An iterative polyphosphorylation approach is described, which is based on ap hosphoramidite (P-amidite) derived reagent (c-PyPA) obtained from the cyclization of pyrophosphate with areactive diisopropylaminodichlorophosphine.T his type of reagent is unprecedented as it represents ar eactive P-amidite without protecting groups.T he reagent proved to be stable in solution over several weeks.Its utility is described in the context of iterative monodirectional and bidirectional polyphosphorylations.T he ensuing functionalized cyclotriphosphate can be opened with av ariety of nucleophiles providing ready access to diverse functionalized polyphosphate chains of defined length with several tags, including both P-N and P-O labels.Their interaction with exoand endopolyphosphatases is described.
Targeted α therapy holds tremendous potential as a cancer treatment: it offers the possibility of delivering a highly cytotoxic dose to targeted cells while minimizing damage to surrounding healthy tissue. The metallic α-generating radioisotopes Ac andTh are promising radionuclides for therapeutic use, provided adequate chelation and targeting. Here we demonstrate a new chelating platform composed of a multidentate high-affinity oxygen-donating ligand 3,4,3-LI(CAM) bound to the mammalian protein siderocalin. Respective stability constants log β = 29.65 ± 0.65, 57.26 ± 0.20, and 47.71 ± 0.08, determined for the Eu (a lanthanide surrogate for Ac), Zr, and Th complexes of 3,4,3-LI(CAM) through spectrophotometric titrations, reveal this ligand to be one of the most powerful chelators for both trivalent and tetravalent metal ions at physiological pH. The resulting metal-ligand complexes are also recognized with extremely high affinity by the siderophore-binding protein siderocalin, with dissociation constants below 40 nM and tight electrostatic interactions, as evidenced by X-ray structures of the protein:ligand:metal adducts with Zr and Th. Finally, differences in biodistribution profiles between free and siderocalin-bound Pu-3,4,3-LI(CAM) complexes confirm in vivo stability of the protein construct. The siderocalin:3,4,3-LI(CAM) assembly can therefore serve as a "lock" to consolidate binding to the therapeutic Ac andTh isotopes or to the positron emission tomography emitter Zr, independent of metal valence state.
The complexity of phosphorylation pathways and their downstream effects is vast. Synthetic chemistry has been working side by side with biology to develop phosphate labels for biological processes involving phosphorylated compounds. This chapter discusses recently employed methods for the preparation of several phosphate labels. Synthesis of biomolecules and their analogs and other useful or potentially useful phosphate derivatives is discussed.
Recent efforts to activate the strong uranium-oxygen bonds in the dioxo uranyl cation have been limited to single oxo-group activation through either uranyl reduction and functionalization in solution, or by collision induced dissociation (CID) in the gas-phase, using mass spectrometry (MS). Here we report and investigate the surprising double activation of uranyl by an organic ligand, 3,4,3-LI(CAM), leading to the formation of a formal U 6+ chelate in the gas-phase. The cleavage of both uranyl oxo bonds was experimentally evidenced by CID, using deuterium and 18 O isotopic substitutions, and by infrared multiple photon dissociation (IRMPD) spectroscopy.Density functional theory (DFT) computations predict that the overall reaction requires only 132 kJ/mol, with the first oxygen activation entailing about 107 kJ/mol. Combined with analysis of similar, but unreactive ligands, these results shed light on the chelation-driven mechanism of uranyl oxo bond cleavage, demonstrating its dependence on the presence of ligand hydroxyl protons available for direct interactions with the uranyl oxygens.
The combinatorial synthesis of a new library of tetrameric peptoid ligands is introduced, enabling coordination and characterization of f-block metals.
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