Recent Advances in the Synthesis of the Marine-Derived Alkaloid Fascaplysin and Its Metabolites Homofascaplysins A-C.

The fascaplysin and homofascaplysin class of marine natural products has a characteristic 12H-pyrido[1,2-a:3,4-b']diindole pentacyclic structure. Fascaplysin was isolated in 1988 from the marine sponge Fascaplysinopsis bergquist sp. The analogs of fascaplysin, such as homofascaplysins A, B, and C, were discovered late in the Fijian sponge F. reticulate, and also have potent antimicrobial activity and strong cytotoxicity against L-1210 mouse leukemia. In this review, the total synthesis of fascaplysin and its analogs, such as homofascaplysins A, B, and C, will be reviewed, which will offer useful information for medicinal chemistry researchers who are interested in the exploration of marine alkaloids.

Manipulating Assemblies in Metallosupramolecular Gels, Driven by Isomeric Ligands, Metal Coordination, and Adaptive Binary Gelator Systems.

Metallosupramolecular gel (MSG) is a unique combination of metal-ligand coordination chemistry and supramolecular gel chemistry with extraordinary adaptivity and softness. Such materials find broad uses in industry, pharmaceutical and biomedical sectors, and in technology generation among many others. Pyridyl-appended bis(urea) gelator systems have been extensively studied as potential MSG-forming materials in the presence of various metal ions. The previous molecular engineering approaches depicted competitive intermolecular and intramolecular binding modes involving urea and pyridyl groups and further fine-tuned by the presence of various molecular spacers. In those studies, formation of intermolecular hydrogen bonding among urea moieties to form urea tape was found to be the key factor in one-dimensional assembly and gel formation. In the present study, we show how two isomeric pyridyl-appended bis(urea) ligands can be designed appropriately to essentially eliminate the interference of competitive factors, leaving the intermolecular urea assembly practically unaffected even in the presence of metal ions. We found that one of the two ligands (L2) and the mixed ligand (L1 + L2) assemblies formed gel in the presence and absence of various metal ions. A metal ion with a linear coordination geometry significantly strengthened the gels. Moreover, an inherently weak L1 + L2 assembly appears to be more adaptive in accommodating larger metal ions especially with nonlinear coordination geometry preferences. Small-angle neutron scattering and rheological, spectroscopic, and morphological characterizations, collectively, capture a detailed interplay among ligand assembly, metal-ligand coordination, and adaptivity, driven by the pure versus mixed ligand assemblies. The knowledge gathered from the present study would be highly beneficial in engineering the metallosupramolecular polymeric assemblies toward their functional applications.

Effects of a Multicomponent Perfume Accord and Dilution on the Formation of ST2S/CAPB Mixed-Surfactant Microemulsions.

Perfume mixtures contain perfume raw materials (PRMs) with varying structures and hydrophobicities, which influence PRM localization within a surfactant-based formulation and thereby affect the phase behavior. In rinse-off products, the addition of water can further affect the phase behavior. In this study, a mixture of 12 PRMs was used as the oil phase in an aqueous system consisting of sodium trideceth-2 sulfate as a primary surfactant, cocamidopropyl betaine as a cosurfactant, and dipropylene glycol as a cosolvent. A series of phase diagrams were constructed with increasing water content, simulating the use conditions for rinse-off products, to determine how the phase boundaries shift with dilution. Using these phase diagrams, the compositions of interest in the micelle without perfume, micelle with perfume, microemulsion, and micelle-microemulsion transition regions were identified at each dilution level. The structural changes were probed through combined small-angle neutron scattering (SANS) and cryo-transmission electron microscopy analyses. The SANS results showed that ellipsoidal micelles were maintained as the perfume content and the dilution level increased. With ≥50 wt % water, increasing the perfume content increased the micelle volume. Interestingly, a higher rate of volume increase was observed at ≥70 wt % water. Notably, the volumes of the micelles with and without perfume increased steadily with dilution, whereas the volumes of the assemblies in the transition region and the microemulsion region increased more rapidly once diluted to 70 and 80 wt % water, respectively.

Recent synthetic methodologies for imidazo[1,5-a]pyridines and related heterocycles.

Imidazo[1,5-a]pyridine is a significant structural component of a large number of agrochemicals and pharmaceuticals. The synthesis of imidazo[1,5-a]pyridine has been a subject of intense research for numerous decades. A large number of transformations are now available to conveniently access imidazo[1,5-a]pyridine from readily available starting materials. This review details the recent development in imidazo[1,5-a]pyridine construction involving cyclocondensation, cycloaddition, oxidative cyclization, and transannulation reactions.

Structural insights into self-assembly of a slow-evolving and mechanically robust supramolecular gel via time-resolved small-angle neutron scattering.

The supramolecular assembly process is a widespread phenomenon found in both synthetically engineered and naturally occurring systems, such as colloids, liquid crystals and micelles. However, a basic understanding of the evolution of self-assembly processes over time remains elusive, primarily owing to the fast kinetics involved in these processes and the complex nature of the various non-covalent interactions operating simultaneously. With the help of a slow-evolving supramolecular gel derived from a urea-based gelator, we aim to capture the different stages of the self-assembly process commencing from nucleation. In particular, we are able to study the self-assembly in real time using time-resolved small-angle neutron scattering (SANS) at length scales ranging from approximately 30 Å to 250 Å. Systems with and without sonication are compared simultaneously, to follow the different kinetic paths involved in these two cases. Time-dependent NMR, morphological and rheological studies act complementarily to the SANS data at sub-micron and bulk length scales. A hollow columnar formation comprising of gelator monomers arranged radially along the long axis of the fiber and solvent in the core is detected at the very early stage of the self-assembly process. While sonication promotes uniform growth of fibers and fiber entanglement, the absence of such a stimulus helps extensive bundle formation at a later stage and at the microscopic domain, making the gel system mechanically robust. The results of the present work provide a thorough understanding of the self-assembly process and reveal a path for fine-tuning such growth processes for applications such as the cosmetics industry, 3D printing ink development and paint industry.

Pirfenidone as a potential antifibrotic injectable for Dupuytren's disease.

Dupuytren's disease is a progressive fibrotic condition of the hand that causes contracture of fingers in later stages. Our previous in vitro studies suggest that the transformation of fibroblasts to myofibroblasts induced by transforming growth factor-beta can be inhibited by the addition of the antifibrotic drug, pirfenidone (PFD). We hypothesize that the local delivery of PFD directly to nodules can potentially prevent the progression to cords and, furthermore, that injection of PFD after the resection of cords can limit the recurrence of the disease. The purpose of this research was to develop a PFD injectable solution and to assess its safety in mice. Based on preformulation observations, a sterile solution containing up to 8 mg/0.4 mL of PFD was prepared in a phosphate buffer with and without 15%v/v N-methyl-2-pyrrolidone. Accelerated stability studies suggested that the product should be kept at refrigerated temperature (2-8 °C) for long-term storage. Safety studies involving subcutaneous administration to mice showed that 2-4 mg of PFD in 0.4 mL aqueous buffer did not elicit a significant inflammatory reaction. However, 4 mg PFD in 0.4 mL (FB) of buffer: NMP cosolvent system led to a significant increase in the influx of inflammatory cells and 8 mg PFD (FA) in the cosolvent system was lethal to the animals.

Solution-Phase Magnetic Mechanistic Study of Ni-Seamed Pyrogallol[4]arene Nanocapsules Reveal Presence of Novel Cylindrical and Spherical Species.

The magnetic properties of nickel-seamed C-pyrogallol[4]arene (PgC3 Ni) hexamers and dimers are studied for the first time in solution. The combination of small-angle neutron scattering and superconducting quantum interference device magnetometer measurements of the solution species reveal their paramagnetic and weakly antiferromagnetic behaviour. Surprisingly, the magnetic results indicated the presence of an unprecedented 13 Å-radius species, larger than both the dimeric and hexameric nanocapsules with both octahedral and square-planar metal centers. To confirm the presence of this novel species, we performed a mechanistic study of PgC3 Ni as a function of temperature and solvent and deduced the presence of two additional new species: a) an 11 Šcylinder with Ni atoms seaming the tubular framework and b) an 8 Å-radius sphere with non-interacting Ni centers located within the internal cavity. Select parameters that shift the equilibrium towards desired species are also identified.

Assessment of the in vitro toxicity of calixarenes and a metal-seamed calixarene: a chemical pathway for clinical application.

Calixarenes are known to form host-guest complexes and supramolecular nanoassemblies with well-defined architectures. However, the use of these materials in conjunction with drug moieties is still under explored. One reason is the insuffcient biocompatibility studies. Our present study represents a systematic in vitro investigation of the cytotoxicity associated with C-methylresorcin[4]arene, C-methylpyrogallol[4]arene, p-phosphonated calix[8]arene and a metal-seamed calixarene-copper(II) complex, using human HEK293 and rat C6G cell lines and two different cell viability assays (MTT and CellTiter-Glo) to avoid species-biased results. All compounds showed low to moderate toxicity. The trend in the CC50 values indicated that the suppression of the coordination ability and the presence of phosphonate groups decrease the overall cytotoxicity of the compounds. The results of this study not only establish calixarenes and their immediate families as potential drug carriers and drug modifiers, but also reveal a pathway for fine-tuning their toxicological behaviour by appropriate chemical modification.

Low Molecular Weight Supramolecular Gels Under Shear: Rheology as the Tool for Elucidating Structure-Function Correlation.

Self-healing low molecular weight supramolecular gels (SMGs) represent an emerging class of smart materials, which can closely mimic the complex biological healing process, such as blood clotting, bone repair or wound healing. However, a lack of understanding of the structure-function correlation in the self-assembly process limits their molecular design and subsequent property tuning. The indispensability of a rheological study on supramolecular gels lies in direct transcription of the assembly property to the viscoelastic behavior of the material. This is similarly relevant to healable and non-healable systems. Thus, using rheology as a tool for elucidating structure-function relationships in self-assembled systems has huge potential. This review article will depict a general introduction of rheology in the field of soft matter including SMGs, followed by representative studies with interpretations, and discussion on future challenges. Altogether, this would be an effort, where an in-depth rheological study complemented with a real-time visualization with the help of microscopy, and introduction of other sophisticated real-time experiments, could be a step forward to capture the mystery of self-assembly process.

Investigating the effect of supramolecular gel phase crystallization on gel nucleation.

Supramolecular gel phase crystallization offers a new strategy for drug polymorph screening and discovery. In this method, the crystallization outcome depends on the interaction between solute and gel fibre. While supramolecular gels have shown success in producing new polymorphs and crystals with novel morphologies, role of the gel and nature of gel-solute interaction remains largely unexplored. The present study aims to provide a comprehensive picture of the structural evolution of a supramolecular gel produced from a bis(urea) based gelator (G) in the presence of a polymorphic drug carbamazepine (CBZ). The structural aspects of the gel have been assessed by single crystal X-ray analysis, X-ray powder diffraction (XRPD) and solid state NMR spectroscopy. Small Angle Neutron Scattering (SANS) has been used to follow the changes in gel structure in the presence of CBZ. Visual evidence from morphological study and structural evolution observed at a macroscopic level from rheological measurements, shows good agreement with the SANS results. The concentration of the gelator and the relative proportion of G to CBZ were found to be crucial factors in determining the competitive nucleation events involving gelation and crystallization. At a critical G to CBZ ratio the effect of CBZ on gel structure was maximum and fiber bundling in the gel was found to be critically affected. This study offers important information about how the interplay of gelator assembly and gel-solute interactions can fine-tune the nucleation events in a supramolecular gel phase crystallization.

Multifaceted Supramolecular Interactions from C-Methylresorcin[4]arene Lead to an Enhancement in In Vitro Antibacterial Activity of Gatifloxacin.

Mimicking the antibacterial activity of polyphenols in synthetic systems is an attractive approach for the development of new active pharmaceutical ingredients. Resorcinarenes represent a class of polyphenols, which have been exploited for decades for their attractive chemical scaffold suitable for forming host-guest complexes with hydrophobic guest molecules. However, the polyphenolic character of resorcinarenes, which could be a potential asset to the pharmaceutical industry, have been least exploited. The present work represents an unprecedented interplay of antimicrobial activity of resorcinarene together with its ability to interact chemically with an antibacterial drug gatifloxacin, improving the overall antibacterial activity. The chemistry and the clinical activities involved in this study were investigated simultaneously by spectroscopic techniques, as well as by in vitro measurement of antibacterial activity toward two human bacterial pathogens, a Gram-positive pathogen Staphylococcus aureus and a Gram-negative lung pathogen Legionella pneumophila. The initial positive result obtained from this study could revolutionize the use of synthetically modifiable resorcinarenes and their analogues in fine tuning the clinical behavior of drugs.

Solution structures of nanoassemblies based on pyrogallol[4]arenes.

Nanoassemblies of hydrogen-bonded and metal-seamed pyrogallol[4]arenes have been shown to possess novel solution-phase geometries. Further, we have demonstrated that both guest encapsulation and structural rearrangements may be studied by solution-phase techniques such as small-angle neutron scattering (SANS) and diffusion NMR. Application of these techniques to pyrogallol[4]arene-based nanoassemblies has allowed (1) differentiation among spherical, ellipsoidal, toroidal, and tubular structures in solution, (2) determination of factors that control the preferred geometrical shape and size of the nanoassemblies, and (3) detection of small variations in metric dimensions distinguishing similarly and differently shaped nanoassemblies in a given solution. Indeed, we have shown that the solution-phase structure of such nanoassemblies is often quite different from what one would predict based on solid-state studies, a result in disagreement with the frequently made assumption that these assemblies have similar structures in the two phases. We instead have predicted solid-state architectures from solution-phase structures by combining the solution-phase analysis with solid-state magnetic and elemental analyses. Specifically, the iron-seamed C-methylpyrogallol[4]arene nanoassembly was found to be tubular in solution and predicted to be tubular in the solid state, but it was found to undergo a rearrangement from a tubular to spherical geometry in solution as a function of base concentration. The absence of metal within a tubular framework affects its stability in both solution and the solid state; however, this instability is not necessarily characteristic of hydrogen-bonded capsular entities. Even metal seaming of the capsules does not guarantee similar solid-state and solution-phase architectures. The rugby ball-shaped gallium-seamed C-butylpyrogallol[4]arene hexamer becomes toroidal on dissolution, as does the spherically shaped gallium/zinc-seamed C-butylpyrogallol[4]arene hexamer. However, the arenes are arranged differently in the two toroids, a variation that accounts for the differences in their sizes and guest encapsulation. Guest encapsulation of biotemplates, such as insulin, has demonstrated the feasibility of synthesizing nanocapsules with a volume three times that of a hexamer. The solution-phase studies have also demonstrated that the self-assembly of dimers versus hexamers can be controlled by the choice of metal, solvent, and temperature. Controlling the size of the host, nature of the metal, and identity of the guest will allow construction of targeted host-guest assemblies having potential uses as drug delivery agents, nanoscale reaction vessels, and radioimaging/radiotherapy agents. Overall, the present series of solid- and solution-phase studies has begun to pave the way toward a more complete understanding of the properties and behavior of complex supramolecular nanoassemblies.

Anion- and Spacer-Directed Host-Guest Complexes of Bipyridine with Pyrogallol[4]arene.

New oval-shaped capsular and bilayer-type hydrogen-bonded arrangements of C-propyl-ol-pyrogallol[4]arene (PgC3-OH) with bipyridine-type spacer complexes are reported here. These complexes are engineered by virtue of derivatization of C-alkyl tails of pyrogallol[4]arene and the use of divergent spacer ligands. Complexes of PgC3-OH, PgC3-OH with bpy (4,4'-bipyridine) and PgC3-OH with bpa (1,2-bis(4-pyridyl)acetylene) have bilayer type arrangements; however, the use of hydrogen chloride causes protonation of bpy molecule, which is then entrapped flat within an offset oval-shaped dimeric hydrogen-bonded PgC3-OH nanocapsule. The presence of chloride anion in the crystal lattice controls the geometry of the resultant nanoassembly.

Fluorous 'ponytails' lead to strong gelators showing thermally induced structure evolution.

Appending perfluoroalkyl substituents to bis(urea) gelators results in significantly decreased inter-chain interactions with markedly thinner fibres and hence more cross-linked and more transparent gels with potential applications in the crystallisation of fluorinated pharmaceuticals. Gel structure has been probed by detailed SANS measurements which indicate a surprising structure evolution on thermal cycling, not seen for hydrocarbon analogues. The SANS data are complemented by the single crystal X-ray structure of one fluorinated gelator.

Strong cation···π interactions promote the capture of metal ions within metal-seamed nanocapsule.

Thallium ions are transported to the interior of gallium-seamed pyrogallol[4]arene nanocapsules. In comparison to the capture of Cs ions, the extent of which depends on the type and position of the anion employed in the cesium salt, the enhanced strength of Tl···π vs Cs···π interactions facilitates permanent entrapment of Tl(+) ions on the capsule interior. "Stitching-up" the capsule seam with a tertiary metal (Zn, Rb, or K) affords new trimetallic nanocapsules in solid state.

Entrapment of elusive guests within metal-seamed nanocapsules.

Anions play a crucial role in locking alkali metals on the interior of metal-organic capsules that contain structural water gates. This role is further evidenced when stitching-up the capsule seam, resulting in either expulsion or trapping of cesium ions depending on the anion employed.

Vortex fluidic regulated phospholipid equilibria involving liposomes down to sub-micelle size assemblies.

Conventional channel-based microfluidic platforms have gained prominence in controlling the bottom-up formation of phospholipid based nanostructures including liposomes. However, there are challenges in the production of liposomes from rapidly scalable processes. These have been overcome using a vortex fluidic device (VFD), which is a thin film microfluidic platform rather than channel-based, affording ∼110 nm diameter liposomes. The high yielding and high throughput continuous flow process has a 45° tilted rapidly rotating glass tube with an inner hydrophobic surface. Processing is also possible in the confined mode of operation which is effective for labelling pre-VFD-prepared liposomes with fluorophore tags for subsequent mechanistic studies on the fate of liposomes under shear stress in the VFD. In situ small-angle neutron scattering (SANS) established the co-existence of liposomes ∼110 nm with small rafts, micelles, distorted micelles, or sub-micelle size assemblies of phospholipid, for increasing rotation speeds. The equilibria between these smaller entities and ∼110 nm liposomes for a specific rotational speed of the tube is consistent with the spatial arrangement and dimensionality of topological fluid flow regimes in the VFD. The prevalence for the formation of ∼110 nm diameter liposomes establishes that this is typically the most stable structure from the bottom-up self-assembly of the phospholipid and is in accord with dimensions of exosomes.

Magnetic differentiation of pyrogallol[4]arene tubular and capsular frameworks.

The differences in magnetic properties of metal-based nanometric assemblies are due to distinct contributions from host-guest interactions, structural integrity, and magnetic interactions. To disentangle these contributions, it is necessary to control the self-assembly process that forms these entities. Herein we study the effect of host-to-guest ratios to identify remarkably different structural-magnetic contributions of C-methylpyrogallol[4]arene⊂ferrocene/(PgC1)2⊂Fc dimers vs (PgC1)3⊂Fc nanotubes. At low temperature, a weak anti-ferromagnetic alignment is observed, suggesting a weak dipolar interaction between Fc guest moieties within adjacent dimers or tubes. Also, differences are observed between magnetic atom occupancy as a function of guest (PgC1⊂Fc tube/dimer) versus magnetic atom occupancy within the framework wall (PgC3Ni hexamer/dimer). Identification of the role of the framework shape and metal-metal distances in the crystal lattice opens up unparalleled prospects for materials engineering.

Pyrogallol[4]arenes as frustrated organic solids.

Two forms of interdigitated layered arrangements of C-pentylpyrogallol[4]arene (PgC5) have been structurally elucidated and show variations in packing arrangements and host-guest interactions. Molecular dynamics simulations reveal a propensity for formation of self-included dimers, with or without incorporated solvent. Combined gas sorption and PXRD results show the presence of seven forms of PgC5, with and without CO2 (and their interconversions). This is the first CO2 gas sorption study of pyrogallol[4]arenes, and it provides evidence that pyrogallol[4]arenes may act as frustrated organic solids.

Introducing defects into metal-seamed nanocapsules using mixed macrocycles.

The synthesis and single-crystal X-ray diffraction structure of a dimeric zinc-seamed nanocapsule using a mixed pyrogallol/resorcinol[4]arene are presented. The use of "mixed" macrocycles results in an incomplete seam of coordination bonds around the nanocapsule's typically octa-metalated belt. The self-assembly of the nanocapsule occurs such that the single resorcinol moiety of each macrocycle aligns transversely. This yields a hepta-metalated capsule where the defect occurs in such a way as to provide minimal disruption to the overall structure of the nanocapsule.