Knots may ultimately prove just as versatile and useful at the nanoscale as at the macroscale. However, the lack of synthetic routes to all but the simplest molecular knots currently prevents systematic investigation of the influence of knotting at the molecular level. We found that it is possible to assemble four building blocks into three braided ligand strands. Octahedral iron(II) ions control the relative positions of the three strands at each crossing point in a circular triple helicate, while structural constraints on the ligands determine the braiding connections. This approach enables two-step assembly of a molecular 8 knot featuring eight nonalternating crossings in a 192-atom closed loop ~20 nanometers in length. The resolved metal-free 8 knot enantiomers have pronounced features in their circular dichroism spectra resulting solely from topological chirality.

Introduction: Late-stage functionalization (LSF) can introduce important chemical groups in the very last steps of the synthesis. LSF has the potential to speed up the preparation of novel chemical entities and diverse chemical libraries and have a major impact on drug discovery. Functional group tolerance and mild conditions allows access to new molecules not easily accessible by conventional approaches without the need for laborious de novo chemical synthesis. Areas Covered: A historical overview of late-stage functionalization and its applicability to drug discovery is provided. Pioneering methodologies that laid the foundations for the field are briefly covered and archetypal examples of their application to drug discovery are discussed. Novel methodologies reported in the past few years mainly stemming from the recent renaissances of photoredox catalysis and radical chemistry are reviewed and their application to drug discovery considered. Expert opinion: It is envisioned that late-stage functionalization will improve the efficiency and efficacy of drug discovery. There is evidence of the widespread uptake of LSF by the medicinal chemistry community and it is expected that the recent and continuing endeavors of many academic laboratories and pharmaceutical companies will soon have an impact on drug development.

Post-translational modifications (PTMs) of proteins are becoming the focus of intense research due to their implications in a broad spectrum of neurodegenerative diseases. Various PTMs have been identified to alter the toxic profiles of proteins which play critical roles in disease etiology. In Alzheimer’s disease (AD), dysregulated phosphorylation is reported to promote pathogenic processing of the microtubule-associated tau protein. Among the PTMs, the enzymatic addition of N-acetyl-d-glucosamine (GlcNAc) residues to Ser/Thr residues is reported to deliver protective effects against the pathogenic processing of both amyloid precursor protein (APP) and tau. Modification of tau with as few as one single O-GlcNAc residue inhibits its toxic self-assembly. This modification also has the same effect on the assembly of the Parkinson’s disease (PD) associated α-synuclein (ASyn) protein. In fact, O-GlcNAcylation (O-linked GlcNAc modification) affects the processing of numerous proteins implicated in AD, PD, amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD) in a similar manner. As such, manipulation of a protein’s O-GlcNAcylation status has been proposed to offer therapeutic routes toward addressing multiple neurodegenerative pathologies. Here we review the various effects that O-GlcNAc modification, and its modulated expression, have on pathogenically significant proteins involved in neurodegenerative disease.

The α-helical coiled coil is one of the best-studied protein–protein interaction motifs. As a result, sequence-to-structure relationships are available for the prediction of natural coiled-coil sequences and the de novo design of new ones. However, coiled coils adopt a wide range of oligomeric states and topologies, and our understanding of the specification of these and the discrimination between them remains incomplete. Gaps in our knowledge assume more importance as coiled coils are used increasingly to construct biomimetic systems of higher complexity; for this, coiled-coil components need to be robust, orthogonal, and transferable between contexts. Here, we explore how the polar side chain asparagine (Asn, N) is tolerated within otherwise hydrophobic helix–helix interfaces of coiled coils. The long-held view is that Asn placed at certain sites of the coiled-coil sequence repeat selects one oligomer state over others, which is rationalized by the ability of the side chain to make hydrogen bonds, or interactions with chelated ions within the coiled-coil interior of the favored state. We test this with experiments on de novo peptide sequences traditionally considered as directing parallel dimers and trimers, and more widely through bioinformatics analysis of natural coiled-coil sequences and structures. We find that when located centrally, rather than near the termini of such coiled-coil sequences, Asn does exert the anticipated oligomer-specifying influence. However, outside of these bounds, Asn is observed less frequently in the natural sequences, and the synthetic peptides are hyperthermostable and lose oligomer-state specificity. These findings highlight that not all regions of coiled-coil repeat sequences are equivalent, and that care is needed when designing coiled-coil interfaces.

Current strategies for the synthesis of molecular knots focus on twisting, folding and/or threading molecular building blocks. Here we report that Zn(II) or Fe(II) ions can be used to weave ligand strands to form a woven 3×3 molecular grid. We find that the process requires tetrafluoroborate anions to template the assembly of the interwoven grid by binding within the square cavities formed between the metal-coordinated criss-crossed ligands. The strand ends of the grid can subsequently be joined through within-grid alkene metathesis reactions to form a topologically-trivial macrocycle (unknot), a doubly-interlocked [2]catenane (Solomon link) and a knot with seven crossings in a 258-atom-long closed loop. This 7 4 knot topology corresponds to that of the endless knot, which is a basic motif of Celtic interlace, the smallest Chinese knot and one of the eight auspicious symbols of Buddhism and Hinduism. The weaving of molecular strands within a discrete layer by anion template, metal ion coordination opens the way for the synthesis of other molecular knot topologies and to woven polymer materials.

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A molecular Solomon link was synthesized through the assembly of an interwoven molecular grid consisting of four bis(benzimidazolepyridyl)benzthiazolo[5,4-d]thiazole ligands and four zinc(II), iron(II), or cobalt(II) cations, followed by ring-closing olefin metathesis. NMR spectroscopy, mass spectrometry, and X-ray crystallography confirmed the doubly interlocked topology, and subsequent demetalation afforded the wholly organic Solomon link. The synthesis, in which each metal ion defines the crossing point of two ligand strands, suggests that interwoven molecular grids should be useful scaffolds for the rational construction of other topologically complex structures.

[4]Rotaxanes featuring three axles threaded through a single ring have been prepared through active metal template synthesis. Nickel-catalyzed sp(3)-sp(3) homocouplings of alkyl bromide "half-threads" through 37- and 38-membered 2,2':6',2″-terpyridyl macrocycles generate triply threaded [4]rotaxanes in up to 11% yield. An analogous 39-membered macrocycle produced no rotaxane products under similar conditions. The constitutions of the [4]rotaxanes were determined by NMR spectroscopy and mass spectrometry. Doubly threaded [3]rotaxanes were also obtained from the reactions but no [2]rotaxanes were isolated, suggesting that upon demetalation the axle of a singly threaded rotaxane can slip through a macrocycle that is sufficiently large to accommodate three threads.