Selective Separation of Hazardous Chemicals from Vapor Phase by an Easily Accessible Breathing Coordination Polymer Derived from Terpyridyl/terephthalate Mixed Ligands.

Coordination polymers are extensively studied materials because of their various potential applications. Amongst them, breathing coordination polymers that are capable of exchanging lattice occluded guest molecules with other guests via single-crystal-to-single-crystal (SC-SC) fashion are particularly intriguing. Herein, we disclose an easily accessible breathing coordination polymer namely DMF@Zn-CP capable of exchanging as many as 23 guest molecules of various kinds in SC-SC fashion when the crystals of the coordination polymer were exposed to the corresponding vapor of the guests. Selectivity experiments revealed that it was also capable of separating selectively hazardous chemicals such as dichloro-methane, benzene and fluorobenzene from the corresponding complex mixture of vapors of halomethanes, aromatic hydrocarbons and halobenzenes. The breathing coordination polymer could also be exploited as drug delivery vehicle; slow and sustained release of anti-bacterial agents (benzyl alcohol/phenethyl amine) as guests against both gram positive and gram negative bacteria was evident in zone inhibition assays. A mixed ligand strategy wherein a nitrile containing terpyridyl ligand (L) and terephthalate (TA) co-ligand were reacted with Co(II)/Ni(II)/Zn(II) nitrate salts was adopted herein. Three coordination polymers namely MeOH@Co-CP, DMF/H2 O@Ni-CP and DMF@Zn-CP were isolated and characterized by single crystal X-ray diffraction. Studies revealed that only DMF@Zn-CP possessed the ability to breath in response to the vapors of the guests as stimuli.

Real-time Observation of Macroscopic Helical Morphologies under Optical Microscope: A Curious Case of π-π Stacking Driven Molecular Self-assembly of an Organic Gelator Devoid of Hydrogen Bonding.

Supramolecular assemblies such as tubules/helix/double helix/helical tape etc. are usually submicron objects preventing direct observation under optical microscope. Chiral-pure form of these assemblies is important for potential applications. Herein, we report a rare phenomenon wherein a DMSO gel of a simple terpyridine derivative [(4-CNPhe)4PyTerp] produced macroscopic helical morphologies (µm length scale) which could be observed under optical microscope, formation of which could be monitored by optical videography, stable enough to withstand acidic vapour, robust enough to display reversible gel↔sol in response to acidic and ammonia vapour and sturdy enough to be maneuvered with a needle. These properties appeared to be unique to the title compound as the other related derivatives failed to display such assembly structures. SXRD and MD simulation studies suggested that weak interactions (π-π stacking) played a crucial role in the self-assembly process.

Anchoring Drugs to a Zinc(II) Coordination Polymer Network: Exploiting Structural Rationale toward the Design of Metallogels for Drug-Delivery Applications.

A new series of coordination polymers (CPs) were synthesized and crystallographically characterized by single-crystal X-ray diffraction with the aim of developing drug-delivery systems via metallogel formation. Structural rationale was employed to design such coordination-polymer-based metallogels. As many as nine CPs were obtained by reacting two bis(pyridyl)urea ligands, namely, 1,3-dipyridin-3-ylurea (3U) and 1,3-dipyridin-4-ylurea (4U), and the sodium salt of various nonsteroidal antiinflammatory drugs, namely, ibuprofen (IBU), naproxen (NAP), fenoprofen (FEN), diclofenac (DIC), meclofenamic acid (MEC), mefenamic acid (MEF), and Zn(NO3)2. All of the CPs displayed 1D polymeric chains that were self-assembled through various hydrogen-bonding interactions involving the urea N-H and carboxylate O atoms and, in a few cases, lattice-occluded water molecules. The reacting components of the CPs produced five metallogels in dimethyl sulfoxide/water. The gels were characterized by rheology and transmission electron microscopy. Three selected metallogelators, namely, 3UMEFg, 3UNAPg, and 3UMECg, showed in vitro anticancer, cell imaging, and multidrug delivery for antibacterial applications, respectively. The shear-thinning properties of 3UMECg (rheoreversibility and injectability) make it a potential candidate for plausible topical application.

Exfoliated Nanosheets of a CuII Coordination Polymer Modulate Enzyme Activity of α-Chymotrypsin.

A 2D coordination polymer derived from 5-azidoisophthalic acid (AIA) and Cu(NO3 )2 was designed with the aim of modulating the activity of a digestive enzyme α-chymotrypsin (ChT). The coordination polymer namely {[Cu0.5 (µ-AIA)0.5 (H2 O)]⋅2 H2 O}α (CP1) was successfully synthesized and fully characterized by single-crystal X-ray diffraction (SXRD). An exfoliated nanosheet (ENS) of CP1 was readily produced by overnight stirring of hand-ground CP1 crystals dispersed in DMSO. ENS(CP1) was demonstrated to be acting as an inhibitor of ChT; as much as ≈97 % inhibition of ChT was achieved with 100 µm of ENS(CP1) using N-succinyl-l-phenylalanine-p-nitroanilide (SPNA) as substrate. Enzyme kinetics data revealed that the inhibition of ChT followed a competitive pathway. An enzyme assay under varying ionic strength and varying concentration of free histidine revealed that the active site His-57 participated in coordination with the CuII metal center of ENS(CP1) thereby preventing the substrate (SPNA) from binding with the enzyme resulting in efficient inhibition.

Supramolecular Hydrogel Derived from a C3-Symmetric Boronic Acid Derivative for Stimuli-Responsive Release of Insulin and Doxorubicin.

A C3-symmetric triazine based triboronic acid (HG1) was designed and synthesized. HG1 was found to give hydrogel in DMSO-water (1:9). The hydrogel was rheo-reversible and thermoreversible over a few cycles. Single-crystal X-ray diffraction (SXRD) studies on the crystals of HG1 established the presence of honeycomb network in which solvent molecules (DMSO and water) were occluded. SXRD data corroborated well with the hypothesis based on which HG1 was designed. Stimuli responsive release (in vitro) of insulin and doxorubicin from the hydrogel was also achieved.

Supramolecular Synthon Approach in Developing Anti-Inflammatory Topical Gels for In†Vivo Self-Delivery.

A new series of tertiary-butyl ammonium (TBA) salts of various nonsteroidal anti-inflammatory drugs (NSAIDs) have been synthesized and characterized. Nearly 90 % of the NSAID-derived primary ammonium monocarboxylate (PAM) salts displayed remarkable gelation ability with various solvents including methyl salicylate. Single crystal X-ray diffraction data (SXRD) revealed the existence of 1D PAM synthon in the gelator salts. Structure-property correlation studies based on SXRD and powder X-ray diffraction (PXRD) data established the presence of the 1D PAM synthon in the bulk salts as well as in the corresponding xerogels. A parallel series of salts derived from TRIS (2-amino-2-(hydroxymethyl)-1,3-propanediol) and the same set of NSAIDs displayed poor gelation ability; only 33 % of the salts in the series displayed gelation ability. A few selected gelator salts of both TBA and TRIS were found to be biocompatible (MTT assay with RAW 264.7 cell line) and two of the selected salts (FLR.TBA and FLR.TRIS) possessed anti-inflammatory properties equal to the parent drug FLR (flurbiprofen). Finally a methyl salicylate topical gel derived from FLR.TRIS was successfully delivered in a self-delivery fashion to treat inflamed skin conditions in the mice model. Histological studies of the dorsal tissues of the untreated and treated mice clearly demonstrated the effect of topical gels in such treatment.

Hand-Ground Nanoscale ZnII -Based Coordination Polymers Derived from NSAIDs: Cell Migration Inhibition of Human Breast Cancer Cells.

Increased levels of intracellular prostaglandin E2 (PGE2 ) have been linked with the unregulated cancer cell migration that often leads to metastasis. Non-steroidal anti-inflammatory drugs (NSAIDs) are known inhibitors of cyclooxygenase (COX) enzymes, which are responsible for the increased PGE2 concentration in inflamed as well as cancer cells. Here, we demonstrate that NSAID-derived ZnII -based coordination polymers are able to inhibit cell migration of human breast cancer cells. Various NSAIDs were anchored to a series of 1D ZnII coordination polymers through carboxylate-Zn coordination, and these structures were fully characterized by single-crystal X-ray diffraction. Hand grinding in a pestle and mortar resulted in the first reported example of nanoscale coordination polymers that were suitable for biological studies. Two such hand-ground nanoscale coordination polymers NCP1 a and NCP2 a, which contained naproxen (a well-studied NSAID), were successfully internalized by the human breast cancer cells MDA-MB-231, as was evident from cellular imaging by using a fluorescence microscope. They were able to kill the cancer cells (MTT assay) more efficiently than the corresponding mother drug naproxen, and most importantly, they significantly inhibited cancer cell migration thereby displaying anticancer activity.

An Easy Access to Organic Salt-Based Stimuli-Responsive and Multifunctional Supramolecular Hydrogels.

By exploiting orthogonal hydrogen bonding involving supramolecular synthons and hydrophobic/hydrophilic interactions, a new series of simple organic salt based hydrogelators derived from pyrene butyric acid and its ß-alanine amide derivative, and various primary amines has been achieved. The hydrogels were characterised by microscopy, table-top rheology and dynamic rheology. FTIR, variable-temperature (1) H NMR and emission spectroscopy established the role of various supramolecular interactions such as hydrogen bonding and π-π stacking in hydrogelation. Single-crystal X-ray diffraction (SXRD) studies supported the conclusion that orthogonal hydrogen bonding involving amide-amide and primary ammonium monocarboxylate (PAM) synthons indeed played a crucial role in hydrogelation. The hydrogels were found to be stimuli-responsive and were capable of sensing ammonia and adsorbing water-soluble dye (methylene blue). All the hydrogelators were biocompatible (MTT assay in RAW 264.7 cells), indicating their suitability for use in drug delivery.

Coordination Polymers Derived from Non-Steroidal Anti-Inflammatory Drugs for Cell Imaging and Drug Delivery.

A new series of Mn(II) coordination polymers, namely, [{Mn(L)(H2 O)2 }⋅2 Nap]∞ (CP1), [{Mn(L)(Ibu)2 (H2 O)2 }]∞ (CP2), [{Mn(L)(Flr)2 (H2 O)2 }]∞ (CP3), [{Mn(L)(Ind)2 (H2 O)2 }⋅H2 O]∞ (CP4), [{Mn2 (L)2 (µ-Flu)4 (H2 O)}⋅L]∞ (CP5), [{Mn2 (L)2 (µ-Tol)4 (H2 O)2 }]∞ (CP6) and [{Mn2 (L)2 (µ-Mef)4 (H2 O)2 }]∞ (CP7) (Nap=naproxen, Ibu=ibuprofen, Flr=flurbiprofen, Ind=indometacin, Flu=flufenamic acid, Tol=tolfenamic acid and Mef=mefenamic acid) derived from various non-steroidal anti-inflammatory drugs (NSAIDs) and the organic linker 1,2-bis(4-pyridyl)ethylene (L) have been synthesized with the aim of being used for cell imaging and drug delivery. Single-crystal X-ray diffraction (SXRD) studies revealed that the NSAID molecules were part of the coordination polymeric network either through coordination to the metal center (in the majority of the cases) or through hydrogen bonding. Remarkably, all the Mn(II) coordination polymers were found to be soluble in DMSO, thereby making them particularly suitable for the desired biological applications. Two of the coordination polymers (namely, CP1 and CP3) reported herein, were found to be photoluminescent both in the solid as well as in the solution state. Subsequent experiments (namely, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), and PGE2 (prostaglandin E2 ) assays) established their biocompatibility and anti-inflammatory response. In vitro studies by using a macrophage cell line (i.e., RAW 264.7) revealed that both CP1 and CP3 were excellent cell imaging agents. Finally, biodegradability studies under simulated physiological conditions in phosphate-buffered saline (PBS) at pH 7.6 showed that slow and sustained release of the corresponding NSAID was indeed possible from both CP1 and CP3.

Supramolecular Gels by Design: Towards the Development of Topical Gels for Self-Delivery Application.

Following a supramolecular synthon approach, simple salt formation has been employed to gain access to a series of supramolecular gelators derived from the well-known non-steroidal anti-inflammatory drug (NSAID) ibuprofen. A well-studied gel-inducing supramolecular synthon, namely primary ammonium monocarboxylate (PAM), has been exploited to generate a series of PAM salts by reacting ibuprofen with various primary amines. Remarkably, all of the salts (S1-S7) thus synthesized proved to be good to moderate gelators of various polar and nonpolar solvents. Single-crystal and powder X-ray diffraction studies established the existence of the PAM synthons in the gel network, confirming the efficacy of the supramolecular synthon approach employed. Most importantly, the majority of the salts (S2, S3, S6, and S7) were capable of gelling methyl salicylate (MS), an important ingredient found in many commercial topical gels. In vitro experiments (MTT and PGE2 assays) revealed that all of the salts (except S3 and S7) were biocompatible (up to 0.5 mm concentration), and the most suited one, S6, displayed anti-inflammatory ability as good as that of the parent drug ibuprofen. A topical gel of S6 with methyl salicylate and menthol was found to be suitable for delivering the gelator drug in a self-delivery fashion in treating skin inflammation in mice. Histological studies, including immunohistology, were performed to further probe the role of the gelator drug S6 in treating inflammation. Cell imaging studies supported cellular uptake of the gelator drug in such biomedical application.

Nanoscale MnII -Coordination Polymers for Cell Imaging and Heterogeneous Catalysis.

A mixed ligand approach was exploited to synthesize a new series of MnII -based coordination polymers (CPs), namely, CP1 {[Mn(µ-dpa)(µ-4,4'-bp)]⋅MeOH}∞ , CP2 {[Mn3 (µ-dpa)3 (2,2'-bp)2 ]}∞ , CP3 {[Mn3 (µ-dpa)3 (1,10-phen)2 ]⋅2 H2 O}∞ , CP4 {[Mn(µ-dpa)(µ-4,4'-bpe)1.5 ]⋅H2 O}∞ , CP5 {[Mn2 (µ-dpa)2 (µ-4,4'-bpe)2 ]⋅1/2 DEF}∞ , and CP6 {[Mn(µ-dpa)(µ-4,4'-bpe)1.5 ]⋅1/2 DMA}∞ (dpa=3,5-dicarboxyphenyl azide, 2,2'-bp=2,2'-bipyridine, 1,10-phen=1,10-phenanthroline, 4,4'-bpe=1,2-bis(4-pyridyl)ethylene, 4,4'-bp=4,4'-bipyridine, DEF=N,N-diethylformamide, DMA=N,N-dimethylacetamide), to develop multifunctional CPs. Various techniques, such as single-crystal X-ray diffraction (SXRD), FTIR spectroscopy, elemental analysis, and thermogravimetric analysis, were employed to fully characterize these CPs. The majority of the CPs displayed a four-connected sql topology, whereas CP4 and CP6 exhibited a two-dimensional SnS network architecture, which was further entangled in a polycatenation mode. Compound CP1 displayed an open framework structure. The CPs were scaled down to the nanoregime in a ball mill for cell imaging studies. Whereas CP2 and CP4 were employed for cell imaging with RAW264.7 cells, CP1 was exploited for both cell imaging and heterogeneous catalysis in a cyanosilylation reaction.

Multidrug-Containing, Salt-Based, Injectable Supramolecular Gels for Self-Delivery, Cell Imaging and Other Materials Applications.

Both molecular and crystal-engineering approaches were exploited to synthesize a new class of multidrug-containing supramolecular gelators. A well-known nonsteroidal anti-inflammatory drug, namely, indomethacin, was conjugated with six different l-amino acids to generate the corresponding peptides having free carboxylic acid functionality, which reacted further with an antiviral drug, namely, amantadine, a primary amine, in 1:1 ratio to yield six primary ammonium monocarboxylate salts. Half of the synthesized salts showed gelation ability that included hydrogelation, organogelation and ambidextrous gelation. The gels were characterized by table-top and dynamic rheology and different microscopic techniques. Further insights into the gelation mechanism were obtained by temperature-dependent 1 H NMR spectroscopy, FTIR spectroscopy, photoluminescence and dynamic light scattering. Single-crystal X-ray diffraction studies on two gelator salts revealed the presence of 2D hydrogen-bonded networks. One such ambidextrous gelator (capable of gelling both pure water and methyl salicylate, which are important solvents for biological applications) was promising in both mechanical (rheoreversible and injectable) and biological (self-delivery) applications for future multidrug-containing injectable delivery vehicles.

Metallogels derived from silver coordination polymers of C3-symmetric tris(pyridylamide) tripodal ligands: synthesis of Ag nanoparticles and catalysis.

By applying a recently developed crystal engineering rationale, four C3 symmetric tris(pyridylamide) ligands namely 1,3,5-tris(nicotinamidomethyl)-2,4,6-triethylbenzene, 1,3,5-tris(isonicotinamidomethyl)-2,4,6-triethylbenzene, 1,3,5-tris(nicotinamidomethyl)-2,4,6-trimethylbenzene, and 1,3,5-tris(isonicotinamidomethyl)-2,4,6-trimethylbenzene, which contain potential hydrogen-bonding sites, were designed and synthesized for generating Ag(I) coordination polymers and coordination-polymer-based gels. The coordination polymers thus obtained were characterized by single-crystal X-ray diffraction. The silver metallogels were characterized by transmission electron microscopy (TEM) and dynamic rheology. Upon exposure to visible light, these silver metallogels produced silver nanoparticles (AgNPs), which were characterized by TEM, powder X-ray diffraction, energy dispersive X-ray and X-ray photoelectron spectroscopy. These NPs were found to be effectively catalyzed the reduction of 4-nitrophenolate to 4-aminophenolate without the use of any exogenous reducing agent.

A supramolecular topical gel derived from a non-steroidal anti-inflammatory drug, fenoprofen, is capable of treating skin inflammation in mice.

A new series of bioconjugates derived from a non-steroidal anti-inflammatory drug (NSAID), namely fenoprofen, has been synthesised by amidation with various biogenic molecules such as ß-alanine, aminocaproic acid and tyramine with the aim of converting the NSAID into a supramolecular gelator for plausible biomedical applications. One such bioconjugate (2) showed gelation ability with methylsalicylate (MS) and 1% menthol in methyl salicylate (MMS) solvents. These gels were characterized by table top rheology, high resolution-transmission electron microscopy (HR-TEM) and dynamic rheology. Gelator 2 was found to be biostable both in proteolytic enzymes and in blood serum of BALB/c mouse under physiological conditions. It was also found to be biocompatible, as revealed by the methyl thiazolyldiphenyl tetrazolium bromide (MTT) assay in mouse macrophage RAW 264.7 and mouse myoblast C2C12 cells. The anti-inflammatory response (prostaglandin E2 assay, denoted PGE2 assay) of 2 was comparable to that of the parent drug fenoprofen calcium salt. Finally, a topical gel formulation of 2 displayed in vivo self-delivery application in treating imiquimod (IMQ) induced skin inflammation in BALB/c mice.

Exploiting supramolecular synthons in designing gelators derived from multiple drugs.

A simple strategy for designing salt-based supramolecular gelators comprised of various nonsteroidal anti-inflammatory drugs (NSAIDs) and amantadine (AMN) (an antiviral drug) has been demonstrated using a supramolecular synthon approach. Single-crystal and powder X-ray diffraction established the existence of the well-studied gel-forming 1D supramolecular synthon, namely, primary ammonium monocarboxylate (PAM) synthon in all the salts. Remarkably five out of six salts were found to be capable of gelling methyl salicylate (MS)-an important ingredient in commercially available topical gels; one such selected biocompatible salt displayed an anti-inflammatory response in prostaglandin E2 (PGE2 ) assay, thereby indicating their plausible biomedical applications.

Developing Supramolecular Metallogel Derived from Pd2L4 Cage Molecule for Delivering an Anti-Cancer Drug to Melanoma Cell B16-F10.

Supramolecular gels are an important class of materials that are promising for its wide range of applications including drug delivery. While supramolecular gels are intrinsically porous because of the 3D nano-matrix (gel matrix) that is being formed due to supramolecular self-assembly process involving the gelator molecules during gelation, additional nanopores can be introduced to the overall gel if the gelator molecule itself holds molecular cavity such as metal-organic-cage (MOC) molecules. A MOC having the molecular formula [(Pd2L24).4NO3].3H2O.2DMF.MeOH (Pd-cage) (L2=5-Azido-N,N'-di-pyridin-3-yl-isophthalamide) was successfully synthesized and characterized by FT-IR, 1H NMR, ESI-MS and single crystal X-ray diffraction. Stimuli-reversible supramolecular metallogel PdG could easily be formed from Pd-cage in DMSO/water mixture. The molecular cage of Pd-cage was demonstrated to be available for loading an anti-cancer drug namely doxorubicin (DOX). Subsequently, DOX was also loaded within PdG and delivered to melanoma cell line B16-F10 displaying significant anti-cancer activity as revealed by both MTT and scratch assay. Rheoreversibility of PdG and its ability to load and deliver DOX to cancer cells clearly raised hope for developing this metallogel further as topical anticancer gel.

ß-Amino acid and amino-alcohol conjugation of a nonsteroidal anti-inflammatory drug (NSAID) imparts hydrogelation displaying remarkable biostability, biocompatibility, and anti-inflammatory properties.

A well-known nonsteroidal anti-inflammatory drug (NSAID), namely, naproxen (Np), was conjugated with ß-alanine and various combinations of amino alcohols and l-alanine. Quite a few bioconjugates, thus synthesized, were capable of gelling pure water, NaCl solution (0.9 wt %), and phosphate-buffered saline (PBS) (pH 7.4). The hydrogels were characterized by rheology and electron microscopy. Hydrogelation was probed by FT-IR and temperature-variable (1)H NMR studies. Single-crystal X-ray diffraction (SXRD) of a nonhydrogelator and a hydrogelator in the series established a useful structure-property (gelation) correlation. MTT assay of the hydrogelators in the mouse macrophage RAW 264.7 cell line showed excellent biocompatibility. The prostaglandin E2 (PGE2) assay of the hydrogelators revealed their anti-inflammatory response, which was comparable to that of the parent NSAID naproxen sodium (Ns).

Coordination polymers: what has been achieved in going from innocent 4,4'-bipyridine to bis-pyridyl ligands having a non-innocent backbone?

The last two decades have witnessed the research activities in the area of coordination polymers (CPs), which are structurally diverse and functionally intriguing materials. In this endeavor, the most exploited ligand has been a structurally rigid N-donor compound having an innocent backbone (incapable of forming hydrogen bond) namely 4,4'-bipyridine. Much has been achieved by exploiting this wonder ligand in the area of CPs. However, the positional isomers such as 3,3'-bipyridine or 4,3'-bipyridine (which understandably induce diverse ligating topology as compared to their more symmetrical 4,4' counterpart) were not exploited in much detail presumably because of the difficulty in their synthetic accessibility. To get access to such N-donor ditopic ligands having diverse ligating topology, much efforts have been focused in the last decade or so to design such positional isomers of 4,4'-bipyridine having a non-innocent backbone (capable of forming hydrogen bond). The principal focus of such studies is to decipher the effect of diverse ligating topology and the non-innocent backbone of the ligands on the overall supramolecular structures and functions of the resultant CPs. This tutorial review aims at highlighting some of the developments of such structurally diverse and functionally intriguing CPs derived from N-donor ditopic ligands having a non-innocent backbone.