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

Abstract

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.