title: Multifunctional Pt(II) Reagents: Covalent Modifications of Pt Complexes Enable Diverse Structural Variation and In-Cell Detection.
abstract: To enhance the functionality of Pt-based reagents, several strategies have been developed that utilize Pt compounds modified with small, reactive handles. This Account encapsulates work done by us and other groups regarding the use of Pt(II) compounds with reactive handles for subsequent elaboration with fluorophores or other functional moieties. Described strategies include the incorporation of substituents for well-known condensation or nucleophilic displacement-type reactions and their use, for example, to tether spectroscopic handles to Pt reagents for in vivo investigation. Other chief uses of displacement-type reactions have included tethering various small molecules exhibiting pharmacological activity directly to Pt, thus adding synergistic effects. Click chemistry-based ligation techniques have also been applied, primarily with azide- and alkyne-appended Pt complexes. Orthogonally reactive click chemistry reactions have proven invaluable when more traditional nucleophilic displacement reactions induce side-reactivity with the Pt center or when systematic functionalization of a larger number of Pt complexes is desired. Additionally, a diverse assortment of Pt-fluorophore conjugates have been tethered via click chemistry conjugation. In addition to providing a convenient synthetic path for diversifying Pt compounds, the use of click-capable Pt complexes has proved a powerful strategy for postbinding covalent modification and detection with fluorescent probes. This strategy bypasses undesirable influences of the fluorophore camouflaged as reactivity due to Pt that may be present when detecting preattached Pt-fluorophore conjugates. Using postbinding strategies, Pt reagent distributions in HeLa and lung carcinoma (NCI-H460) cell cultures were observed with two different azide-modified Pt compounds, a monofunctional Pt(II)-acridine type and a difunctional Pt(II)-neutral complex. In addition, cellular distribution was observed with an alkyne-appended difunctional Pt(II)-neutral complex analogous in structure to the aforementioned difunctional azide-Pt(II) reagent. In all cases, significant accumulation of Pt in the nucleolus of cells was observed, in addition to broader localization in the nucleus and cytoplasm of the cell. Using the same strategy of postbinding click modification with fluorescent probes, Pt adducts were detected and roughly quantified on rRNA and tRNA from Pt-treated Saccharomyces cerevisiae; rRNA adducts were found to be relatively long-lived and not targeted for immediate degradation. Finally, the utility and feasibility of the alkyne-appended Pt(II) compound has been further demonstrated with a turn-on fluorophore, dansyl azide, in fluorescent detection of DNA in vitro. In all, these modifications utilizing reactive handles have allowed for the diversification of new Pt reagents, as well as providing cellular localization information on the modified Pt compounds.
authors.affiliation: Department of Chemistry and Biochemistry, University of Oregon , Eugene, Oregon 97403-1253, United States.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: White
authors.affiliation: Department of Chemistry and Biochemistry, University of Oregon , Eugene, Oregon 97403-1253, United States.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Haley
authors.affiliation: Department of Chemistry and Biochemistry, University of Oregon , Eugene, Oregon 97403-1253, United States.
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: DeRose
mesh_terms: D002466:Cell Nucleolus / Q000378:metabolism; D057930:Click Chemistry; D005456:Fluorescent Dyes / Q000032:analysis / Q000737:chemistry / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000032:analysis* / Q000737:chemistry* / Q000378:metabolism; D012313:RNA / Q000737:chemistry; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D005456:Fluorescent Dyes; D009944:Organoplatinum Compounds; D012313:RNA