Rajdip Roy

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.

Peptide conjugates of a nonsteroidal anti-inflammatory drug as supramolecular gelators: synthesis, characterization, and biological studies.

Indomethacin (IND), which is a well-known nonsteroidal anti-inflammatory drug (NSAID), was conjugated with various naturally occurring amino acids. Most of these bioconjugates were capable of gelling pure water, a solution of NaCl (0.9 wt%), and phosphate-buffered saline (pH 7.4), as well as a few organic solvents. The gels were characterized by table-top and dynamic rheology, and electron microscopy. Variable-temperature (1)H NMR spectroscopy studies on a selected gel were performed to gain insights into the self-assembly process during gel formation. Both 1D and 2D hydrogen-bonded networks were observed in the single-crystal structures of two of the gelators. Plausible biological applications of the hydrogelators were evaluated with the ultimate aim of drug delivery in a self-delivery fashion. All hydrogelators were stable in phosphate-buffered saline at pH 7.4 at 37 °C, and biocompatible in mouse macrophage RAW 264.7 cell line (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay). Two of the most biocompatible hydrogelators displayed an anti-inflammatory response comparable to that of the parent drug IND in prostaglandin E2 assay. Release of the bioconjugates into the bulk solvent interfaced with the corresponding hydrogels indicated their plausible future application in drug delivery.

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.

Supramolecular Gels Derived from the Salts of Variously Substituted Phenylacetic Acid and Dicyclohexylamine: Design, Synthesis, Structures, and Dye Adsorption

A well-studied supramolecular synthon, namely, secondary ammonium monocarboxylate (SAM), was exploited to generate a new series of organic salts derived from variously substituted phenylacetic acid and dicyclohexylamine as potential low-molecular-weight gelators. As much as 25 % of the SAM salts under study were gelators. The gels were characterized by rheology, and the morphology of the gel networks was studied by high-resolution electron microscopy. Single-crystal and powder XRD data were employed to study structure-property (gelation) correlations. One of the gels could adsorb a hydrophobic dye (Nile Red) more efficiently than that of a hydrophilic dye (Calcein) from dimethyl sulfoxide; this might provide useful clues towards the development of stain-removing gels.

Chapter 2:Designing Soft Supramolecular Materials Using Intermolecular Interactions

Gelation of solvent(s) by low molecular weight gelators (LMWGs – small molecules having MW <3000) is a supramolecular phenomenon. Aggregation of 1D fibres resulting from supramolecular self-assembly of gelator molecules, giving rise to a 3D gel network known as self-assembled fibrillar networks (SAFiNs), is believed to be the key factor in gelation. Molecules containing metal atoms that take part in forming SAFiNs resulting in gels (known as metallogels) are also known. Solvent molecules are immobilized due to surface tension or capillary force actions within such 3D network resulting in gel. The wide range of applications that these soft materials offer attracted worldwide attention and there has been an upsurge in research activities involving LMWGs in recent years. Due to the lack of molecular level insights of the gelation mechanism, designing LMWGs is a daunting task and as a consequence, serendipity plays a prominent role in discovering most of the gelators and subsequent design of the next generation gelators are based on modifying the serendipitously-obtained parent gelator molecules. This chapter focuses on the designing aspects and applications of LMWGs, including metal-containing gelator molecules. It particularly covers the development of supramolecular synthon approach in the context of crystal engineering along with the other strategies to design such rewarding soft-materials.

Salt metathesis for developing injectable supramolecular metallohydrogelators as a multi-drug-self-delivery system

Salt metathesis has been exploited to generate a series of non-steroidal anti-inflammatory drug (NSAID) based Zn(ii) metallohydrogels displaying both anti-inflammatory and anti-bacterial properties. Relatively low cytotoxicity, rheoreversibility and injectibility of one of these hydrogels make it suitable for multi-drug-self-delivery application.

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.

Supramolecular Synthon Approach in Designing Molecular Gels for Advanced Therapeutics

Low‐molecular‐weight gelators (LMWGs) are an important class of soft materials that offer various potential applications including drug delivery. Structural diversities of the reported LMWGs and lack of molecular‐level understanding of the self‐assembly process of gelation make it difficult to design a gelator a priori. Most often gelators are discovered in a serendipitous manner and second‐generation gelators are designed by modifying known gelling scaffolds. Since gel network within which the solvent molecules are immobilized is often found to be crystalline, a supramolecular synthon approach in the context of crystal engineering is demonstrated to be quite effective in designing LMWGs for various applications including therapeutics. Self‐drug‐delivery systems, wherein the need for a delivery vehicle does not exist, are becoming an effective alternative to conventional drug delivery systems. In the form of a simple gel (for non‐invasive topical application) or injectable gel (for invasive subcutaneous applications), LMWGs derived from drugs provide an effective way to develop self‐drug‐delivery systems. This review article encompasses the early development of LMWG research, describes gradual transition from discovering just a gelator to a gelator having potential material applications including drug delivery, and highlights the merit of supramolecular synthon approach in designing LMWGs for self‐drug‐delivery applications.

Designing Charge-Assisted Hydrogen Bonded Supramolecular Gelators

Immobilization of solvent(s) by a small amount of solute(s) resulting in a gel is a supramolecular phenomenon. Small molecular compounds (MW < 3,000) capable of displaying such supramolecular properties are known as low molecular weight gelators (LMWGs). Self-assembly of LMWGs driven by strong and directional hydrogen bonding interactions generates 1D fibrous aggregates that entangle to form self-assembled fibrillar networks (SAFiNs) within which the solvent molecules are immobilized (gel formation) due to surface tension or capillary force actions. Research on LMWGs has witnessed an exponential growth in recent years because of the wide range of applications that these materials offer. However, designing LMWGs is a daunting task as precise molecular level information on gelation is still not available and as a consequence, most of the gelators are discovered serendipitously and subsequent design of the next generation of gelators is based on modifying the serendipitously obtained parent gelator molecules. This chapter focuses on the designing aspects and applications of LMWGs derived from various hydrogen-bond-capable molecules. It particularly covers the development of organic salt-based gelators that are designed by following supramolecular synthon approach in the context of crystal engineering-based structure–property correlation.