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We describe the use of low-molecular-weight supramolecular gels as media for the growth of molecular crystals. Growth of a range of crystals of organic compounds, including pharmaceuticals, was achieved in bis(urea) gels. Low-molecular-weight supramolecular gelators allow access to an unlimited range of solvent systems, in contrast to conventional aqueous gels such as gelatin and agarose. A detailed study of carbamazepine crystal growth in four different bis(urea) gelators, including a metallogelator, is reported. The crystallization of a range of other drug substances, namely sparfloxacin, piroxicam, theophylline, caffeine, ibuprofen, acetaminophen (paracetamol), sulindac and indomethacin, was also achieved in supramolecular gel media without co-crystal formation. In many cases, crystals can be conveniently recovered from the gels by using supramolecular anion-triggered gel dissolution; however, crystals of substances that themselves bind to anions are dissolved by them. Overall, supramolecular gel-phase crystallization offers an extremely versatile new tool in pharmaceutical polymorph screening. Supramolecular gels based on small-molecule gelators have been shown to be effective media for the growth of organic crystals, including pharmaceutical compounds. Moreover, the gel-to-sol transition can be triggered by molecular recognition with anions, thereby enabling facile recovery of the crystals.

Bacteria possess transcription factors whose DNA-binding activity is altered upon binding to specific metals, but metal binding is not specific in vitro. Here we show that tight regulation of buffered intracellular metal concentrations is a prerequisite for metal specificity of Zur, ZntR, RcnR and FrmR in Salmonella Typhimurium. In cells, at non-inhibitory elevated concentrations, Zur and ZntR, only respond to Zn(II), RcnR to cobalt and FrmR to formaldehyde. However, in vitro all these sensors bind non-cognate metals, which alters DNA binding. We model the responses of these sensors to intracellular-buffered concentrations of Co(II) and Zn(II) based upon determined abundances, metal affinities and DNA affinities of each apo- and metalated sensor. The cognate sensors are modelled to respond at the lowest concentrations of their cognate metal, explaining specificity. However, other sensors are modelled to respond at concentrations only slightly higher, and cobalt or Zn(II) shock triggers mal-responses that match these predictions. Thus, perfect metal specificity is fine-tuned to a narrow range of buffered intracellular metal concentrations. Bacteria possess transcription factors whose DNA-binding activity is altered upon binding to specific metals, but the binding of metals is not specific in vitro. Here, Osman et al. show that tight regulation of buffered intracellular metal concentrations is a prerequisite for metal specificity.

Three novel bis-urea fluorescent low-molecular-weight gelators (LMWGs) based on the tetraethyl diphenylmethane spacer—namely, L1, L2, and L3, bearing indole, dansyl, and quinoline units as fluorogenic fragments, respectively, are able to form gel in different solvents. L2 and L3 gel in apolar solvents such as chlorobenzene and nitrobenzene. Gelator L1 is able to gel in the polar solvent mixture DMSO/H2O (H2O 15% v/v). This allowed the study of gel formation in the presence of anions as a third component. An interesting anion-dependent gel formation was observed with fluoride and benzoate inhibiting the gelation process and H2PO4−, thus causing a delay of 24 h in the gel formation. The interaction of L1 with the anions in solution was clarified by 1H-NMR titrations and the differences in the cooperativity of the two types of NH H-bond donor groups (one indole NH and two urea NHs) on L1 when binding BzO− or H2PO4− were taken into account to explain the inhibition of the gelation in the presence of BzO−. DFT calculations corroborate this hypothesis and, more importantly, demonstrate considering a trimeric model of the L1 gel that BzO− favours its disruption into monomers inhibiting the gel formation.

Supramolecular gels are topical soft materials involving the reversible formation of fibrous aggregates using non-covalent interactions. There is significant interest in controlling the properties of such materials by the formation of multicomponent systems, which exhibit non-additive properties emerging from interaction of the components. The use of hydrogen bonding to assemble supramolecular gels in organic solvents is well established. In contrast, the use of halogen bonding to trigger supramolecular gel formation in a two-component gel (‘co-gel’) is essentially unexplored, and forms the basis for this study. Here, we show that halogen bonding between a pyridyl substituent in a bis(pyridyl urea) and 1,4-diiodotetrafluorobenzene brings about gelation, even in polar media such as aqueous methanol and aqueous dimethylsulfoxide. This demonstrates that halogen bonding is sufficiently strong to interfere with competing gel-inhibitory interactions and create a ‘tipping point’ in gel assembly. Using this concept, we have prepared a halogen bond donor bis(urea) gelator that forms co-gels with halogen bond acceptors. Supramolecular gels whose properties can be tuned through non-covalent interactions — typically metal coordination or hydrogen bonding — are attracting attention in various fields. Researchers have now shown that halogen bonding is also strong enough to be relied on; it interferes with competitive, gel-inhibitory hydrogen bonding to induce co-gelation between two urea-based components.

The study of supramolecular gels has developed into a well-recognised field of materials science, pertaining to the general area of soft matter. The use of small molecules that aggregate through supramolecular interactions (such as hydrogen bonds, π – π interactions, coordination bonds and van der Waals interactions) has given materials scientists an alternative to polymeric compounds for the development of practical gels. There have been further attempts to functionalize, activate or control the physical properties of such gels by means of the reversibility of the interactions between the component molecules. Tuning of these characteristics has been accomplished by using mechanical, thermal, electrochemical, electromagnetic and chemical stimuli. The use of anions as a chemical stimulus has been a recent development and is the subject of this Perspective. Small anions can be used to modulate the physical properties of supramolecular gels by interacting with the low-molecular-weight gelators from which such materials are composed. A better understanding of this anion-tuning effect will aid in the rational design of responsive gels that may prove useful for a number of practical applications.

Three simple bisamide derivatives (G1, G2 and G3) with different structural modifications were synthesized with easy synthetic procedures in order to test their gel behaviour. The outcomes showed that hydrogen bonding was essential in gel formation; for this reason, only G1 provided satisfactory gels. The presence of methoxy groups in G2 and the alkyl chains in G3 hindered the hydrogen bonding between N-H and C=O that occurred G1. In addition, G1 provided thermally and mechanical stable gels, as confirmed with Tsol and rheology experiments. The gels of G1 were also responsive under pH stimuli and were employed as a vehicle for drug crystallization, causing a change in polymorphism in the presence of flufenamic acid and therefore providing the most thermodynamically stable form III compared with metastable form IV obtained from solution crystallization.

There is a challenge for metalloenzymes to acquire their correct metals because some inorganic elements form more stable complexes with proteins than do others. These preferences can be overcome provided some metals are more available than others. However, while the total amount of cellular metal can be readily measured, the available levels of each metal have been more difficult to define. Metal-sensing transcriptional regulators are tuned to the intracellular availabilities of their cognate ions. Here we have determined the standard free energy for metal complex formation to which each sensor, in a set of bacterial metal sensors, is attuned: the less competitive the metal, the less favorable the free energy and hence the greater availability to which the cognate allosteric mechanism is tuned. Comparing these free energies with values derived from the metal affinities of a metalloprotein reveals the mechanism of correct metalation exemplified here by a cobalt chelatase for vitamin B 12 . The sensitivities of a set of bacterial metal-sensing transcriptional regulators explain how a protein, such as the cobalt chelatase CbiK, is metalated with its cognate metal in cells rather than mis-metalated with more tightly binding metals.

Helical nanofibres play key roles in many biological processes. Entanglements between helices can aid gelation by producing thick, interconnected fibres, but the details of this process are poorly understood. Here, we describe the assembly of an achiral oligo(urea) peptidomimetic compound into supramolecular helices. Aggregation of adjacent helices leads to the formation of fibrils, which further intertwine to produce high-fidelity braids with periodic crossing patterns. A braid theory analysis suggests that braiding is governed by rigid topological constraints, and that branching occurs due to crossing defects in the developing braids. Mixed-chirality helices assemble into relatively complex, odd-stranded braids, but can also form helical bundles by undergoing inversions of chirality. The oligo(urea) assemblies are also highly sensitive to chiral amplification, proposed to occur through a majority-rules mechanism, whereby trace chiral materials can promote the formation of gels containing only homochiral helices. Helical structures play important roles in biological processes, yet their aggregation into fibres—which can in turn form gels—is poorly understood. Now, the self-assembly of a linear pentakis (urea) peptidomimetic compound into helices that further intertwine into well-defined braided structures has been described and analysed through braid theory. Homochiral gels may be formed by exposing the precursor sol to a chiral material.

A series of podands based on two or three hydrogen bonding \"arms\" situated in mutually ortho, meta, or para relationships about an aryl core have been prepared, and their affinities for simple inorganic anions were measured. Of the two-arm hosts the meta compound and to a lesser extent the ortho host exhibit a cooperative anion binding effect. The two arms function essentially independently in the para derivative. The mutually meta three-arm host shows dramatically enhanced cooperative binding. Conformational changes within the meta two-arm host result in significantly enhanced electrochemical anion sensing compared with the more conformationally rigid three-arm host.