Knotting a molecular strand can invert macroscopic effects of chirality

Transferring structural information from the nanoscale to the macroscale is a promising strategy for developing adaptive and dynamic materials. Here we demonstrate that the knotting and unknotting of a molecular strand can be used to control, and even invert, the handedness of a helical organization within a liquid crystal. An oligodentate tris(2,6-pyridinedicarboxamide) strand with six point-chiral centres folds into an overhand knot of single handedness upon coordination to lanthanide ions, both in isotropic solutions and in liquid crystals. In achiral liquid crystals, dopant knotted and unknotted strands induce supramolecular helical organizations of opposite handedness, with dynamic switching achievable through in situ knotting and unknotting events. Tying the molecular knot transmits information regarding asymmetry across length scales, from Euclidean point chirality (constitutional chirality) via molecular entanglement (conformation) to liquid-crystal (centimetre-scale) chirality. The magnitude of the effect induced by the tying of the molecular knots is similar to that famously used to rotate a glass rod on the surface of a liquid crystal by synthetic molecular motors. [Figure not available: see fulltext.

Effect of aliskiren on post-discharge outcomes among diabetic and non-diabetic patients hospitalized for heart failure: insights from the ASTRONAUT trial

Aims The objective of the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) was to determine whether aliskiren, a direct renin inhibitor, would improve post-discharge outcomes in patients with hospitalization for heart failure (HHF) with reduced ejection fraction. Pre-specified subgroup analyses suggested potential heterogeneity in post-discharge outcomes with aliskiren in patients with and without baseline diabetes mellitus (DM). Methods and results ASTRONAUT included 953 patients without DM (aliskiren 489; placebo 464) and 662 patients with DM (aliskiren 319; placebo 343) (as reported by study investigators). Study endpoints included the first occurrence of cardiovascular death or HHF within 6 and 12 months, all-cause death within 6 and 12 months, and change from baseline in N-terminal pro-B-type natriuretic peptide (NT-proBNP) at 1, 6, and 12 months. Data regarding risk of hyperkalaemia, renal impairment, and hypotension, and changes in additional serum biomarkers were collected. The effect of aliskiren on cardiovascular death or HHF within 6 months (primary endpoint) did not significantly differ by baseline DM status (P = 0.08 for interaction), but reached statistical significance at 12 months (non-DM: HR: 0.80, 95% CI: 0.64-0.99; DM: HR: 1.16, 95% CI: 0.91-1.47; P = 0.03 for interaction). Risk of 12-month all-cause death with aliskiren significantly differed by the presence of baseline DM (non-DM: HR: 0.69, 95% CI: 0.50-0.94; DM: HR: 1.64, 95% CI: 1.15-2.33; P < 0.01 for interaction). Among non-diabetics, aliskiren significantly reduced NT-proBNP through 6 months and plasma troponin I and aldosterone through 12 months, as compared to placebo. Among diabetic patients, aliskiren reduced plasma troponin I and aldosterone relative to placebo through 1 month only. There was a trend towards differing risk of post-baseline potassium ≥6 mmol/L with aliskiren by underlying DM status (non-DM: HR: 1.17, 95% CI: 0.71-1.93; DM: HR: 2.39, 95% CI: 1.30-4.42; P = 0.07 for interaction). Conclusion This pre-specified subgroup analysis from the ASTRONAUT trial generates the hypothesis that the addition of aliskiren to standard HHF therapy in non-diabetic patients is generally well-tolerated and improves post-discharge outcomes and biomarker profiles. In contrast, diabetic patients receiving aliskiren appear to have worse post-discharge outcomes. Future prospective investigations are needed to confirm potential benefits of renin inhibition in a large cohort of HHF patients without D

Stereoselective Synthesis of Molecular Square and Granny Knots

We report on the stereoselective synthesis of both molecular granny and square knots through the use of lanthanide-complexed overhand knots of specific handedness as three-crossing “entanglement synthons”. The composite knots are assembled by combining two entanglement synthons (of the same chirality for a granny knot; of opposite handedness for a square knot) in three synthetic steps: first, a CuAAC reaction joins together one end of each overhand knot. Ring-closing olefin metathesis (RCM) then affords the closed-loop knot, locking the topology. This allows the lanthanide ions necessary for stabilizing the entangled conformation of the synthons to subsequently be removed. The composite knots were characterized by 1H and 13C NMR spectroscopy and mass spectrometry and the chirality of the knot stereoisomers compared by circular dichroism. The synthetic strategy of combining building blocks of defined stereochemistry (here overhand knots of Λ- or Δ-handed entanglement) is reminiscent of the chiron approach of using minimalist chiral synthons in the stereoselective synthesis of molecules with multiple asymmetric centers

Mechanical scission of a knotted polymer

Molecular knots and entanglements form randomly and spontaneously in both biological and synthetic polymer chains. It is known that macroscopic materials, such as ropes, are substantially weakened by the presence of knots, but until now it has been unclear whether similar behaviour occurs on a molecular level. Here we show that the presence of a well-defined overhand knot in a polymer chain substantially increases the rate of scission of the polymer under tension (≥2.6× faster) in solution, because deformation of the polymer backbone induced by the tightening knot activates otherwise unreactive covalent bonds. The fragments formed upon severing of the knotted chain differ from those that arise from cleavage of a similar, but unknotted, polymer. Our solution studies provide experimental evidence that knotting can contribute to higher mechanical scission rates of polymers. It also demonstrates that entanglement design can be used to generate mechanophores that are among the most reactive described to date, providing opportunities to increase the reactivity of otherwise inert functional groups

Social Self-Sorting Synthesis of Molecular Knots

[Image: see text] We report the synthesis of molecular prime and composite knots by social self-sorting of 2,6-pyridinedicarboxamide (pdc) ligands of differing topicity and stereochemistry. Upon mixing achiral monotopic and ditopic pdc-ligand strands in a 1:1:1 ratio with Lu(III), a well-defined heteromeric complex featuring one of each ligand strand and the metal ion is selectively formed. Introducing point-chiral centers into the ligands leads to single-sense helical stereochemistry of the resulting coordination complex. Covalent capture of the entangled structure by ring-closing olefin metathesis then gives a socially self-sorted trefoil knot of single topological handedness. In a related manner, a heteromeric molecular granny knot (a six-crossing composite knot featuring two trefoil tangles of the same handedness) was assembled from social self-sorting of ditopic and tetratopic multi-pdc strands. A molecular square knot (a six-crossing composite knot of two trefoil tangles of opposite handedness) was assembled by social self-sorting of a ditopic pdc strand with four (S)-centers and a tetratopic strand with two (S)- and six (R)-centers. Each of the entangled structures was characterized by (1)H and (13)C NMR spectroscopy, mass spectrometry, and circular dichroism spectroscopy. The precise control of composition and topological chirality through social self-sorting enables the rapid assembly of well-defined sequences of entanglements for molecular knots

Dissipative Catalysis with a Molecular Machine

We report on catalysis by a fuel-induced transient state of a synthetic molecular machine. A [2]rotaxane molecular shuttle containing secondary ammonium/amine and thiourea stations is converted between catalytically inactive and active states by pulses of a chemical fuel (trichloroacetic acid), which is itself decomposed by the machine and/or the presence of additional base. The ON-state of the rotaxane catalyzes the reduction of a nitrostyrene by transfer hydrogenation. By varying the amount of fuel added, the lifetime of the rotaxane ON-state can be regulated and temporal control of catalysis achieved. The system can be pulsed with chemical fuel several times in succession, with each pulse activating catalysis for a time period determined by the amount of fuel added. Dissipative catalysis by synthetic molecular machines has implications for the future design of networks that feature communication and signaling between the components

Effects of turn-structure on folding and entanglement in artificial molecular overhand knots

The length and constitution of spacers linking three 2,6-pyridinedicarboxamide units in a molecular strand influence the tightness of the resulting overhand (open-trefoil) knot that the strand folds into in the presence of lanthanide(iii) ions. The use of β-hairpin forming motifs as linkers enables a metal-coordinated pseudopeptide with a knotted tertiary structure to be generated. The resulting pseudopeptide knot has one of the highest backbone-to-crossing ratios (BCR)—a measure of knot tightness (a high value corresponding to looseness)—for a synthetic molecular knot to date. Preorganization in the crossing-free turn section of the knot affects aromatic stacking interactions close to the crossing region. The metal-coordinated pseudopeptide knot is compared to overhand knots with other linkers of varying tightness and turn preorganization, and the entangled architectures characterized by NMR spectroscopy, ESI-MS, CD spectroscopy and, in one case, X-ray crystallography. The results show how it is possible to program specific conformational properties into different key regions of synthetic molecular knots, opening the way to systems where knotting can be systematically incorporated into peptide-like chains through design