The anticancer drug cisplatin (cis-diamminedichloroplatinum-II) and related Pt(II) compounds form exchange-inert complexes with nucleic acids and other biomolecules. To better understand the range of cellular interactions available to these compounds, robust methods to track and analyze Pt-bound species are needed. A bioorthogonally reactive handle on a Pt ligand would allow for post-treatment covalent modification, streamlining separation, purification, and subsequent identification of Pt-bound species. To this end we have designed and synthesized a family of azide-containing Pt(II) derivatives capable of undergoing cycloaddition 'click' reactions with functionalized alkynes (White et al., JACS 2013). Successful proof-of-principle reactions demonstrating target binding and click reactivity have allowed fluorescent detection of Pt-bound DNA, RNA, and protein models in vitro. Using cyclic ring-strained alkynes for Cu-free click reactions, rRNA extracted from S. cerevisiae treated with Pt-azide in vivo was labeled without observable degradation. Preliminary studies have also demonstrated alkyne-modified biotin tagging and selective neutravidin conjugation of Pt-azide-bound DNA oligomers, highlighting the potential for these reagents in the desired enrichment of in vivo biomolecule targets. Currently being investigated are post-treatment fluorescent labeling and imaging of Pt-treated HeLa cells, as well as a family of additional Pt-azide-derivatives. Also being explored is the preferential isomeric binding of certain Pt derivatives and their effect on click reactivity. Current work remains focused on optimizing these systems for further in vitro and in vivo analyses of Pt-bound species.

New azide-modified Pt(II) compounds for biomolecule analysis by click chemistry

248th National Meeting (2014)

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