Exploiting Urea-Carboxylate Synthon for Designing Supramolecular Topical Hydrogel via Simple Organic Salt Formation: Synthesis, Crystal Structures, and Anticancer Behavior against Melanoma B16–F10 Cells

Abstract

A supramolecular synthon-based crystal engineering approach was adopted to design an exceptional class of gelators utilizing simple organic salt formation between monocarboxylic acid drugs (NSAIDs and 5-fluorouracil acetic acid or 5F) and N,N′-bis(4-pyridyl)urea (4U) reacted in 1:1 and 2:1 molar ratio, respectively. Among 14 salts, 6 turned to be aqueous gelators. In fact, 2_5F•4U, an organic salt formed by the combination of two molecules of 5F and one molecule of 4U having molecular weight <300 produced a pure water gel. Single-crystal X-ray diffraction performed with six salts indicated the presence of 1D Hbonding networks and the characteristic supramolecular synthons as envisaged. Several in vitro assays showed that the salt 2_5F•4U effectively induced apoptotic death in skin melanoma B16−F10 cells. Along with excellent rheoreversibility, the 2_5F•4U hydrogel could be shaped into a highly stable shape-sustaining translucent patch which could be placed on an adhesive tape for topical applications. The biological studies and material properties proved the 2_5F•4U hydrogel to be a potential topically applicable anticancer agent, highlighting the merits of the proposed rationale of designing supramolecular therapeutic hydrogels reported herein.