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. Designing supramolecular gelators are challenging. Crystal engineering inspired structure-property correlation-based strategy has been employed to synthesize a series of carbamoyl azide-drug conjugates as potential supramolecular gelators. Five non-steroidal-anti-inflammatory-drugs (NSAIDs) based carbamoyl azides were synthesized employing ibuprofen (Ibu), naproxen (Nap), ketoprofen (Keto), flurbiprofen (Flur) and diclofenac (Diclo) as starting materials. The corresponding carbamoyl azides were isolated in good yields and characterized by single crystal X-ray diffraction (SXRD) alongside FT-IR, 1 H, 13 C NMR and mass spectrometry. Single crystal structure analysis revealed that the self-assembly of the molecules leading to gelation-conducive 1D hydrogen bonded network in all these carbamoyl azides was 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. Anti-inflammatory activity of Diclo-Az against lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages was confirmed by PGE 2 assay. Studies conducted using a melanoma cell line (B16-F10) revealed that Diclo-Az had appreciable anti-melanoma properties displaying apoptosis induced cell death whereas it was noncytotoxic against a 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 property. The aqueous gel of Diclo-Az showed excellent rheo-reversible property over a few cycles suggesting its application via topical route. Moreover, a small patch of Diclo-Az gel adherable to commercially available medical bandage also suggested its proof-of-concept validation of its utility as a vehicle-free drug delivery system.