Carbamoyl azide–drug conjugates as supramolecular gelators: design, synthesis, crystal structures and anti-melanoma property

Abstract

Supramolecular gels are an important class of materials because of their various potential applications. However, designing supramolecular gelators is challenging. Herein, a crystal engineering-inspired, structure–property correlation-based strategy was employed to synthesize a series of carbamoyl azide–drug conjugates as potential supramolecular gelators. Five non-steroidal anti-inflammatory drugs (NSAIDs), ibuprofen (Ibu), naproxen (Nap), ketoprofen (Keto), flurbiprofen (Flur) and diclofenac (Diclo), were used as starting materials to synthesize carbamoyl azides. The synthesized carbamoyl azides were isolated in good yields and characterized by single-crystal X-ray diffraction (SXRD) alongside FT-IR spectroscopy, ¹H and ¹³C NMR and mass spectrometry. Single-crystal structural analysis revealed that the self-assembly of these molecules, leading to gelation-conducive 1D hydrogen-bonded networks in all the carbamoyl azides, is driven by N–H⋯O interactions involving the amide functionality, as anticipated. Two of the carbamoyl azide–drug conjugates, namely Nap-Az and Diclo-Az, were gelators, producing supramolecular gels in aqueous solvents (DMSO/water) at room temperature. The anti-inflammatory activity of Diclo-Az against lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages was confirmed by the PGE₂ assay. Studies conducted using the melanoma cell line (B16-F10) revealed that Diclo-Az exhibits appreciable anti-melanoma properties, displaying apoptosis induced cell death, whereas it was noncytotoxic toward the normal skin fibroblast cell line E. Derm. Interestingly, growth-delay experiments carried out on 3D multicellular spheroids derived from B16-F10 cells proved the effectiveness of Diclo-Az to retard and completely destroy the spheroids, thereby simulating its anti-tumour properties. The aqueous gel of Diclo-Az showed an excellent rheo-reversible property over a few cycles, suggesting its application via the topical route. Moreover, a small patch of Diclo-Az gel adherable to a commercially available medical bandage provided proof-of-concept for its utility as a vehicle-free drug delivery system.