勁固(rigid)雙核鑭系稀土離子之大環多氨基酸配位化學

Abstract

本研究計畫為一多年期基礎研究及應用計畫，其主要目的是對三價鑭系金屬離子(Ln3+)與大環多氨基酸配位子所形成錯合物之配位化學（熱力學、動力學、光譜學及結構學）作進一步的探討，進而找出影響鑭系稀土離子多氨基酸錯合物之物理化學性質（如穩定性、選擇性、反應速率、特殊結構、及螢光性質等）之重要因素，以便能在磁振造影劑、稀土離子之萃取分離、photodynamic療法、生物分子之螢光附著劑及切斷RNA及DNA反應之催化劑等有所應用。最近之研究結果顯示Eu(DO2A)+切割phosphodiester bond之速率與pH有類似滴定曲線之關係，而動力學判定是在高pH時，Eu(DO2A)+會形成更具活性之hydroxo-bridged [EuL(μ-OH)]2雙體之故；Eu(NO2A)+, Eu(ONO2A)+, 及Eu(ODO2A)+亦有類似之結果。然而Eu(DO2A)+, Eu(NO2A)+, Eu(ONO2A)+, 及Eu(ODO2A)+在較高濃度時，會形成沉澱物，可能為多核錯化物，如[EuL(μ-OH)]4，為進一步證實此假設，並設計更具活性之稀土大環錯合物，本期之研究以勁固(rigid)雙核鑭系稀土離子之大環多氨基酸錯合物為主要目標。研究要點包括： （1） 大環多氨基酸配位子勁固(rigid)雙體(如NO2A、DO2A dimers)的合成及特性研究（NMR，IR，X光單晶結構, pKa）。 （2） 測量鑭系金屬離子多氨基酸配位子錯化物的穩定常數(stability constant)及選擇性(selectivity)。 （3） 測量鑭系金屬離子大環多氨基酸配位子錯化物形成(formation)、解離(dissociation)及金屬離子或配位基置換(metal or ligand exchange)反應之速率及反應機理。 （4） 探討鑭系金屬離子大環多氨基酸配位子錯化物之熱力學與動力學因素是否與多氨基酸配位子之preorganization或ring strain之能量有直接關係，並以分子模擬研究驗證之。 （5） 合成鑭系稀土離子與大環多氨基酸配位子之錯化物，並作NMR、螢光光譜及X光單晶結構的特性研究，並試圖建立物性-化性-結構之間的關係。 （6） 試用鑭系稀土離子與多氨基酸配位子形成之陽離子錯合物如Ln(DO2A)+、Ln(NO2A)+之dimers切割磷酸酯類(如BNPP)及DNA和RNA之phosphate diester bond，並研究其反應速率與結構之關係。

The primary objective of this multi-year proposed research is to develop fundamental understanding of the major thermodynamic, kinetic, and structural factors that influence the desired physico-chemical properties of trivalent lanthanide complexes of macrocyclic polyaminocarboxylate ligands (e.g. complex formation stability and selectivity, reaction kinetics, NMR relaxation, luminescence, and structure) for applications in magnetic resonance imaging (MRI), solvent extraction, photodynamic therapy, luminescence labeling for biomolecules and catalysis for DNA and RNA phosphate diester bond cleavage. Recently, we have found that the rate constants measured for the Eu(DO2A)+ reaction with BNPP (a model compound with phosphate diester bond) had a titration-curve-like dependence with pH. Our initial kinetic studies revealed that at high pH, Eu(DO2A)+ could form more reactive hydroxo-bridged [EuL(μ-OH)]2 dimers, Eu(NO2A)+, Eu(ONO2A)+, and Eu(ODO2A)+ have similar results. However, Eu(DO2A)+, Eu(NO2A)+, Eu(ONO2A)+, and Eu(ODO2A)+ at high pH tend to form hydroxo-bridged polynuclear species and precipitates, e.g. [EuL(μ-OH)]4. To verify this point, and to develop more reactive and stable complexes as artificial nucleases, the research targets of this present project are primarily on the rigid dimeric lanthanide macrocyclic complexes. The specific aims include the following: (1) Synthesize and characterize (NMR, IR, X-ray structural determination and potentiometry) new dimeric macrocyclic polyaminocarboxylate ligands (e.g. DO2A and NO2A dimers) with variable cumulative ring strains and pendent arms (e.g. carboxymethyl, amidemethyl and hydroxyethyl groups). (2) Determine the thermodynamic and conditional complex formation constants of these macrocyclic ligands with various metal ions including all trivalent lanthanide ions, alkaline earth metal ions, selected first and second row divalent transition metal ions (e.g. Ni2+, Cu2+, Zn2+ and Cd2+) and post transition metal ions (e.g. Pb2+) in aqueous solution. Evaluate ligand selectivity toward lanthanide complex formation. (3) Determine the macrocyclic lanthanide complex formation, dissociation, and metal/ligand exchange reaction rates in aqueous solution at various conditions (i.e. changing pH, metal ion/ligand concentration, temperature and ionic strength) and evaluate possible reaction mechanisms. (4) Determine if the thermodynamic and kinetic parameters, i.e. stability and selectivity constants, formation and dissociation reaction rates, activation enthalpy and entropy, of lanthanide DO2A/NO2A dimeric complexes correlate with the ligand conformation, whether preorganized or not. And verify it with molecular modeling studies. (5) Synthesize and characterize (while possible, by single-crystal X-ray analyses, solution NMR, laser-excitation luminescence spectroscopy, NMR relaxation and molecular mechanics calculations) the macrocyclic complexes of La3+, Ce3+, Eu3+, Gd3+, and Yb3+. Correlate structural features (e.g. number of inner-sphere coordinated water molecules, number of ligand coordinated donor atoms, NMR chemical shifts, ligand cavity size, ligand cumulative ring strain, and metal ionic radii) with previously found thermodynamic and kinetic properties. (6) Use the designed dimeric macrocyclic lanthanide complexes and structural analogues to promote the cleavage of phosphate ester bonds of model compounds (e.g. disodium 4-nitrophenyl phosphate and diphenyl 4-nitrophenyl phosphate) and DNA and RNA. Determine reaction rates and possible mechanisms. Examine the effects of structure, lanthanide ionic radius and charge of the complexes.