Development of stimulus-responsive ligands for the modulation of copper and iron coordination

We seek to develop compounds that change their metal binding characteristics in response to external stimuli. Herein we report the previously unrecognized photochemistry of aroylhydrazone metal chelator ((E)-N¿-[1-(2-hydroxyphenyl)ethyliden]isonicotinoylhydrazide) (HAPI) and its relation to HAPI metal binding properties. Based on initial results, a series of HAPI analogues was prepared to probe the structure-function relationships of aroylhydrazone photochemistry. These efforts elucidate the tunable nature of aroylhydrazone photoswitching properties.Compounds called prochelators switch from low to high metal binding affinity upon activation by a stimulus of interest. The multifunctional prochelator 2-((E)-1-(2-isonicotinoylhydrazono)ethyl)phenyl (E)-3-(2,4-dihydroxyphenyl)acrylate (PC-HAPI) is masked with a trans-cinnamic acid protecting group that releases umbelliferone, a UV-absorbing, antioxidant coumarin along with HAPI upon UV irradiation. Photoreleased HAPI inhibits metal-catalyzed production of damaging reactive oxygen species, complementing the coumarin antioxidant response. Finally a H2O2-sensitive prochelator quinolin-8-yl (Z)-3-(4-hydroxy-2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)acrylate (BCQ) has been prepared using a novel synthetic route for functionalized cis-cinnamate esters. BCQ activation triggers a 90-fold increase in fluorescence emission, along with the release of a desired chelator, in the presence of H2O2.