendly cost–benefit ratio, even for large-scale production. In addition, a digital workflow was established focusing on common desktop FFF printers in the medical sector. It comprises the simulation-based optimization of personalized print objects, considering the inherent material properties such as warping tendency, through to validation of the process chain by 3D scanning, sterilization, and biocompatibility analysis of the printed part. This combination of digital data processing and 3D printing with a sustainable and medically certified material showed great promise in establishing decentralized additive manufacturing in everyday hospital life to meet peaks in demand, supply bottlenecks, and enhanced personalized patient treatment.     

Metalla‐Assembled Electron‐Rich Tweezers: Redox‐Controlled Guest Release Through Supramolecular Dimerization

Developing methodologies for on‐demand control of the release of a molecular guest requires the rational design of stimuli‐responsive hosts with functional cavities. While a substantial number of responsive metallacages have already been described, the case of coordination‐tweezers has been less explored. Herein, we report the first example of a redox‐triggered guest release from a metalla‐assembled tweezer. This tweezer incorporates two redox‐active panels constructed from the electron‐rich 9‐(1,3‐dithiol‐2‐ylidene)fluorene unit that are facing each other. It dimerizes spontaneously in solution and the resulting interpenetrated supramolecular structure can dissociate in the presence of an electron‐poor planar unit, forming a 1:1 host–guest complex. This complex dissociates upon tweezer oxidation/dimerization, offering an original redox‐triggered molecular delivery pathway.     

Covalent Adaptable Networks with Tunable Exchange Rates Based on Reversible Thiol–yne Cross‐Linking

The design of covalent adaptable networks (CANs) relies on the ability to trigger the rearrangement of bonds within a polymer network. Simple activated alkynes are now used as versatile reversible cross‐linkers for thiols. The click‐like thiol–yne cross‐linking reaction readily enables network synthesis from polythiols through a double Michael addition with a reversible and tunable second addition step. The resulting thioacetal cross‐linking moieties are robust but dynamic linkages. A series of different activated alkynes have been synthesized and systematically probed for their ability to produce dynamic thioacetal linkages, both in kinetic studies of small molecule models, as well as in stress relaxation and creep measurements on thiol–yne‐based CANs. The results are further rationalized by DFT calculations, showing that the bond exchange rates can be significantly influenced by the choice of the activated alkyne cross‐linker.     

Selective Enzymatic Oxidation of Silanes to Silanols

Compared to the biological world's rich chemistry for functionalizing carbon, enzymatic transformations of the heavier homologue silicon are rare. We report that a wild‐type cytochrome P450 monooxygenase (P450_BM3 from Bacillus megaterium, CYP102A1) has promiscuous activity for oxidation of hydrosilanes to give silanols. Directed evolution was applied to enhance this non‐native activity and create a highly efficient catalyst for selective silane oxidation under mild conditions with oxygen as the terminal oxidant. The evolved enzyme leaves C?H bonds present in the silane substrates untouched, and this biotransformation does not lead to disiloxane formation, a common problem in silanol syntheses. Computational studies reveal that catalysis proceeds through hydrogen atom abstraction followed by radical rebound, as observed in the native C?H hydroxylation mechanism of the P450 enzyme. This enzymatic silane oxidation extends nature's impressive catalytic repertoire.     

Air‐Stable Oxyallyl Patterns and a Switchable N‐Heterocyclic Carbene

Oxyallyl derivatives are typically elusive compounds. Even recently reported “stabilized” 1,3‐diaminooxyallyl species are still highly reactive and have short lifetimes at room temperature. Herein, we report the synthesis and preliminary study of mesoionic pyrimidine derivatives that feature 1,3‐bis(dimethylamino)oxyallyl patterns with an unprecedented level of stabilization. The latter are not only insensitive towards air and moisture, but they are also compatible with the formation of an ancillary stable N‐heterocyclic carbene moiety. As the oxyallyl pattern is proton‐responsive, it allows the reversible switching of the electronic properties of the carbene, as a ligand.     

What's Hot,What's Not: The Trends of the Past 20 Years in the Chemistry of Odorants

This review is the sequel to the 2000 report on the recent advances in the chemistry of odorants and it summarizes the developments in fragrance chemistry over the past 20 years. Following the olfactory spectrum set out in that report, trendsetting so‐called captive odorants (patent‐protected ingredients unavailable to the market) are presented according to the main odor families: “fruity”, “marine”, “green”, “floral”, “spicy”, “woody”, “amber”, and “musky”. The design of odorants, their chemical synthesis, and their use in modern perfumery are illustrated with prominent examples. Featured are new fruity odorants that provide signature in the top note, as well as precursor technology. In the green domain, focus is on leafy notes and green pear. New benzodioxepines and benzodioxoles have modernized the marine family and required a revision of the existing olfactophore models. The replacement of Lilial and Lyral kept the industry busy in the floral domain with a plethora of new “muguets”. There was continued activity in the domain of rose odorants, especially in the area of rose ketones. Biotechnology became significant, for example, with Clearwood and Ambrofix, and the principal odorants of vetiver oil in the woody family have been found. Fourth and fifth families of musk odorants were also discovered and populated. Thus, new avenues for further explorations into fragrance chemistry have been opened.     

Modification of Adhesive and Latex Properties for Starch Nanoparticle‐Based Pressure Sensitive Adhesives

Starch nanoparticle (SNP)‐based pressure sensitive adhesives (PSAs) with core‐shell particle morphology (starch nanoparticle core/acrylic polymer shell) are produced via seeded, semi‐batch emulsion polymerization at 15 wt% SNP loading (relative to total polymer weight) and 40 wt% latex solids. Crosslinker and chain transfer agent (CTA) are introduced to the acrylic shell polymer formulation at a range of concentrations according to a 3² factorial design to tailor the latex and adhesive properties of SNP‐based latexes. The crosslinker and CTA show no significant effect on polymerization kinetics, particle size, and viscosity. Latex gel content is predicted using an empirical model, which is a function of crosslinker and CTA concentration. Both the gel content and glass transition temperature strongly affect the adhesive properties (tack, peel strength, and shear strength) of the SNP‐based latex films. 3D response surfaces for the adhesive properties are constructed to facilitate the design of SNP‐based PSAs with desired properties.