Transition-Metal Mediated Chemistry in Cells

ended

Over the past decade, metals which were previously restricted to conventional organic synthesis have begun to be used in an increasing number of biological settings. This has been dominated by copper mediated catalysis of the azide-alkyne Huisgen cycloaddition (1,3-dipolar addition) chemistry (the well know “click reaction”) but other, less toxic, metals such as palladium are now beginning to establish themselves in the chemical biology/ chemical medicine arenas. In this proposal, building on chemistry from the Bradley group (see Nature Chemistry, 2011 and Nature Communication, 2014) the potential of palladium mediated chemistry in living systems will be exploited. This will cover three main avenues of exploration: (i). The fabrication of active palladium catalysts conjugated to antibodies and small targeting peptides; (ii) Development of assays to allow the activity of the active catalysts to be determined both in vitro and inside cells and (iii). The application of these active palladium catalysts enable the conjugation of two drug “halves” to allow the in situ synthesis (inside cells) of active anticancer drugs. This fellowship will bring together chemistry, biology and medicine, with potential longer-term biomedical applications with the training of the applicant in learning new chemistry and biological technique. This will be tied into an improvement of my independent thinking and leadership skills, gain of experience in writing grants and research articles and peer-reviewing and working in a multidisciplinary manner, with major opportunities to broaden my “soft-skills” set.