Investigation Of The Decorporation Efficacy And Mechanism Of 3,2-hydroxypyridinone-based Chelators For Uranium And Thorium

Once the actinides were introduced into the human body,they predominately and eventually deposited in tissues of kidney,liver and bone,leading to both acute and chronic renal damage as well as liver and kidney dysfunction,osteosarcoma.The chelation therapy is considered as the most effective method for actinides decorporation.By applying a proper multidentate ligand,which can competitively form highly thermodynamically favorable and water-soluble molecular complexes with actinides,the excretion of actinides from the body is accelerated.However,the study of actinides decorporation agent was very limited in the past 30 years,and no effective agent was obtained for the protection of the public safety.A series of ligands have been extensively studied for in vivo actinides chelation.DTPA is the only chelating agent approved by FDA for the clinical treatment of actinide internal contamination,but DTPA can not effectively remove uranium from either kidneys or bones,which is ascribed to its poor selective uranium binding affinity.5LIO-（Me-3,2-HOPO）and 3,4,3-LI-1,2-HOPO have been regarded as the optimal ligands for actinides decorporation and are under preclinical trials.However,both HOPO ligands show little effect on removing uranium from bone.Furthermore,the study regarding the mechanism of actinides decorporation is very limited,which is highly important for the rational design of effective chelators.Therefore,new ligands that bear advantages of low cost,convenient synthetic route,and high decorporation efficiency are still highly desired.In this thesis,the author has rationally designed and synthesized new HOPO-based decorporation ligands according to the actinide coordination chemistry,and systematically explored the mechanism of actinides decorporation.The results show that the newly synthesized HOPO ligands could significanlty remove uranium deposited in bones and can remove both uranium and thorium simutaneously.Meanwhile,searching for new ligand beyond HOPO unit with low toxicity and high decorporation efficiency is also urgent for the safety development of nuclear energy in China and for national security.Firstly,Deferiprone（3-Hydroxy-1,2-dimethyl-4（1H）-pyridone,DFP）,which is a drug clinically used for removing iron in vivo,was preliminarily explored for the purpose of actinides decorporation.In my work,potentiometric titrations were performed to study the complextion behavior of DFP and uranyl in aqueous solution.A uranyl-DFP complex was crystallized and the coordination mode between uranyl and DFP was investigated with single crystal X-ray diffraction technique.The uranium removal efficacy of DFP was examined at the cellular level and in mice,indicating that it can significantly reduce cellular uptake and increase cellular release of U（VI）in NRK-52E cells and reduce the amount of uranium deposited in kidneys.Therefore,DFP,which is a clinical available drug for iron decorporation can also be used as a sequestering agent for uranium.Secondly,previous studied HOPO ligands were intentionally designed to form intramolecular hydrogen bonds between the amide and hydroxide groups in order to be pre-deprotonated in the physiological p H range.However,this strategy of the formation of the intramolecular hydrogen bonding would partially offset the negative potential of the oxygen donors in the HOPO units,possibly leading to the sacrifice of the ligand’s affinity for cations.Based on the above,weakening the formation of the intramolecular hydrogen bondes may sufficiently release the binding ability of hydroxide group and improve its affinity towards uranyl.Therefore,we designed and synthesized a series of tetradentate HOPO ligands with different linker,3LI-1-Cm-3,2-HOPO(L^5a),5LIO-1-Cm-3,2-HOPO(L^5b),and 7LIO-1-Cm-3,2-HOPO(L^5c).Among these ligands,5LIO-1-Cm-3,2-HOPO was considered as the optimal agent for uranyl because of its’ high affinity and low toxicity.The solution thermodynamic studies of UO2-5LIO-1-Cm-3,2-HOPO were carried out by potentiometric titrations,and the result show that 5LIO-1-Cm-3,2-HOPO exhibits an elevated affinity with uranyl comparing to the reported tetradentate HOPO ligands and high selectivity of uranyl over other metal ions.The combination of NMR,EXAFS,FTIR,elemental analysis,and LC-MS measurements suggests that this ligand bind to the uranyl cation via chelation in the equatorial plane vertical to the linear uranyl unit.DFT calculations indicate that the formation of strong intramolecular hydrogen bond is greatly prohibited,giving rise to strengthened uranium-HOPO interaction consequently.In vivo uranium decorporation assays demonstrate that this new ligand show a record high removal efficiency of uranium from bones,which is six times more than 5LIO-（Me-3,2-HOPO）.And such a high decorporation efficiency remains even for the oral and 24 h delayed treatments.What’s more,5LIO-1-Cm-3,2-HOPO could effectively reduce both the uranium and thorium deposited in liver,kidney,and bones simutaneously.More than 90% and 55% of uranium from kidney and bone,and 55% of thorium from liver can be removed,respectively.Overall,the practical application of this ligand is highly desirable in the near future.Finally,uranium poses severe renal and bone damage in vivo.As the rapid development of nuclear industry,it is more urgent than ever to search for potential in vivo uranium chelators.3-hydroxy-2-pyrrolidinone（HPD）is firstly investigated as a new potential uranium decorporation ligand,which shows low cytotoxicity and the cell survival rate is up to 90% even in a high dosage（2.76 mM）.In vivo uranium decorporation assays demonstrate that HPD can remove 52% of uranium deposited in kidney.The solution complexation behavior and solid state coordination mode studies show that HPD resembles the chelation coordination of HOPO ligand with uranyl ions.By attaching to a suitable backbone,this bidentate ligand can be easily converted into tetradentate and octadentate ligand,which presumably have higher removal efficacy,thus posing high potential in the design and synthesis of new actinide decorporation agents.