Synthon Approach Research Articles

Supramolecular Gels Derived from Primary Ammonium salts of Naproxen and its Amino Acid Derivatives: Design, Synthesis, Structures and its Application as Anti-cancer Agent Against Melanoma Cell B16-F10.

Supramolecular synthon approach was employed to develop a self-drug-delivery system based on organic salt based supramolecular gelators. One such key gelator NAP-PHE∙PEA derived from naproxen-phenylalanine conjugate and phenethylamine showed ability to gel both water and organic solvents. Supramolecular interactions such as π-π and C-H…π were probed by variable-temperature 1H-NMR spectroscopy in the hydrogelation process of NAP-PHE∙PEA. Single crystal structures of nine out of twelve salts were determined and the supramolecular synthon present therein was carefully analyzed. Intriguing insights of the gel-network structure was also investigated by structure-property correlation based on single-crystal and powder X-ray diffraction analysis of gelator/nongelator salts. The gelator salt NAP-PHE∙PEA displayed significant anti-cancer property against cancer cells (B16-F10. HeLa and A375); it was found non-cytotoxic against normal cell lines (E.derm and HEK-293) at comparable concentrations as revealed by MTT assays. The gelator salt NAP-PHE∙PEA also displayed significant anti-cancer behaviour against B16-F10 (scratch assay) and HeLa (multi-cellular tumour spheroid). The methyl salicylate gel of NAP-PHE∙PEA displayed shape-sustaining, load-bearing, self-healing properties along with rheoreversibility, which are considered important for topical applications.

Biochanin-A co-crystal formulation improves bioavailability and ameliorates cerulein-induced pancreatitis by attenuating the inflammation

Co-crystallization of a therapeutic ingredient with an appropriate co-former is a powerful technique to augment the physicochemical and pharmacokinetic properties and the effectiveness of Active Pharmaceutical Ingredients (APIs). Biochanin A (BCA), a flavonoid with medicinal potential, is limited by poor solubility and low oral bioavailability. This study aimed to design and develop a novel BCA-nicotinamide cocrystal as BCC to enhance BCA’s oral bioavailability and explore its therapeutic potential for ameliorating cerulein-induced acute pancreatitis (CIAP) by elucidating the target identification utilizing tissue/serum metabolite profiles. The cocrystal was designed by the supramolecular synthon approach and characterized by single-crystal X-ray diffraction that confirms a robust three-dimensional hydrogen-bonded network of BCA and Nicotinamide (NCT) in the crystal. FT-IR and DSC were used to analyze the cocrystal’s intermolecular interactions and thermal behavior. BCC exhibited enhanced solubility and drug release compared to BCA alone, resulting in enhanced oral bioavailability and pancreatic tissue concentration. Comparing BCC to BCA in the CIAP model, BCC therapy remarkably reduced cerulein-induced pancreatitis, evidenced by significant reductions in inflammation, acinar cell atrophy, and amylase levels in pancreatic tissues. Further, the cocrystal formulation also down-regulated the oxidative stress markers, inflammatory cytokines and macrophage-related proteins. The study has identified distinct metabolomic signatures linked with AP with the help of Orbitrap Exploris mass spectrometry, which could pave the way for creating focused diagnostic tools for a better prognosis. In conclusion, these results offer new insights into exploring mechanistic pathways associated with specific biomarkers and underscore BCC cocrystal as a promising approach to enhance BCA’s therapeutic potential.

The potential of supramolecular synthon to develop coamorphous systems with tailored physical stability: Mechanistic insights integrating kinetics and thermodynamics

Coamorphous drug delivery systems have received increasing interest owing to their potential to improve the solubility, dissolution and bioavailability of poorly water-soluble drugs. However, the crystallization risk is one of major limitations in their application. It has been widely recognized that the coformer plays a vital role in physical stability of coamorphous formulation. Unfortunately, the screen of optimal coformer still adopts a trial-and-error method, which is time-consuming and expensive. Herein, a supramolecular synthon approach based on the interaction between functional groups, was exploited to design coamorphous systems (CMs) consisting of lurasidone hydrochloride (LH) and three coformers, saccharin (SAC), L-tryptophan (TRP), and L-cysteine hydrochloride (CYS). X-ray powder diffraction suggested the order of physical stability of the coamorphous systems was ranked as LH-CYS CM > LH-TRP CM > LH-SAC CM. The charge-assisted hydrogen bond between LH and coformer was confirmed by infrared spectroscopy and solid-state 13C NMR. Moreover, structural, electronic, and molecular interaction information, especially hydrogen bonding interactions, were quantified by theoretical calculations, including miscibility calculations, molecular dynamics simulations and quantum chemical calculations. It was revealed that LH-CYS CM exhibited the best miscibility, strongest binding energy and strongest H-bond with partially covalent character, demonstrating the significant role of supramolecular synthon in stabilizing coamorphous formulations. Interestingly, LH-TRP CM, not LH-CYS CM, exhibited the lowest molecular mobility among three coamorphous systems, which was inconsistent with their physical stability. But from thermodynamic perspective, the order of configurational entropy and physical stability of coamorphous systems was completely consistent. We shed light on the comprehensive effects of molecular mobility and configurational entropy on physical stability of coamorphous systems. Importantly, the relationship between supramolecular synthon and kinetic/thermodynamic mechanisms was also discussed, and the positive correlation between configurational entropy and intermolecular interactions was proposed in this paper. Our findings demonstrated the great potential of supramolecular synthon in designing coamorphous systems with tailored physical stability, and further provided a deeper insight into the mechanisms of physical stability of coamorphous systems.

Synthon Approach in Crystal Engineering to Modulate Physicochemical Properties in Organic Salts of Chlorpropamide.

The formulation of drug with improved bioavailability is always challenging and indispensable in the field of pharmaceutics. The control of intermolecular interactions via crystal engineering approach and solid-state molecular recognition results in the formation of active drug molecules with modulated pharmacological benefits. Therefore, with the aim to improve the solubility and dissolution rate of the drug chlorpropamide (CPA), the mechanochemical liquid-assisted grinding (LAG) of the drug with several pharmaceutically accepted excipients was performed. This contributed to the discovery of six novel solid phases, namely salts, salt cocrystals and salt cocrystal hydrate─the salt of CPA with 3, 4-diaminopyridine (DAP); salt and salt cocrystal (SC) polymorph (Z″=3) with 1, 4-diazabicyclo [2.2.2] octane (DABCO); a salt, SC polymorph (Z″=9), and a SC hydrate (Z″=9) with piperazine (PIP). The formation of these salts and salt cocrystals are mainly guided by the strong hydrogen bonds with tunable strength having high electrostatic contribution. This attractive interaction brings the donor and the acceptor atoms close to each other for a facile proton transfer. Furthermore, the conformational constraints on the drug molecules, provided by the excipients via strong and directional hydrogen bonds, are quite impressive as this leads to the identification and characterization of "new conformational isomers" for the CPA molecules. The new crystalline phases exhibit enhanced intrinsic dissolution rate in comparison to that of the pure drug, the magnitude being 7, 131, and 120 folds for CPADAP, CPADABCO_II, and CPAPIP_III, respectively. Furthermore, it is interesting to note that the order of solubility is enhanced by 2.7-, 3-, and 7-fold, respectively, for the abovementioned salts. This also mirrors the trends in the magnitude of the binding energy, the higher magnitude being reflected in the lower solubility. Additionally, the in vivo experiments performed in SD rats results in the enhancement of the magnitude of the pharmacokinetic properties, when compared to the pristine drug. The concentration of the drug in CPADABCO_II and CPAPIP_III formulations exhibits 6- and 4-fold increments, respectively. Indeed, these results corroborate to the trends observed in the structural characterization, intermolecular energy calculations, solubility, and in vitro dissolution assessments.

Accurate Geometries of Large Molecules by Integration of the Pisa Composite Scheme and the Templating Synthon Approach.

An effective yet reliable computational workflow is proposed, which permits the computation of accurate geometrical structures for large flexible molecules at an affordable cost thanks to the integration of machine learning tools and DFT models together with reduced scaling computations of vibrational averaging effects. After validation of the different components of the overall strategy, a panel of molecules of biological interest have been analyzed. The results confirm that very accurate geometrical parameters can be obtained at reasonable cost for molecules including up to about 50 atoms, which are the largest ones for which comparison with high-resolution rotational spectra is possible. Since the whole computational workflow can be followed employing standard electronic structure codes, accurate results for large-sized molecules can be obtained at DFT cost also by nonspecialists.

Enabling Chemoenzymatic Strategies and Enzymes for Synthesizing Sialyl Glycans and Sialyl Glycoconjugates.

Sialic acids are fascinating negatively charged nine-carbon monosaccharides. Sialic acid-containing glycans and glycoconjugates are structurally diverse, functionally important, and synthetically challenging molecules. We have developed highly efficient chemoenzymatic strategies that combine the power of chemical synthesis and enzyme catalysis to make sialic acids, sialyl glycans, sialyl glycoconjugates, and their derivatives more accessible, enabling the efforts to explore their functions and applications. The Account starts with a brief description of the structural diversity and the functional importance of naturally occurring sialic acids and sialosides. The development of one-pot multienzyme (OPME) chemoenzymatic sialylation strategies is then introduced, highlighting its advantages in synthesizing structurally diverse sialosides with a sialyltransferase donor substrate engineering tactic. With the strategy, systematic access to sialosides containing different sialic acid forms with modifications at C3/4/5/7/8/9, various internal glycans, and diverse sialyl linkages is now possible. Also briefly described is the combination of the OPME sialylation strategy with bacterial sialidases for synthesizing sialidase inhibitors. With the goal of simplifying the product purification process for enzymatic glycosylation reactions, glycosphingolipids that contain a naturally existing hydrophobic tag are attractive targets for chemoenzymatic total synthesis. A user-friendly highly efficient chemoenzymatic strategy is developed which involves three main processes, including chemical synthesis of lactosyl sphingosine as a water-soluble hydrophobic tag-containing intermediate, OPME enzymatic extension of its glycan component with a single C18-cartridge purification of the product, followed by a facile chemical acylation reaction. The strategy allows the introduction of different sialic acid forms and diverse fatty acyl chains into the products. Gram-scale synthesis has been demonstrated. OPME sialylation has also been demonstrated for the chemoenzymatic synthesis of sialyl glycopeptides and in vitro enzymatic N-glycan processing for the formation of glycoproteins with disialylated biantennary complex-type N-glycans. For synthesizing human milk oligosaccharides (HMOs) which are glycans with a free reducing end, acceptor substrate engineering and process engineering strategies are developed, which involve the design of a hydrophobic tag that can be easily installed into the acceptor substrate to allow facile purification of the product from enzymatic reactions and can be conveniently removed in the final step to produce target molecules. The process engineering involves heat-inactivation of enzymes in the intermediate steps in multistep OPME reactions for the production of long-chain sialoside targets in a single reaction pot and with a single C18-cartridge purification process. In addition, a chemoenzymatic synthon strategy has been developed. It involves the design of a derivative of the sialyltransferase donor substrate precursor, which is tolerated by enzymes in OPME reactions, introduced to enzymatic products, and then chemically converted to the desired target structures in the final step. The chemoenzymatic synthon approach has been used together with the acceptor substrate engineering method in the synthesis of complex bacterial glycans containing sialic acids, legionaminic acids, and derivatives. The biocatalysts characterized and their engineered mutants developed by the Chen group are described, with highlights on synthetically useful enzymes. We anticipate further development of chemoenzymatic strategies and biocatalysts to enable exploration of the sialic acid space.

Next generation fibroblast activation protein (FAP) targeting PET tracers - The tetrazine ligation allows an easy and convenient way to 18F-labeled (4-quinolinoyl)glycyl-2-cyanopyrrolidines

Small-molecular fibroblast activation protein inhibitor (FAPI)-based tracer have been shown to be promising Positron Emission Tomography (PET) 68Ga-labeled radiopharmaceuticals to image a variety of tumors including pancreatic, breast, and colorectal cancers, among others. In this study, we developed a novel 18F-labeled FAPI derivative. [18F]6 was labeled using a synthon approach based on the tetrazine ligation. It showed subnanomolar affinity for the FAP protein and a good selectivity profile against known off-target proteases. Small animal PET studies revealed high tumor uptake and good target-to-background ratios. [18F]6 was excreted via the liver. Overall, [18F]6 showed promising characteristics to be used as a PET tracer and could serve as a lead for further development of halogen-based theranostic FAPI radiopharmaceuticals.

Binary to ternary drug-drug molecular adducts of the antihypertensive drug ketanserin (KTS) with advanced physicochemical properties.

Focusing on a reliable supramolecular synthon approach, novel molecular salts of the antihypertensive medication ketanserin (KTS) with aromatic carboxylic acid derivatives (benzoic acid (BA), 2-hydroxybenzoic acid (2-HBA), and 2,5-dihydroxybenzoic acid (2,5-DHBA)) are reported. Binary salts of KTS with the respective salt former were obtained via solvent-assisted grinding followed by solution crystallization. Salt production was confirmed through crystal structure investigations that revealed proton transfer from the carboxylic acid group of the salt former to the piperidine nitrogen atom of KTS. A rigorous investigation of the crystal packing of novel binary salts of KTS inspired the construction of ternary adducts, and a ternary crystalline product was subsequently identified using milrinone (MLN), another cardiotonic drug. According to our knowledge, this is the first instance of a dual-drug ternary co-crystal combining both antihypertensive drugs. In order to evaluate the impacts of co-crystallization on the in vitro release behaviour of binary and ternary adducts, solubility tests for the cocrystal were carried out under a variety of physiological pH conditions. The results indicate that, in contrast to the parent drug and binary adducts, the solubility rate of the ternary adducts is significantly increased. Finally, the stability of the synthesised adduct was evaluated under a range of conditions, including temperature (40 ± 1 °C), humidity (90% ± 5% RH, 25 °C) and various solvents media, and it was established that they have good stability. We anticipate that the present findings will work with a wide range of medication combinations, providing a potential new approach to create multi-drug systems for cardiovascular disease.

Unravelling the Origin of Solvate Formation in the Anticancer Drug Trametinib: Insights from Crystal Structure Analysis and Computational Modeling

The discovery of new crystalline forms of large, flexible drug molecules is of significant interest to the pharmaceutical industry as a means of improving one or more physicochemical properties of the active pharmaceutical ingredient (API). Trametinib (TRMB) is an anticancer drug, for which no solid-state forms are yet reported. Here, we report the results of an extensive screen for cocrystals of TRMB in an effort to improve the poor aqueous solubility of this API. Contrary to expectations, this effort led to the discovery of only six isostructural solvates of TRMB, where the solvent molecules fill the voids of the crystal structure and are stabilized by various intermolecular interactions. Computational crystal structure prediction methods were used to rationalize the high propensity for solvent inclusion in TRMB as arising from the poor crystal packing in TRMB. All predicted polymorphs of TRMB within a relative lattice energy of 44 kJ mol–1 of the global minimum display solvent accessible voids ranging from 1.4 to 16.5% of the unit cell volume. The serendipitous discovery of solvates in experiments targeting cocrystals,strongly suggests that the well-established synthon approach for the discovery of cocrystals works relatively well for documented literature examples that use rigid coformers with minimal conformational flexibility. However, for large APIs such as TRMB, in-silico screening methods should be adopted to reduce the need for extensive experimental cocrystal screens as the ability to form a cocrystal for drug candidates relies on more than synthon complementarity.

Computational and Experimental Insights in Design and Development of Aceclofenac Co-Crystals

The present study is aimed at the design and development of aceclofenac co-crystals. Co-crystallization is one of the important techniques which helps to enhance the aqueous solubility of drugs by modifying the crystal structure using incorporation of the co-former into the formulation.. In the present study, supramolecular synthon approach and computational grid scan methods were used for the co-former selection. The different co-formers such as oxalic acid (OA), succinic acid (SA), maleic acid (MA), and benzoic acid (BA) were used. Aceclofenac (ACF) co-crystals were prepared by solvent evaporation and dry grinding method. Based on the computational results and experimental saturation solubility studies, maleic acid was considered as the suitable co-former for the preparation. The solid-state characterization showed partial conversion of ACF crystallinity to the amorphization as evident from the decrease in peak intensity and the number of peaks. The co-crystals showed increased aqueous solubility of ACF and higher drug release in basic pH. All the characterization parameters proved the co-crystal formation and the in vitro release studies showed that the solubility enhancement of the ACF by preparing ACF-MA co-crystals. Thus, it can be concluded that co-crystallization is one of the novel method for improving the bioavailability of aceclofenac.

Dual Functionality of Bile Acid: Physical Stabilization of Drugs in the Amorphous Form and Solubility Enhancement in Solution.

Drugs containing an amino aromatic nitrogen moiety were stabilized in the amorphous form by the surfactant cholic acid (CA). Coamorphous systems of lamotrigine (LAM), pyrimethamine (PYR), and trimethoprim (TRI) were each prepared with CA. Drug-CA interactions, investigated by IR and solid-sate NMR spectroscopy, revealed deprotonation of the carboxylic acid group in CA and the protonation of the most basic nitrogen of the drug. The coamorphous systems exhibited exceptional physical stability and resisted crystallization at (i) elevated temperatures (>100 °C) and (ii) accelerated storage conditions, 40 °C/75% relative humidity for 15 months. The dissolution performance of each coamorphous system was compared with the respective crystalline drug based on the area under the curve (AUC) of the concentration-time profiles. A 25-fold increase in AUC was observed in the PYR-CA coamorphous system. The solubility enhancement is attributed not only due to drug amorphization but also due to solubilization by CA. The supramolecular synthon approach, through a drug-CA interaction, yielded physically stable coamorphous systems with enhanced aqueous drug solubility.

Synthesis and Characterization of Transition-State Analogue Inhibitors against Human DNA Methyltransferase 1.

Hypermethylation of CpG regions by human DNA methyltransferase 1 (DNMT1) silences tumor-suppression genes, and inhibition of DNMT1 can reactivate silenced genes. The 5-azacytidines are approved inhibitors of DNMT1, but their mutagenic mechanism limits their utility. A synthon approach from the analogues of S-adenosylhomocysteine, methionine, and deoxycytidine recapitulated the chemical features of the DNMT1 transition state in the synthesis of 16 chemically stable transition-state mimics. Inhibitors causing both full and partial inhibition of purified DNMT1 were characterized. The inhibitors show modest selectivity for DNMT1 versus DNMT3b. Active-site docking predicts inhibitor interactions with S-adenosyl-l-methionine and deoxycytidine regions of the catalytic site, validated by direct binding analysis. Inhibitor action with purified DNMT1 is not reflected in cultured cells. A partial inhibitor activated cellular DNA methylation, and a full inhibitor had no effect on cellular DNA methylation. These compounds provide chemical access to a new family of noncovalent DNMT chemical scaffolds for use in DNA methyltransferases.

Strategic synthon approach in obtaining cocrystals and cocrystal polymorphs of a high-Z′ system deferiprone – an anti-thalassemia drug

Compounds with more than one molecule in the crystallographic asymmetric unit (Z′ > 1) display a noticeably stronger propensity to form cocrystals. Deferiprone is an anti-thalassemia drug known to exhibit polymorphic behaviour. Previously, three polymorphs were reported out of which one of them exhibited Z′ > 1. In the present manuscript, a fourth polymorph of deferiprone was identified and it also possessed Z′ > 1. All the four polymorphs showed similar hydrogen bonding features and differed in crystal packing. The ability of deferiprone to crystallize as Z′ > 1 prompted us to investigate the hydrogen bonding and synthon variation upon cocrystallization of deferiprone with hydroxyl-group-containing coformers such as catechol, hydroquinone, phloroglucinol, resorcinol and pyrogallol. Crystallization attempts along with PXRD analysis aided in obtaining 11 new cocrystal structures which involve different stoichiometric cocrystals and some polymorphs. Synthon analysis, crystal packing as well as thermal behaviour were assessed and compared. The presence of multiple phases in each cocrystal system in its respective bulk powders was identified and quantified using PXRD and Rietveld analysis. Homosynthons were observed in three co-crystal systems, while a heterosynthon was observed in five systems. The combination of both homo- and heterosynthon was observed in three cocrystal systems. The phase transformation events were observed in most of the systems. In nine co-crystal systems, the melting points were observed intermediate between those of the API and the coformers.

Supramolecular Synthon Approach in Designing Organic Sulfonates as Supramolecular Gelators: An Easily Accessible Topical Gel with Antibacterial Properties

The supramolecular synthon approach in the context of the crystal engineering rationale has been exploited to synthesize a new series of primary ammonium sulfonate salts derived from primary alkyl amines with varying alkyl chain lengths (An = CH3–(CH2)n–NH2; n = 2–11, 13–15, 17) and naphthalene-2-sulfonic acid (N2S) as potential supramolecular gelators. The sulfonate salts AnN2S with n ≥ 9 showed the ability to immobilize a number of polar and nonpolar solvents including dimethyl sulfoxide/water, resulting in supramolecular gels which were characterized by dynamic rheology and transmission electron microscopy. Single-crystal X-ray diffraction studies carried out on eight such salts confirmed the presence of gel-inducing hydrogen bonded supramolecular synthons. Anti-bacterial studies (zone inhibition, turbidity, and tetrazolium assays) revealed that the salt A14N2S had the ability to kill the Gram-positive bacterium Staphylococcus aureus. Laser scanning confocal microscopy and flow cytometry data taken under various staining conditions suggested reactive oxygen species-mediated RNA depletion as the plausible cause of bacterial cell death in the presence of the gelator salt. Shear thinning of the aqueous gel of A14N2S along with its anti-bacterial activity indicated that it could be a potential candidate for topical application.

Crystallographic and theoretical interpretation of supramolecular architecture in a new salt hydrate of DL-Tartaric acid and Dimethylamine (DLTA-DA)

Herein, DL-tartaric acid normally used as a coformer in cocrystal engineering is exploited to create the hybrid molecule with secondary amine utilizing the supramolecular synthon approach. The crystal engineering tactics are potentially applied to a wide range of crystalline materials and the nature of the intermolecular interactions, hydrogen bonds in particular which decide the supramolecular stabilization of the solid form can be studied. The mechanochemical mixing of DL-tartaric acid and aqueous dimethylamine showed salt-pseudopolymorphism, resulted in N-methylmethanaminium-3-carboxy-2,3-dihydroxypropanoate hydrate. The interactions present between the molecules were demonstrated by simulating the FTIR spectrum which showed O − H stretching of the carboxylic group that did not match with experimental value as only one supramolecular unit was considered; whereas the experimental spectrum displayed a broad band for O − H stretch at 3200 cm−1. The salt crystallized in the monoclinic system with space group I2/a. The complementary hydrogen bond functionalities present in the molecules instilled the formation of O–H···O, O–H···N, and N − H···O intermolecular contacts. From the graph set analysis, it was noted that the supramolecular architecture was maintained by the homosynthon dimer and one-dimensional O–H···O anionic chain built by R22(12)and C(7) motifs. Additionally, the cage type assembly was formed by additional hydrogen bonds present in between the chains with H2O as a linker. The 2D fingerprint plots confirmed the maximum percentage contribution of -O–H (59%) towards the Hirshfeld surface. Hence, a full analysis of crystal packing and discussions in the context of the supramolecular chemistry of the salt hydrate is presented.

Designing Supramolecular Gelators: Challenges, Frustrations, and Hopes.

This article is a personal account of the author, who serendipitously entered the field of supramolecular gels nearly two decades ago. A supramolecular synthon approach in the context of crystal engineering was utilized to develop a working hypothesis to design supramolecular gelators derived from simple organic salts. The activity not only provided a way to occasionally predict gelation, but also afforded clear understanding of the structural landscape of such supramolecular materials. Without waiting for an ab initio approach for designing a gel, a large number of supramolecular gelators derived from organic salts were designed following the working hypothesis thus developed. Organic salts possess a number of advantages in terms of their ease of synthesis, purification, high yield and stability and, therefore, are suitable for developing materials for various applications. Organic salt-based gel materials for containing oil spills, synthesizing inorganic nanostructures and metal nanoparticles, sensing hazardous gas and dissolved glucose, adsorbing dyes, and facilitating drug delivery in self-delivery fashion have been developed. The journey through the soft world of gelators which was started merely by serendipity turned out to be rewarding, despite the challenges and frustrations in the field.

A supramolecular synthon approach to design amorphous solid dispersions with exceptional physical stability.

A supramolecular synthon approach was exploited to design amorphous solid dispersions (ASDs) of drugs containing an amino aromatic nitrogen moiety and a polyacrylic acid polymer. The interaction between a drug and polymer was confirmed by differential scanning calorimetry, spectroscopy (IR and 15N NMR), and X-ray crystallography. The interaction decreased the molecular mobility, conferred exceptional physical stability and enhanced the drug dissolution.

Co-crystallization and polymorphic behaviour of 5-fluorouracil

Hydrogen donors and acceptors in 5-fluorouracil allow the formation of co-crystalline compounds with nontoxic co-formers of the GRAS list and an alternative target-oriented synthon approach from methanol or ethanol to form II of 5-fluorouracil is presented.

Supramolecular Synthon Approach in Designing Molecular Gels for Advanced Therapeutics

AbstractLow‐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.

2+2] solid-state photodimerisation in a ternary co-crystal: a synthon approach

2+2] solid-state photodimerisation in a ternary co-crystal: a synthon approach