WO2024258974A1 - Ligands et complexes et leurs utilisations - Google Patents

Ligands et complexes et leurs utilisations Download PDF

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WO2024258974A1
WO2024258974A1 PCT/US2024/033623 US2024033623W WO2024258974A1 WO 2024258974 A1 WO2024258974 A1 WO 2024258974A1 US 2024033623 W US2024033623 W US 2024033623W WO 2024258974 A1 WO2024258974 A1 WO 2024258974A1
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salt
rare earth
earth metal
ligand
hopo
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Valerie Christine Pierre
Thibaut L. M. MARTINON
Mandapati V. Ramakrishnam Raju
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University of Minnesota Twin Cities
University of Minnesota System
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University of Minnesota System
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F1/00—Treatment of water, waste water, or sewage
    • C02F1/68—Treatment of water, waste water, or sewage by addition of specified substances, e.g. trace elements, for ameliorating potable water
    • C02F1/683—Treatment of water, waste water, or sewage by addition of specified substances, e.g. trace elements, for ameliorating potable water by addition of complex-forming compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • C—CHEMISTRY; METALLURGY
    • C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F2101/00—Nature of the contaminant
    • C02F2101/10—Inorganic compounds
    • C02F2101/105—Phosphorus compounds
    • C—CHEMISTRY; METALLURGY
    • C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F2305/00—Use of specific compounds during water treatment
    • C02F2305/08—Nanoparticles or nanotubes

Definitions

  • Hyperphosphatemia is a condition whereby phosphate concentration in the blood reaches levels above 1.46 mmol/L. It appears primarily in patients with chronic kidney diseases (CKD) and those undergoing dialysis because the latter is inefficient at removing phosphate from the blood (Desoi, C. A.; et al., J. Am. Soc. Nephrol. 1993, 1214-1218). If left untreated, the condition leads to vascular calcification, up to 200 mg/week, and thus, in the long term, increased morbidity and mortality (Cupisti, A.; et al., Int. J. Nephrol. Renovasc. Dis. 2013, 193-205).
  • Hyperphosphatemia is currently managed by phosphate binders, oral salts such as CaCCh or La2(CO3)2, or polymers such as Sevelamer®, that bind phosphate in the blood (G. London.; et al. Clin. Nephrol. 2010, 74, 423-432; Zhang, C.; et al., BMC Nephrol. 2013, 14, 226; Steven Fishbane; Am. J. of Kidney Dis. 2009, 55, 307-315). Beyond significant side effects and poor patient compliance due to the high pill burden, phosphate binders have limited success rates. For instance, in one study only 17% of patients taking La2(CO3)3 achieved target blood phosphate levels (Bhargava, R.; et al., BMC Nephrol. 2019, 20, 37).
  • Affinity for phosphate can then be fine-tuned without affecting selectivity by either changing the lanthanide ion (Wilharm, R. K.; et al., Inorg. Chem. 2021, 60, 15808-15817) or the charge of the complex (Huang, S.-Y.; et al., Inorg. Chem. 2019, 58, 16087-16099).
  • ligands and metal complexes e.g., rare earth metal complexes such as Eu 111 complexes
  • Such ligands and metal complexes may be more stable (e.g., less leaching of metal) and/or may be useful for detecting ions (e.g., anions such as phosphate), for capturing and/or removing ions (e.g., anions such as phosphate) from aqueous solutions or mixtures (e.g., aqueous mixtures, blood, serum, waste water), and/or for treating hyperphosphatemia.
  • ions e.g., anions such as phosphate
  • aqueous solutions or mixtures e.g., aqueous mixtures, blood, serum, waste water
  • One embodiment provides a ligand of formula I or a salt thereof, or a rare earth metal complex of the ligand of formula I or a salt thereof or hydrate thereof,
  • X is -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) P N(CH 2 ) q -
  • Y 1 is -(CH 2 )-, or -(CH 2 ) 2 -;
  • Y 2 is -(CH 2 )-, or -(CH 2 ) 2 -; wherein Y 1 is -(CH 2 ) 2 - when X is -(CH 2 ) 2 - and Y 2 is -(CH 2 )-; p is 2 or 3; q is 2 or 3; and wherein the compound of formula I is optionally substituted with one or more (e.g., 1, 2, or 3) linking groups.
  • One embodiment provides a material or device comprising one or more ligands or a salt thereof, or one or more metal complexes or a salt thereof or a hydrate thereof, as described herein.
  • One embodiment provides a method to detect or capture inorganic phosphate, comprising contacting the phosphate with a ligand or salt thereof, or a metal complex or a salt thereof or a hydrate thereof, or a material or device as described herein.
  • One embodiment provides a method to treat hyperphosphatemia in a mammal in need thereof comprising contacting the blood of the mammal in need thereof, with a ligand or salt thereof, or a metal complex or a salt thereof or a hydrate thereof, or a material or device as described herein.
  • One embodiment provides the use of a ligand or salt thereof, or a rare earth metal complex or a salt thereof, or a material or device as described herein for the treatment of hyperphosphatemia in a mammal in need thereof.
  • One embodiment provides the use of a ligand or salt thereof, or a rare earth metal complex or a salt thereof, or a material or device as described herein for medical therapy.
  • One embodiment provides the use of a ligand or salt thereof, or a rare earth metal complex or a salt thereof as described herein to prepare a device or material for the treatment of hyperphosphatemia.
  • One embodiment provides processes and intermediates disclosed herein that are useful for preparing a ligand of formula I or a salt thereof, or a metal complex of (e.g., a rare earth metal complex) of a ligand of formula I or a salt thereof.
  • a metal complex of e.g., a rare earth metal complex
  • Figure 1 shows the chemical structures structure of the linear phosphate receptors Eu 111 - 3,3-Ser-HOPO (1), Eu ni -3,3-Gly-HOPO (2), and Eu ni -2,2-Li-HOPO (3) as well as the macrocyclic Eu ni -TACN-HOPO (4), Eu ni -TACD-HOPO (5), Eu ni -cyclen-HOPO (6), and Eu 111 - cyclam-HOPO (7).
  • Figure 2 shows the time-delayed luminescence intensity of Eu ni -L-HOPO upon titration with HPO 4 2 7H 2 PO 4 -.
  • the binding isotherms (solid lines) were fitted to a 1 : 1 stoichiomery for Eu ni -TACN-HOPO (4) or a 1 :2 stoichiometry for Eu ni -cyclen-HOPO (6) and Eu ni -cyclam-HOPO (7) based on the results from the luminescence lifetimes studies.
  • Figures 3 A-3C show the selectivity of macrocylic compounds.
  • Figure 3 A shows Eu 111 - cyclen-HOPO
  • Figure 3B shows Eu ni -cyclam-HOPO
  • Figure 3C shows Eu ni -TACN-HOPO for competing anions in water.
  • White bars represent the time-delayed relative luminescence intensity after addition of 10 equiv of the appropriate anions (NaF, NaCl, NaBr, Nal, K2SO4, NaHCCE, KNO3, Na2AsO 4 , Na 4 P2O?, NaC2HsO2, NasCeHsCE, and NaCsHsCE).
  • Dark grey bars represent the time-delayed relative luminescence intensity after subsequent addition of 10 eq. of phosphate.
  • I integrated luminescence intensity from 550 to 750 nm
  • Io integrated luminescence intensity in absence of [HPO 4 2 /H2PO 4 ].
  • Figure 4 shows intensity time traces of ligand exchange of Eu ni -L-HOPO complexes with DTPA (diethylene triamine peracetic acid).
  • I integrated luminescence intensity from 550 to 750 nm in the presence of 5 equivalents of DTPA
  • Io integrated luminescence intensity in absence of DTPA.
  • Ligand exchange with Eu ni -Ser-HOPO (1) and Eu ni -TACN-HOPO (4) follows first order kinetics, whereas ligand exchange with Eu ni -cyclam-HOPO (7) follows second order kinetics.
  • Ligand exchange with Eu ni -cyclen-HOPO (6) does not fit either first or second order kinetics suggesting a more complex mechanism of ligand exchange.
  • Figures 5A-5C show excitation (black (left side)) and emission (grey (right side)) profiles of Eu ni -L-HOPO.
  • Figure 5 A shows Eu ni -cyclen-HOPO.
  • Figure 5B shows Eu ni -cyclam-HOPO, and
  • Figure 5C shows Eu ni -TACN-HOPO.
  • Figure 6 shows time-delayed luminescence host-guest titration data of Eu ni -cyclen-HOPO to phosphate. Intensity was closely monitored between two samples of identical concentration; the non-aggregated sample having been left to equilibrate at 60°C overnight and sonicated prior to measurement.
  • Figures 8A-8C show time-dependent luminescence response of Eu ni -L-HOPO to phosphate.
  • Figure 8A shows Eu ni -cyclen-HOPO;
  • Figure 8B shows Eu ni -cyclam-HOPO;
  • Figure 8C shows Eu ni -TACN-HOPO.
  • I integrated luminescence intensity from 550-750 nm in the prescence of 10 eq. of phosphate
  • Io integrated luminescence intensity in the absence of phosphate.
  • Figures 9A-9C show gradients of Eu 111 complexes and coumarin utilized to determine relative quantum yield. Intensity of coumarin was integrated from 335-590 nm. Intensity of Eu 111 - L-HOPO was integrated from a varying range to avoid Rayleigh scattering from the excitation wavelength.
  • Figure 9A shows Eu ni -cyclen-HOPO (515-640 nm, 693-750 nm)
  • Figure 9B shows Eu ni -cyclam-HOPO (515-635 nm, 685-750 nm)
  • Figure 9C shows Eu ni -TACN-HOPO (515- 645 nm, 705-750 nm).
  • Figure 11 shows the time-dependent luminescence competition titration data of Eu 111 - cyclen-HOPO to DTPA approaching thermodynamic equilibrium KL in presence of 0.01 M HEPES.
  • I integrated luminescence intensity from 550-750 nm in the prescence of 10 eq. of phosphate
  • Io integrated luminescence intensity in the absence of phosphate
  • leq the integrated luminescence intensity once thermodynamic equilibrium is reached.
  • Plotted nonlinear fittings demonstrate the data fit to the respective decay kinetics.
  • Figure 12 shows the time-delayed luminescence competition titration data of Eu ni -L- HOPO to DTPA approaching thermodynamic equilibrium KL unadjusted for leq: integrated luminescence intensity at equilibrium.
  • I integrated luminescence intensity from 550-750 nm in the prescence of 10 eq. of phosphate
  • Io integrated luminescence intensity in the absence of phosphate.
  • Figures 13A-13D show the time-dependent luminescence competition titration data of Eu ni -L-HOPO to DTPA approaching thermodynamic equilibrium KL.
  • Figure 13 A shows Eu 111 - Ser-HOPO
  • Figure 13B shows Eu ni -TACN-HOPO
  • Figure 13C shows Eu ni -cyclen-HOPO
  • Figure 13D shows Eu ni -cyclam-HOPO.
  • I integrated luminescence intensity from 550-750 nm in the prescence of 10 eq. of phosphate
  • Io integrated luminescence intensity in the absence of phosphate.
  • leq the integrated luminescence intensity once thermodynamic equilibrium is reached.
  • the plotted nonlinear fittings demonstrate the data fit to the respective decay kinetics.
  • Figure 14 shows the time-delayed luminescence competition titration data of Eu ni -L- HOPO to DTPA.
  • I integrated luminescence intensity from 550 nm to 750 nm in the presence of 1-15 eq.
  • DTPA integrated luminescence intensity in the absence of DTPA.
  • the 0-0.8 Flo range is intensified for clarity.
  • halo or halogen is fluoro, chloro, bromo, or iodo.
  • Alkyl and alkoxy, etc. denote both straight and branched groups but reference to an individual radical such as propyl embraces only the straight chain radical (a branched chain isomer such as isopropyl being specifically referred to).
  • linker refers to any molecular moiety that connects the ligand of formula I (or a complex thereof) to another entity such as a material or device.
  • linker also includes linkers which include within the linker a reactive group that is useful to connect the ligand of formula I (or a complex thereof) to another entity such as a material or device (e.g., linkers that include reactive groups wherein the reactive group is useful for covalently binding to the material or device).
  • materials include polymers (e.g., a synthetic or natural polymer), hydrogels, membranes, nanoparticles, or other materials (e.g., solid material). Materials also include conducting polymers and conducting materials (e.g., metal or carbon materials).
  • a device can be any device (e.g., electronic device, solid device) that the metal complex can be attached (e.g., attached through a linker).
  • the linker can be variable, provided it functions to connect the ligand of formula I to another molecular entity, so that both the ligand of formula I (or a complex thereof) and the other molecular entity can function as described herein.
  • the linker can be covalently bonded to the ligand of formula I at any suitable atom such as a carbon or nitrogen atom.
  • the linker can vary in length and atom composition (e.g., C, H, N, O, S, halo, P) and for example can be branched or non-branched or saturated or unsaturated or a combination thereof.
  • the linker connects the ligand of formula I (or a complex thereof) to another entity such as a material or device (e.g., through covalent bonds).
  • the linker includes one or more reactive groups.
  • the reactive group is useful for covalently bonding the remainder of the linker to a material or device. Examples of reactive groups include amines, alcohols, thiols, amides, esters, carboxylic acids, aldehydes and epoxides.
  • polymer includes any polymer suitable for linking to the metal complex described herein (e.g., synthetic or natural polymer).
  • examples include polyamides (including star polyamides), polyethyleneglycol, polyethylenemine, polysulfone, polyethersulfone, and conducting polymers (e.g., conducting polymers for electronic devices).
  • hydrogel includes any hydrogel suitable for linking to the metal complex described herein. Examples include crosslinked poly(N-isopropylacrylamide), crosslinked polyvinyl alcohol, PMA (polymethacrylate), PMMA (polymethylmethacrylate), PEMA (polyethylmethacrylate), and chitosan.
  • membrane includes any membrane suitable for linking to the metal complex described herein.
  • nanoparticle includes any nanoparticle suitable for linking to the metal complex described herein (e.g., metal-based, silica-based). Examples include gold nanoparticles, iron oxide nanoparticles, and silica nanoparticles.
  • material includes any material suitable for linking to the metal complex (e.g., a solid material). Examples include carbon, porous carbon, gold, carbon nanotubes, CuO nanowires, and WO3 nanowires.
  • One embodiment provides a rare earth metal complex of claim or a salt thereof or a hydrate thereof, wherein the rare earth metal complex is a complex of formula II or salt thereof or hydrate thereof:
  • rare earth metal is M 111 .
  • One embodiment provides a rare earth metal complex or a salt thereof of claim 1, wherein the rare earth metal complex is a Eu 111 complex of formula Ila: or salt thereof.
  • X is -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 2 N(CH 2 ) 2 -, or -(CH 2 ) 3 N(CH 2 ) 2 -.
  • Y 1 is -(CH 2 )-.
  • Y 1 is -(CH 2 ) 2 -.
  • Y 2 is -(CH 2 )-.
  • Y 2 is -(CH 2 ) 2 -.
  • another six corresponding embodiments provide P in addition to -O-, -S, -N(R a )- so that one or more of the carbon atoms is optionally replaced independently by -O-, -S, -N(R a )-, and P.
  • the linker is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 1 to 6 carbon atoms wherein one or more of the carbon atoms is optionally replaced by a N(R a )-, wherein the R a is H or (Ci-Ce)alkyl.
  • the linker is -(C2-Ce)alkylNH2 or -(C2-Ce)alkylNH.
  • One embodiment provides a ligand or salt thereof that is or a salt thereof.
  • One embodiment provides a metal complex or a salt thereof that is metal complex is a complex of formula II or salt thereof: wherein the M is a metal (e.g., a rare earth metal).
  • M 111 is a metal (e.g., a rare earth metal).
  • M is a metal (e.g., a rare earth metal, or a metal “M 111 ” or a rare earth metal M 111 ).
  • a metal e.g., a rare earth metal, or a metal “M 111 ” or a rare earth metal M 111 ).
  • One embodiment provides a metal complex or a salt thereof that is or a salt thereof.
  • R is H or OH.
  • M is a rare earth metal and R is H or OH.
  • the rare earth metal is lanthanum(La), cerium(Ce), praseodymium(Pr), neodymium(Nd), samarium(Sm), europium(Eu), gadolinium(Gd), terbium(Tb), dysprosium(Dy), holmium(Ho), erbium(Er), thulium(Tm), ytterbium(Yb), lutetium(Lu), scandium(Sc), yttrium(Y) or promethium (Pm).
  • the rare earth metal is La 111 , Ce 111 , Pr 111 , Nd 111 , Sm 111 , Eu 111 , Gd 111 , Tb 111 ,
  • Dy 111 Ho 111 , Er 111 , Tm 111 , Yb 111 , Lu 111 , Sc 111 , Y 111 or Pm 111 .
  • the rare earth metal is Eu 111 .
  • the metal complex is a metal complex or hydrate thereof.
  • One embodiment provides a material or device comprising one or more ligands or a salt thereof, or one or more complexes or a salt thereof, as described herein.
  • the material or device is a hydrogel, membrane, nanoparticle, or other material.
  • One embodiment provides a method to detect or capture inorganic phosphate, comprising contacting the phosphate with a ligand or salt thereof, or a complex or a salt thereof, or a material or device as described herein.
  • the phosphate is selectively detected or captured in the presence of other anions.
  • the other anions are selected from the group consisting of carbonate, nitrate, sulfate, halides, arsenate and pyrophosphate.
  • the phosphate is contacted with a ligand or salt thereof, or a complex or a salt thereof, or a material or device, as a liquid sample at about neutral pH.
  • the liquid sample is sample is an aqueous sample.
  • the phosphate is detected with fluorescence sensing by an indicator displacement assay.
  • the phosphate is captured.
  • the phosphate is captured from an aqueous mixture or solution.
  • One embodiment provides a method to treat hyperphosphatemia in a mammal in need thereof comprising contacting the blood of the mammal in need thereof, with a ligand or salt thereof, or a complex or a salt thereof, or a material or device as described in herein.
  • the mammal has kidney disease (e.g., chronic kidney disease).
  • One embodiment provides a device or material with a ligand or a rare earth metal complex of the ligand as described herein attached thereto.
  • One embodiment provides a device or material for sensing, detecting, and/or selectively capturing phosphate from a mixture (e.g., aqueous mixture), water or blood with a ligand or a rare earth metal complex of the ligand as described herein attached thereto.
  • a mixture e.g., aqueous mixture
  • water or blood with a ligand or a rare earth metal complex of the ligand as described herein attached thereto.
  • One embodiment provides a method for sensing, detecting, and/or selectively capturing phosphate from a mixture (e.g., an aqueous mixture), water or blood comprising contacting the device or material as described herein with the mixture (e.g., an aqueous mixture), water or blood, wherein the device or material has a ligand or a rare earth metal complex of the ligand as described herein attached thereto.
  • a mixture e.g., an aqueous mixture
  • water or blood comprising contacting the device or material as described herein with the mixture (e.g., an aqueous mixture), water or blood, wherein the device or material has a ligand or a rare earth metal complex of the ligand as described herein attached thereto.
  • One embodiment provides a device or material comprising one or more ligands or arare earth metal complexes of the ligands as described herein attached thereto.
  • One embodiment provides a device or material for sensing, detecting, and/or selectively capturing phosphate from a mixture (e.g., an aqueous mixture), water or blood wherein the device comprises one or more ligands or a rare earth metal complexes of the ligands as described herein.
  • a mixture e.g., an aqueous mixture
  • the device comprises one or more ligands or a rare earth metal complexes of the ligands as described herein.
  • One embodiment provides a method for sensing, detecting, and/or selectively capturing phosphate from a mixture (e.g., aqueous mixture), water or blood comprising contacting the device or material as described herein with the mixture (e.g., an aqueous mixture), water or blood, wherein the device or material comprises one or more ligands or a rare earth metal complexes of the ligands as described herein attached thereto.
  • a mixture e.g., aqueous mixture
  • the mixture e.g., an aqueous mixture
  • the device or material comprises one or more ligands or a rare earth metal complexes of the ligands as described herein attached thereto.
  • ligand geometry is one of the predominant parameters governing the affinity of tripodal, tris-HOPO complexes for phosphate. Minor differences in geometry arising from small modifications in the ligand cap causes substantial effect in the affinity of HOPO-based europium(III) complexes for phosphate (Huang, S.-Y.; et al., Inorg. Chem. 2020, 59, 4096-4108). Moreover, even though such changes also affect the coordination number of the europium(III) complex, there is no relationship between its number of inner-sphere water molecules (q) and its affinity for phosphate.
  • the two complexes comprising a cyclotriaza ligand cap, Eu ni -TACN-HOPO (4) and Eu 111 - TACD-HOPO (5), were synthesized according to Schemes 1 and 2, respectively.
  • all the cyclic secondary amines were TV-alkylated with BOC-protected 2-bromoethylamine to yield the extended caps 8 and 12, respectively.
  • Deprotection with trifluoroacetic acid yielded the primary amines that were then coupled with HOPO(Bn)-Su (9) to yield the protected ligands TACN-HOPO-Bn (10) and TACD-HOPO-Bn (13), respectively.
  • a Reagents and conditions a) BOC-NH-CJh-CJh-Br, Cs 2 CO 3 , DMF, 80°C, 48 h; b) i: CH2CI2, TFA, 0°C to rt; ii: HOPO(Bn)-OSu (9), CH3CN/H2O (1/1 v), K2CO3, 12 h; c) HCl/AcOH (1/1 v), 48 h; d) EuC13*6H 2 O, MeOH, pyridine, 65°C, 60 h.
  • the two complexes comprising a tetraaza ligand cap, Eu ni -cyclen-HOPO (6) and Eu 111 - cyclam-HOPO (7), were synthesized according to Schemes 3 and 4, respectively. Since only three HOPO podands are to be conjugated on a tetraaza ligand cap, the synthesis of the cyclen derivative starts with mono-benzyl protected ligand cap (Massue, J.; et al., Tetrahedron Lett. 2007, 48, 8052-8055). A-alkylation of the unprotected secondary amine with BOC-protected 2- bromoethyl amine yielded the extended cap 16.
  • the cyclam derivative follows a similar scheme except that the cyclam cap did not require mono-protection prior to its A-alkylation.
  • the cyclam is poorly reactive, so that only three of its four secondary amines could be coupled with BOC-protected 2-bromoethylamine to yield the extended cap 19.
  • Deprotection under acidic condition yielded the extended cap that was immediately coupled with HOPO(Bn)-Su (9) moiety to yield the protected ligands cyclam-HOPO-Bn (20).
  • Deprotection under acidic conditions yielded the free ligand cyclam-HOPO (21) that was subsequently complexed with EUC1 3 6H 2 O to yield the final complex Eu ni -cyclam-HOPO (7).
  • 1,2-Hydroxypyridine is an excellent sensitizer of europium (III). Moreover, both the luminescence intensity and the lifetime of Eu 111 complexes are highly dependent on the number of inner-sphere water molecules. As phosphate or other anions coordinate Eu 111 , they displace the inner-sphere water molecules, resulting in an increase in both the luminescence intensity and the lifetimes of the excited states of the Eu 111 center. Together, these characteristics not only facilitate the study of anion recognition by aqueous Eu 111 complexes of 1,2-HOPO with open coordination sites, but essentially render any such complex a luminescent probe (Martinon, T. L. M.; et al., Chem. Asian J. 2022, 77, e202200495; Thibon, A.; Qi a ⁇ . Anal. BioanaL Chem. 2009, 394, 107- 120).
  • the number of inner-sphere water molecule of each receptor in the presence and absence of 10 equivalents of phosphate can be determined from the luminescence lifetime of the complexes in H2O and D2O according to the classical Parker-Horrocks equation (Dickins, R. S.; et al., Chem. Commun. 1996, 697-698; Beeby, A.; et al., J. Chem. Soc., Perkin Trans 2 1999, 493- 504; Supkowski, R. M.; et al., Inorganica Chim.
  • Acta 2002, 340, 44-48 are the luminescence lifetimes of the Eu 111 in H2O and D2O, respectively, and x is the number of N-H oscillators in close proximity to the Eu 111 ion.
  • the luminescence lifetime in D2O was extrapolated from serial dilution of an aqueous solution by D2O (see Figure 7).
  • Eu ni -TACN-HOPO (4) is displaced by water, resulting in the formation of a Eu ni L Pi ternary complex with a 1 : 1 stoichiometry.
  • Eu ni -cyclen-HOPO (6) which has only two inner-sphere water molecules, is the only receptor that has high affinity for phosphate such that the anion displaces all its inner-sphere water molecules.
  • Displacement of the inner-sphere water molecules by phosphate also increases the luminescence intensity of the Eu 111 complex, a characteristic that enables rapid determination of the affinity of each receptor for the anion.
  • the titrations of each Eu 111 complex with phosphate in water at neutral pH and room temperature are shown in Figure 2. Based on kinetic studies, in each case, measurements were performed at least 60 min after addition of the anion so as to ensure that thermodynamic equilibrium is reached.
  • the 1 : 1 and 1 :2 equilibria were fitted to equations 5 and 6, respectively, as described by Thordarson (Thordarson, P., Chem. Soc. Rev. 2011, 40, 1305-1323.) where I and Io are the integrated intensity of the receptor in the presence and absence of phosphate, respectively and j and K are the first and second association constants, respectively.
  • the resulting derived constants (ao, ai and a?) after simplifying the proportionality constant are determined through fitting, of which ao is equal to the Flo prior to introduction of the guest.
  • the stepwise and overall association constants of the three Eu 111 receptors for phosphate are given in Table 2. All three complexes have similar first association constants.
  • the tetraaza derivatives 6 and 7 differentiate themselves from the triaza derivative (4) in that they can also coordinate a second phosphate anion.
  • the second association constant of Eu ni -cyclen-HOPO (6) for Pi is approximately an order of magnitude higher than that of Eu ni -cyclam-HOPO (7).
  • the cyclen derivative 6 has an overall association constant, , for phosphate fifty times higher than the cyclam analog and five order of magnitudes higher than the TACN one. Its high affinity for phosphate makes it a promising receptor for the treatment of hyperphosphatemia.
  • the affinity for phosphate of Eu ni -cyclen-HOPO (6) is comparable to that of Eu ni -2,2-Li-HOPO (3), a HOPO- based Eu 111 receptor previously reported, that also binds the anion in a 1 :2 stoichiometry (Huang, S.-Y.; et al., Inorg. Chem. 2020, 59, 4096-4108). Although it is sufficiently high for medical applications, the overall affinity for Pi (P) remains noticeably lower than that of Eu ni -Gly-HOPO (2), which binds phosphate with a 1 :3 stoichiometry (Huang, S.-Y.; et al., Inorg. Chem.
  • the receptors also do not have any affinity for bicarbonate, nor does bicarbonate affect coordination to phosphate.
  • This selectivity for phosphate over bicarbonate is difficult to achieve for lanthanide-based receptors and probes, but it is crucial for the intended application (Martinon, T. L. M.; et al., Chem. Asian J. 2022, 17, e202200495; Thibon, A.; et aC, Anal. Bioanal. Chem. 2009, 394, 107- 120; Cacheris, W. P.; et al., Magn. Reson. Imaging 1990, 8, 467-481).
  • the macrocyclic HOPO receptors were designed to not only bind phosphate, but to have improved kinetic inertness over their linear analogues.
  • macrocyclic MRI contrast agents were observed to be less toxic and to transmetallate in vivo with physiological ions to a lesser extent then their linear analogues (Radbruch, A.; et al., Invest Radiol 2019, 54, 531- 536).
  • the kinetic inertness of the macrocyclic receptors 1, 4, 6, and the linear analog 7 were determined by monitoring the ligand exchange of the Eu 111 complexes in the presence of a fivefold excess of diethylentriaminepentaaacetate (DTP A) in water at neutral pH by time-gated luminescence spectroscopy (Eq. 8).
  • DTP A diethylentriaminepentaaacetate
  • DTPA was chosen for these studies since the ligand forms stable lanthanide complexes (thereby making it a strong competitor) and because it is a labile ligand that undergoes transmetallation rapidly.
  • 1,2-HOPO is an excellent sensitizer for Eu 111
  • DTPA is not.
  • the equilibrium can thus be readily monitored via the Eu ni -centered luminescence sensitized at 334 nm.
  • the half-life, ti/2, or time required for half of the Eu ni -L-HOPO complexes to transmetallate to DTPA are reported in Table 3. This data corresponds to the time half of the signal have decayed.
  • the linear analog, Eu ni -Ser-HOPO (1) was included in the study as a comparison. HEPES was not utilized in these studies, as it was found to affect the rate of transmetellation (Figure 11).
  • Eu ni -cyclam-HOPO (7) follows a second order kinetics which can be fitted to equation 10:
  • conditional stability constant T C EUL of each europium(III) complex at pH 7.4 can also be measured by direct competition with DTPA. These equilibria were directly monitored by UV-visible spectroscopy using the luminescence spectroscopy using the free and complexed HOPO ligands as references. As depicted in equation 12, because this conditional equilibrium constant essentially reflects the competition between the metal ion and protons for the ligand, Aui. is a function of pH:
  • K K 2 ... are the protonation constants of the ligand L (where L is the fully deprotonated ligand) (Caravan, P.; et al., Chem. Rev. 1999, 99, 2293-2352; Caravan, P.; et al., Chem. Rev. 1999, 99, 2293-2352).
  • the conditional stability constant of Eu ni -DTPA at pH 7.4 calculated from the published formation constant of Eu ni -DTPA ( TEUDTPA) and the protonation constants of DTPA is given in Table 3.
  • conditional stability (A C E U L) of the Eu ni -HOPO complexes can then be calculated from the same spectrophotometric competition data used above and from the conditional stability constant of the completing Eu ni -DTPA, T C EUDTPA, under the specific conditions considered according to equation 13: where [DTPA] f and [L] f are the total (free and metal-bound) concentrations of the competing DTPA and HOPO ligands, respectively.
  • T C EUL The conditional stability constant, T C EUL, of complexes 1, 4, 6, and 7 are given in Table 3. All four complexes show similar stability, with Log 77 C EUL ranging between 17.83 and 17.
  • Macrocyclic tris-bidentate Eu 111 complexes bearing three 1,2-hydroxypyridinonate have lower solubility in water then their linear analogues such that only three of the four complexes could be evaluated.
  • One of these complexes — Eu ni -cyclen-HOPO (6) — is eight coordinate whereas the other two — Eu ni -TACN-HOPO (4) and Eu ni -cyclam-HOPO (7) — are nine coordinate. This difference highlight the closeness in energy of the two coordination geometries.
  • all three macrocyclic complexes bind orthophosphate, albeit with different affinities.
  • the affinities of the macrocyclic complexes for phosphate is lower than the parent Eu ni -Ser-HOPO (1), they remain sufficient for medical applications of phosphate sequestration.
  • all macrocyclics are selective over other competing anions, notably HCCL’ and Cl’, two anions present in higher concentrations in the blood.
  • the macrocyclic ligand caps do, however, affect the kinetic lability of the europium(III) complex and the rate at which it exchanges ligand with DTP A, but not to the same extent.
  • Luminescence data were acquired on a Varian Cary Eclipse fluorescence spectrophotometer using a quartz cell with a path length of 1 cm and a chamber volume of 500 pL. Time-gated luminescent spectra were recorded with a time delay of 0.1 ms and a gate time of 5 ms. Unless otherwise stated, sample solutions were allowed to equilibrate for 10 min before measurement of their luminescence spectra, as it has been demonstrated that this time was sufficient to achieve thermodynamic equilibrium (Figure 8). Luminescence data were processed with Scilab 6.0.2 and QtiPlot 0.9.8.9 software. All pH measurements were performed using a Thermo Scientific Ag/AgCl refillable probe and a Thermo Orion 3 Benchtop pH meter.
  • the benzyl-protected HOPO hydroxysuccinimide activated analogue 9 were synthesized according published procedures with successful synthesis established by 1 H NMR, 13 C NMR and ESI-MS (Guerard, F.; et al., Dalton Trans. 2017, 46, 4749-4758).
  • the linear receptor Eu ni -Ser- HOPO (1) was previously synthesized according to published procedures with successful synthesis established by 'H NMR, 13 C NMR and ESI-MS (Huang, S.-Y.; et al., Inorg. Chem. 2019, 58, 16087-16099.
  • Trifluoroacetic acid (TFA, 5 mL) was added to a stirred solution of the BOC protected ligand cap 8 (500 mg, 0.895 mmol) in CH2Q2 (10 mL) cooled to 0°C.
  • the reaction mixture was stirred at room temperature for 4 h, after which excess solvent and acid were removed under reduced pressure.
  • the resulting TFA salt was used without further purification.
  • This TFA salt was then dissolved in milli-Q water (20 mL).
  • a solution of HOPO(Bn)-OSu (9, 1.01 g, 2.95 mmol) in CH3CN (20 mL) was then added to the reaction mixture, followed by K2CO3 (620 mg, 4.47 mmol).
  • the reaction mixture was stirred for 12 h at room temperature.
  • the homogenous reaction mixture was extracted with ethyl acetate (4 x 40 mL) and the combined organic phases were washed with 10% NaHCCL (2 x 30 mL) and brine (30 mL).
  • the organic phase dried over anhydrous MgSO4 (5) and concentrated under reduced pressure.
  • the crude product was purified by flash column chromatography over neutral alumina, eluting with 1% methanol/99% CThChto yield 10 as a viscous foaming liquid (650 mg, 77.3%).
  • the benzyl-protected TACN-HOPO ligand 10 (100 mg, 0.106 mmol) was dissolved in a 1 : 1 mixture of glacial acetic acid (2.5 mL) and HC1 (2.5 mL). The reaction mixture was stirred at room temperature for 2 days. The volatiles were then removed under reduced pressure. The crude product was further co-evaporated with methanol (3 x 15 mL) and triturated with diethyl ether (2 x 20 mL). The crude product was further purified by Cis-reverse phase column chromatography using 20% acetonitrile/80% CH2Q2 water to afford the TACN-HOPO ligand as a white powder (60 mg, 84%).
  • CS2CO3 (2.28 g, 7.00 mmol) was added to a stirred solution of TACD (200 mg, 1.16 mmol) in dry dimethylformamide (10 mL) under N2 (g) atmosphere at room temperature. The resulting mixture was stirred at room temperature for 20 min, after which /c/7-butyl (2- (bromoamino)ethyl)carbamate (825 mg, 3.67 mmol) was added. The resulting reaction mixture was heated at 80°C for 2 days. The reaction mixture was then cooled to room temperature and filtered. The residue was washed with ethylacetate (40 mL), and the combined organic phases were concentrated under reduced pressure.
  • Trifluoroacetic acid (TFA, 5 mL) was added to a stirred solution of ethylene-BOC protected ligand cap 12 (200 mg, 0.333 mmol) in CH2CI2 (10 mL) at 0°C. The reaction mixture was stirred at room temperature for 4 h, after which excess solvent and acid were removed under reduced pressure. The resulting TFA salt was used without further purification. This deprotected ligand cap was then dissolved in mQ water (20 mL). A solution of HOPO(Bn)-OSu (9, 376 mg, 1.09 mmol) in CH3CN (20 mL) was then added to the reaction mixture, followed by K2CO3 (230 mg, 1.66 mmol).
  • the reaction mixture was stirred for 12 h at room temperature.
  • the homogenous reaction mixture extracted with ethyl acetetate (4 x 40 mL).
  • the combined organic phases were washed with 10% NaHCCL (2 x 30 mL), brine (30 mL) dried over anhydrous MgSO4 (s), and concentrated under reduced pressure.
  • the crude product was purified by flash column chromatography over neutral alumina, eluting with 1% methanol/99% CFhChto yield the protected ligand 13 as a viscous foaming liquid (205 mg, 62.7%).
  • the benzyl-protected TACN-HOPO ligand 13 (0.10 g, 0.10 mmol) was dissolved in a 1 : 1 mixture of glacial acetic acid (2.5 mL) and HC1 (2.5 mL). The reaction mixture was stirred at room temperature for 2 days. The solvents were then removed under reduced pressure. The crude product was further co-evaporated with methanol (3 x 15 mL) and further triturated diethyl ether (2 x 20 mL). The crude product was further purified by Cis-reverse phase column chromatography 20% acetonitrile/80% CH2Q2 water to yield the 14 ligand as white powder (60 mg, 84%).
  • the TACD-HOPO ligand 14 (50 mg, 0.070 mmol) and EuCh 6H2O (25 mg, 0.070 mmol) were dissolved in methanol (10 mL). Pyridine (113 pL, 1.40 mmol) was subsequently added to the reaction mixture, which was stirred at 65 °C for 5 days. The reaction mixture was cooled to room temperature and the volatiles removed under reduced pressure. The product was further triturated with diethyl ether (3 x 10 mL), dissolved in mQ water (5 mL) and lyophilized to yield the Eu 111 complex 5 as a beige powder (45 mg, 75%).
  • ESI-LRMS Calcd for C33H43EUN9O9 [M+H] + : m/z 862.23. Found: m/z 862.24.
  • CS2CO3 (3.72 g, 11.4 mmol) was added to a stirred solution of mono(Bn)-cyclen (500 mg, 1.90 mmol) in dry CH3CN (50 mL) under N2 (g) atmosphere at room temperature.
  • the reaction mixture was stirred at room temperature for 20 min before the addition of tert-butyl (2- (bromoamino)ethyl)carbamate (1.34 g, 6.00 mmol).
  • the resulting reaction mixture was stirred at 80°C for 2 days.
  • the reaction mixture was then cooled to room temperature, filtered and the residue washed with ethyl acetate (40 mL).
  • the protected ligand 15 (600 mg, 0.867 mmol) was dissolved in anhydrous methanol (30 mL) and the solution was degassed before addition of 10 wt% Pd/C (100 mg). The suspension was further stirred under H2 (g) (4 atm) in a Parr hydrogenator. The reaction mixture was further filtered over celite, and the residue washed with methanol (30 mL). The combined organic phases were concentrated under reduced pressure. The crude material was purified by column chromatography on neutral alumina using 0 to 1.5% CH3OH in CH2CI2 to obtain the desired deprotected 16 as a colorless sticky-solid (450 mg, 86.2%).
  • the benzyl-protected cyclen-HOPO ligand 17 (100 mg, 0.0102 mmol) was dissolved in a 1 : 1 mixture of glacial acetic acid (2.5 mL) and HC1 (2.5 mL). The reaction mixture was stirred at room temperature for 2 days. The volatiles were removed under reduced pressure. The crude product was further co-evaporated with methanol (3 x 15 mL) and triturated with diethyl ether (2 x 20 L). The crude product further purified by Cis-revese phase chromatography 20% acetonitrile/80% CH2CI2 water to yield 18 as white powder (62 mg, 86%).
  • CS2CO3 (4.87 g, 15.0 mmol) was added to a stirred solution of cyclam (500 mg, 2.49 mmol) in dry CH3CN (50 mL) under N2 (g) atmosphere at room temperature. The resulting suspension was stirred at room temperature for 20 min, after which tert-butyl (2- (bromoamino)ethyl)carbamate (1.76 g, 7.86 mmol) was added. The resulting reaction mixture was heated at 80°C for 2 days. The reaction mixture was then cooled to room temperature, filtered, and the residues washed with ethyl acetate (40 mL). The organic phases were combined and concentrated under reduced pressure.
  • the reaction mixture extracted with ethyl acetate (4 x 40 mL). The organic phases were combined, washed with 10% NaHCCL (2 x 30 mL) and brine (30 mL), dried over anhydrous MgSO4 (s), and concentrated under reduced pressure. The crude product was purified by flash column chromatography over neutral alumina, eluting with 1% methanol/99% CH2CI2 to yield the protected ligand 20 as a viscous foaming liquid (450 mg, 62.3%).
  • the benzyl-protected cyclam-HOPO ligand 20 (100 mg, 0.0989 mmol) was dissolved in a 1 : 1 mixture of glacial acetic acid (2.5 mL) and HC1 (2.5 mL). The reaction mixture was stirred at room temperature for 2 days. The volatile were removed under reduced pressure. The crude product was further co-evaporated with methanol (3 x 15 mL) and triturated diethyl ether (2 x 20 mL). The crude product was further purified by Cis-revese phase column chromatography using 20% acetonitrile/80% CH2Q2 water to yield the cyclam-HOPO ligand as white powder (65 mg, 89%).
  • the cyclam-HOPO ligand 21 (50 mg, 0.067 mmol) and EuCh 6H2O (24 mg, 0.067 mmol) were dissolved in methanol (10 mL). Pyridine (108 pL, 1.35 mmol) was subsequently added to the reaction mixture, which was stirred at 65 °C for 5 days. The reaction mixture was cooled down to room temperature and further evaporated under reduced pressure. The product was further triturated with diethyl ether (3 x 10 mL), dissolved in MQ water (5 mL) and lyophilized to yield the Eu 111 complex as a beige powder (50 mg, 83%). ESI-LRMS. Calcd for C34H46EUN10O9 [M+H] + : m/z 891.26. Found: m/z 891.35.
  • Relative quantum yield was measured according to the reported procedure (Wurth, C.; et al., Nat. Protoc. 2013, 8, 1535-1550) using coumarin as a reference (0.32%) (Taniguchi, M.; et al., Photochem. PhotobioL 2018, 94, N3 T).
  • DTPA diethyelentriaminepentaacetic acid
  • concentrations of free and complexed ligand in each solution were determined from reference solutions of the pure free ligand and Eu 111 complex.
  • the log/L were determined as previously published from the reported stability constants for DTPA with Eu 111 ions (Moeller, T.; et al., J. Inorg. Nucl. Chem. 1962, 24, 499-510), the complex’s hydrolysis constants (Brown, P.

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Abstract

L'invention concerne des ligands de formule I ou des sels de ceux-ci, et des complexes de métaux des terres rares des ligands de formule I ou des sels de ceux-ci. L'invention concerne également des dispositifs et des matériaux comprenant des ligands de formule I ou des sels de ceux-ci, ou des complexes de métaux des terres rares des ligands de formule I ou des sels de ceux-ci ainsi que des procédés d'utilisation des ligands, des complexes, des dispositifs et des matériaux pour détecter des ions tels que le phosphate, des procédés d'élimination d'ions tels que le phosphate de solutions ou de mélanges aqueux, et des méthodes de traitement de l'hyperphosphatémie. L'invention concerne également des ligands supplémentaires et des complexes métalliques de ceux-ci ainsi que des utilisations de ces ligands et complexes métalliques.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5741912A (en) * 1993-06-15 1998-04-21 Bracco International B.V. Methods for preparing heteroatom-bearing ligands and metal complexes thereof
WO2018097871A2 (fr) * 2016-09-29 2018-05-31 The Regents Of The University Of California Séparation d'ions métalliques par extraction liquide-liquide
US20180273406A1 (en) * 2017-03-23 2018-09-27 Regents Of The University Of Minnesota Compositions, methods, and devices for capturing phosphate from water

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5741912A (en) * 1993-06-15 1998-04-21 Bracco International B.V. Methods for preparing heteroatom-bearing ligands and metal complexes thereof
WO2018097871A2 (fr) * 2016-09-29 2018-05-31 The Regents Of The University Of California Séparation d'ions métalliques par extraction liquide-liquide
US20180273406A1 (en) * 2017-03-23 2018-09-27 Regents Of The University Of Minnesota Compositions, methods, and devices for capturing phosphate from water

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