Disease states resulting from biopolymer deposition can arise when the natural cleavage mechanisms become inoperative or function poorly. Formation of �-amyloid plaques has been connected to the neurodegenerative disease Alzheimer's, while thrombotic diseases involve the formation of insoluble fibrin clots. In a similar vein, many current cancer treatments target the biopolymer DNA, however a drawback of many drugs involves the cells' ability to repair damage. Despite the prevalence of these problems, treatment options are severely limited and often rely on inhibition or activation of the enzymes involved in the natural degradation process. An alternative paradigm would be to employ a reactive species capable of degrading biopolymers in a controlled and non-repairable fashion. Chelation-triggered radical generation and H-atom abstraction may be a novel approach towards dissolution of these biopolymers as metal ions are closely associated with each of these diseases. Previous studies in our group have shown that this radical-generation paradigm is able to cleave DNA and induce apoptosis in cancer cells. Small molecules with N4-coordination have been developed for disaggregation of �-amyloid plaques by in situ activation and radical-formation upon chelation of Zn(II) and Cu(II). Preliminary experiments involving dissolution of purified fibrin clots upon exposure to the radical-generating ligand will also be discussed. These results demonstrate that the use of a chelation-induced radical-generator is viable as a general method for the dissolution of biopolymers.

Development of therapeutic metalloenediynes: Harnessing Bergman cyclization for biopolymer degradation

246th National Meeting (2013)

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