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 synthesize a series of primary ammonium monocarboxylate (PAM) salts derived from a well-known nonsteroidal anti-inflammatory drug (NSAID) naproxen (NAP) and its amino acid conjugates namely naproxen-L-phenylalanine (NAP-PHE) and naproxen-L-alanine (NAP-ALA), and four amines namely tyramine (TYRM), tryptamine (TRPM), 3,4-dimethoxyphenethylamine (DMP) and phenethylamine (PEA) as potential supramolecular gelators for developing self-drug delivery system. Out of the total twelve PAM salts thus synthesized, 75 % of the salts showed gelation ability. Importantly, majority of the gelator salts (67 %) displayed gelling abilities with topical gel formulating solvent methyl salicylate. One such salt, NAP-PHE⋅PEA was an ambidextrous gelator producing hydrogel with pure water and organogel with methyl salicylate with a minimum gelator concentration (MGC) of 0.5 wt % (w/v) thereby qualifying as a supergelator. The gels were extensively characterized by dynamic rheology and transmission electron microscopy (TEM). Supramolecular interactions such as π-π and C-H…π were probed by variable-temperature H-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 (SXRD, PXRD, respectively) 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.