Volume 16 Issue 2, February 2024

Despite the growing clinical use of radium in cancer treatments, the fundamental chemistry of nature’s largest +2 cation remains largely unexplored. Now, structural analysis of a radium complex reveals that its behaviour cannot always be predicted from the chemistry of its closest nonradioactive congener, barium.

Cryptic halogenation reactions result in natural products with diverse structural motifs and bioactivities. However, these halogenated species are difficult to detect with current analytical methods because the final products are often not halogenated. An approach to identify products of cryptic halogenation using halide depletion has now been discovered, opening up space for more effective natural product discovery.

Directional interactions and three-dimensional functional groups are crucial to medicinal compounds. Consequently, new functional groups require stereocontrolled synthetic methods. Now, an enantiopure building block provides controlled and divergent access to valuable sulfonimidoyl functional groups.

Interlocking unstable motifs is a useful way to enhance their stability through shielding protection. Now, stable interlocked polyynes bearing several macrocycles have been prepared, including a [5]rotaxane having 34 contiguous alkynes with properties similar to those of carbyne.

Bottom-up assembly of protocells into networking superstructures represents a further key step towards rudimentary formation of life. Now it has been shown that a pool of biomolecules can self-organize into an interactive binary population of protocell coacervates with a self-sorting chain-like configuration, allowing for biomolecular extraction, translocation and macroscale separation.

Radium complexes are of interest for use as cancer therapeutic agents, but the structure and bonding are poorly understood. Here, the synthesis of a Ra²⁺ complex is reported, and the structure and bonding characteristics are elucidated using single-crystal X-ray diffraction.

Natural products discovery remains an ongoing challenge. Now, halide depletion offers a complementary approach to discover natural products whose biosynthesis requires halides, including products of cryptic halogenation. Halide depletion reveals that nostochlorosides, the products of an orphan biosynthetic gene cluster in Nostoc punctiforme, are polymerized by a halide-displacing etherifying enzyme.

The stereochemical control and bifunctional manipulation of chiral sulfur functional groups is a long-standing challenge. Now, an enantiopure bench-stable S(VI) fluoride exchange reagent enables the asymmetric synthesis of sulfoximines, sulfonimidamides and sulfonimidoyl fluorides. The bifunctional nature of this reagent provides a practical method for the introduction of S(VI) functionality.

Long polyynes have fascinating properties but they are difficult to synthesize as a consequence of their high reactivity. Now, it has been shown that cobalt carbonyl complexes can be used as masked alkyne equivalents, enabling the preparation of stable polyyne polyrotaxanes with up to 34 contiguous triple bonds.

The synthesis of two-dimensional (2D) organic lateral heterostructures with desirable properties from organic single crystals remains challenging. Now, 2D organic lateral heterostructures have been produced by using a liquid-phase growth approach and vapour-phase growth method, enabling the structural inversion of organic lateral heterostructures via a two-step strategy.

Sequences of synthetic polymers are generally heterogeneous and dictate many of their physiochemical properties, but are challenging to determine. Now an imaging method, termed CREATS (coupled reaction approach toward super-resolution imaging), can count, localize and identify each monomer of single polymer chains during (co)polymerization.

Current proteolysis-targeting chimeras can promote the ubiquitination and subsequent degradation of both target and off-target proteins by inducing their respective proximity with the cereblon ubiquitin ligase. Now, by developing and deploying an off-target profiling platform, ‘bumped proteolysis-targeting chimeras’ can maintain on-target degradation efficacy with reduced off-targets.

Detecting genetic mutations, such as single nucleotide polymorphisms (SNPs), is essential for disease diagnostics but can be difficult using homomultivalent DNA hybridization-based approaches. Now, heteromultivalent hybridization is used to fine-tune binding specificity for the detection of one or two SNPs in a single target, enabling straightforward discrimination between adjacent and distant mutations and different viral strains.

Late-stage functionalization of complex drug molecules is challenging. To address this problem, a discovery platform based on geometric deep learning and high-throughput experimentation was developed. The computational model predicts binary reaction outcome, reaction yield and regioselectivity with low error margins, enabling the functionalization of complex molecules without de novo synthesis.

Nucleoside diphosphates and triphosphates impact nearly every aspect of biochemistry. Now, a modular, reagent-based platform has been developed to enable the stereocontrolled and scalable synthesis of a library of such molecules. This operationally simple approach provides access to pure stereoisomers of nucleoside α-thiodiphosphates and α-thiotriphosphates.

Many natural products are produced by non-ribosomal peptide synthetases in an assembly-line fashion. How these molecular machines orchestrate the biochemical sequences has remained elusive. It is now understood that an extended-conformation ensemble is needed to coordinate chemical-transformation steps whereas the biosynthesis directionality is driven by the enzyme’s innate conformational free energies.

Preparation of monocyclic 1,2-azaborines, a unique class of benzene isosteres, has been challenging. Now, an efficient and modular method has been developed to access diverse multi-substituted 1,2-azaborines from readily available cyclopropyl imines/ketones and dibromoboranes. The reaction goes through an unusual ring-opening BN-isostere benzannulation mechanism.

The inherent rigidity of the azaarene ring structure has made it challenging to achieve remote stereocontrol through asymmetric catalysis on these substrates. Now, through a photoenzymatic process, an ene-reductase system facilitates the production of diverse azaarenes with distant γ-stereocentres, highlighting the potential of biocatalysts for stereoselectivity at remote sites.

The bicyclo[1.1.1]pentane (BCP) motif has drawn increasing attention recently in drug discovery. Now, a programmable bis-functionalization strategy has been developed to modularly access bridge-substituted BCP scaffolds, based on the inherent chemoselectivity of BCP bis-boronates (3° > 2°). This strategy should enable further structure–activity relationship studies of BCP-containing drug candidates and open the door to unexplored chemical space.

Thomas Kruse and Søren Østergaard reflect on the development of the GLP-1 analogue, semaglutide, which is reshaping peptide therapeutics in type 2 diabetes, weight management, and beyond.