Design, Synthesis, and Structures of a Series of Cu(II)-NSAID-Pyridyl-Urea/Amide Complexes as Metallogelators: In Vitro Studies with the Dried 3UNAP-Cu(II)-Metallogel for Chemodynamic Therapy against Melanoma

A series of Cu(II)-coordination complexes derived from various nonsteroidal anti-inflammatory drugs (NSAIDs), namely naproxen (NAP), diclofenac (DIC), meclofenamic acid (DEC), ibuprofen (IBU), and 1-(4-methoxyphenyl)-3-(pyridin-3-yl)urea(3U)/N-(4-methoxyphenyl)nicotinamide(3A), were synthesized as potential metallogelators following a crystal engineering-inspired design approach with the aim of developing chemodynamic therapy (CDT) against melanoma. The complexes were characterized crystallographically. Three coordination complexes (3UNAP, 3ANAP, and 3AMEC) out of the seven thus synthesized were metallogelators of aqueous solvents (DMSO/water). The gels were characterized by dynamic rheology and electron microscopy. In vitro studies revealed that 3UNAP triggered intracellular GSH depletion and a Fenton-like reaction induced by Cu(II) of 3UNAP to effectively kill melanoma B16-F10 cells via apoptosis. More effective killing (∼90% cell death) of the cancer cells was observed when B16-F10 cells were treated with both 3UNAP and a commercially available disulfide (PhS-SPh), suggesting a simple thiol exchange reaction (GSH + PhS-SPh = GS-SPh + PhSH) in action that facilitates enhanced GSH depletion. This combination was also proven to be effective against B16-F10-derived three-dimensional (3D) spheroids, demonstrating its efficacy in a multicellular tumor model. Thus, the design strategy adopted herein supported the proof of the concept for developing a topical gel for noninvasive CDT against melanoma.