A metal-templated synthesis (MTS) approach was used to preorganize the forward endo-hydroxamic ac... more A metal-templated synthesis (MTS) approach was used to preorganize the forward endo-hydroxamic acid monomer 4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoic acid (for-PBH) about iron(III) in a 1:3 metal/ligand ratio to furnish the iron(III) siderophore for-[Fe(DFOE)] (ferrioxamine E) following peptide coupling. Substitution of for-PBH with the reverse (retro) hydroxamic acid analogue 3-(6-amino-N-hydroxyhexanamido)propanoic acid (ret-PBH) furnished ret-[Fe(DFOE)] (ret-ferrioxamine E). As isomers, for-[Fe(DFOE)] and ret-[Fe(DFOE)] gave identical mass spectrometry signals ([M + H(+)](+), m/zcalc 654.3, m/zobs 654.3), yet for-[Fe(DFOE)] eluted in a more polar window (tR = 23.44 min) than ret-[Fe(DFOE)] (tR = 28.13 min) on a C18 reverse-phase high-performance liquid chromatography (RP-HPLC) column. for-[Ga(DFOE)] (tR = 22.99 min) and ret-[Ga(DFOE)] (tR = 28.11 min) were prepared using gallium(III) as the metal-ion template and showed the same trend for the retention time. Ring-expanded a...
2.4 Metal Complexes for Derivation of Structural Restraints via Paramagnetic NMR Spectroscopy 2.4... more 2.4 Metal Complexes for Derivation of Structural Restraints via Paramagnetic NMR Spectroscopy 2.4.1 Paramagnetic Relaxation Enhancement (PRE) 2.4.2 Residual Dipolar Coupling (RDC) 2.4.3 Pseudo-Contact Shifts (PCS) 2.4.4 Strategies for Introducing Lanthanide Ions into Bio-Macromolecules 2.5 Metal Complexes as Spin Labels for Distance Measurements via EPR Spectroscopy 2.6 Metal Complexes as Donors for Distance Measurements via Luminescence Resonance Energy Transfer (LRET) 2.7 Concluding Statements and Future Outlook References 3. AAS, XRF, and MS Methods in Chemical Biology of Metal Complexes Ingo Ott, Christophe Biot and Christian Hartinger 4. Metal Complexes for Cell and Organism Imaging
The ability of microbial siderophores to coordinate metal ions, particularly Fe(III), continues t... more The ability of microbial siderophores to coordinate metal ions, particularly Fe(III), continues to generate interest in the potential applications of these bioligands in the environment and medicine. 1À3 Siderophores produced by terrestrial and marine bacteria have evolved to sequester Fe(III) from insoluble Fe(III)-oxy/ hydroxides under oxic and pH neutral environments. 4À7 The formation of the Fe(III)Àsiderophore complex is the first step in siderophore-dependent iron uptake and is essential for the viable growth of almost all environmental and pathogenic bacteria. 8À12 Siderophores have diverse structures and have been classified according to the metal ion-binding functional group as catechol-, hydroxamic acid-or citric acid-based compounds. 13 Clinical applications of hydroxamic acid-based siderophores include the mesylate salt of desferrioxamine B for the treatment of iron-overload disease in patients undergoing frequent blood transfusions and suberoylanilide hydroxamic acid, which acts as an anticancer agent via the inhibition of Zn(II) containing histone deacetylases. 14À18 While siderophores have evolved as high-affinity Fe(III) complexing agents, these ligands have a rich coordination chemistry with other transition-metal ions in the first and second row of the Periodic Table. 19 Siderophores excreted by marine bacteria compete for Fe(III) and other transition-metal ions present in greater abundance in the ocean, such as Mo(VI) and V(V). 20 Nitrogen fixing Azotobacter vinelandii produces a suite of siderophores that bind Fe(III) and V in order to meet its V requirement for the biosynthesis of V-containing nitrogenase. 21 Desferrioxamine B reactivated V(V)-inhibited enzymes by sequestering the V(V) ion at the active site 22 and the V(V)hydroxamic acid complexes inhibited the β-lactamase of Enterobacter cloacae P99. 23 Complexes between V(IV) or V(V) and hydroxamic acids lowered blood glucose levels in rat adipocytes 24 and streptozotocin-induced diabetic mice 25 and are under
Adamantyl-based compounds are used clinically for the treatment of neurological conditions, as an... more Adamantyl-based compounds are used clinically for the treatment of neurological conditions, as antiviral agents and as agents against type 2 diabetes. The value of the adamantyl group in drug design is multidimensional. The hydrophobic substituent constant for the adamantyl group has been estimated from the calculated partition coefficients (clogP values) of 31 adamantyl-bearing compounds in the clinic or in development as p adamantyl ¼ 3.1, which indicates that the logP value of a compound with high water solubility (logP < < 0) could be moved with an adamantyl-based modification to a region that is more clinically useful. The steric bulk of the adamantyl group can: (i) restrict or modulate intramolecular reactivity; and (ii) impede the access of hydrolytic enzymes, thereby increasing drug stability and plasma half life. The value of the adamantyl group in drug design has been recognized most recently in the design of agents to treat iron overload disease (in development), malaria (in clinical trials) and type 2 diabetes (in the clinic).
The reaction between Zr(IV) and the forward endo-hydroxamic acid monomer 4-[(5-aminopentyl)-(hydr... more The reaction between Zr(IV) and the forward endo-hydroxamic acid monomer 4-[(5-aminopentyl)-(hydroxy)amino]-4-oxobutanoic acid (for-PBH) in a 1:4 stoichiometry in the presence of diphenylphosphoryl azide and triethylamine gave the octadentate Zr(IV)-loaded tetrameric hydroxamic acid macrocycle for-[Zr(DFOT 1)] ([M + H] + calc 887.3, obs 887.2). In this metal-templated synthesis (MTS) approach, the coordination preferences of Zr(IV) directed the preorganization of four oxygen-rich bidentate for-PBH ligands about the metal ion prior to ring closure under peptide coupling conditions. The replacement of for-PBH with 5-[(5-aminopentyl) (hydroxy)amino]-5-oxopentanoic acid (for-PPH), which contained an additional methylene group in the dicarboxylic acid region of the monomer, gave the analogous Zr(IV)-loaded macrocycle for-[Zr(PPDFOT 1)] ([M + H] + calc 943.4, obs 943.1). A second, well-resolved peak in the liquid chromatogram from the for-PPH MTS system also characterized as a species with [M + H] + 943.3, and was identified as the octadentate complex between Zr(IV) and two dimeric tetradentate hydroxamic acid macrocycles for-[Zr(PPDFOT 1D) 2 ]. Treatment of for-[Zr(PPDFOT 1)] or for-[Zr(PPDFOT 1D) 2 ] with EDTA at pH 4.0 gave the respective hydroxamic acid macrocycles as free ligands: octadentate PPDFOT 1 or two equivalents of tetradentate PPDFOT 1D (homobisucaberin, HBC). At pH values closer to physiological, EDTA treatment of for-[Zr(DFOT 1)], for-[Zr(PPDFOT 1)], or Zr(IV) complexes with related linear tri-or tetrameric hydroxamic acid ligands showed the macrocycles were more resistant to the release of Zr(IV), which has implications for the design of ligands optimized for the use of Zr(IV)-89 in positron emission tomography (PET) imaging of cancer.
A metal-templated synthesis (MTS) approach was used to preorganize the forward endo-hydroxamic ac... more A metal-templated synthesis (MTS) approach was used to preorganize the forward endo-hydroxamic acid monomer 4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoic acid (for-PBH) about iron(III) in a 1:3 metal/ligand ratio to furnish the iron(III) siderophore for-[Fe(DFOE)] (ferrioxamine E) following peptide coupling. Substitution of for-PBH with the reverse (retro) hydroxamic acid analogue 3-(6-amino-N-hydroxyhexanamido)propanoic acid (ret-PBH) furnished ret-[Fe(DFOE)] (ret-ferrioxamine E). As isomers, for-[Fe(DFOE)] and ret-[Fe(DFOE)] gave identical mass spectrometry signals ([M + H(+)](+), m/zcalc 654.3, m/zobs 654.3), yet for-[Fe(DFOE)] eluted in a more polar window (tR = 23.44 min) than ret-[Fe(DFOE)] (tR = 28.13 min) on a C18 reverse-phase high-performance liquid chromatography (RP-HPLC) column. for-[Ga(DFOE)] (tR = 22.99 min) and ret-[Ga(DFOE)] (tR = 28.11 min) were prepared using gallium(III) as the metal-ion template and showed the same trend for the retention time. Ring-expanded a...
2.4 Metal Complexes for Derivation of Structural Restraints via Paramagnetic NMR Spectroscopy 2.4... more 2.4 Metal Complexes for Derivation of Structural Restraints via Paramagnetic NMR Spectroscopy 2.4.1 Paramagnetic Relaxation Enhancement (PRE) 2.4.2 Residual Dipolar Coupling (RDC) 2.4.3 Pseudo-Contact Shifts (PCS) 2.4.4 Strategies for Introducing Lanthanide Ions into Bio-Macromolecules 2.5 Metal Complexes as Spin Labels for Distance Measurements via EPR Spectroscopy 2.6 Metal Complexes as Donors for Distance Measurements via Luminescence Resonance Energy Transfer (LRET) 2.7 Concluding Statements and Future Outlook References 3. AAS, XRF, and MS Methods in Chemical Biology of Metal Complexes Ingo Ott, Christophe Biot and Christian Hartinger 4. Metal Complexes for Cell and Organism Imaging
The ability of microbial siderophores to coordinate metal ions, particularly Fe(III), continues t... more The ability of microbial siderophores to coordinate metal ions, particularly Fe(III), continues to generate interest in the potential applications of these bioligands in the environment and medicine. 1À3 Siderophores produced by terrestrial and marine bacteria have evolved to sequester Fe(III) from insoluble Fe(III)-oxy/ hydroxides under oxic and pH neutral environments. 4À7 The formation of the Fe(III)Àsiderophore complex is the first step in siderophore-dependent iron uptake and is essential for the viable growth of almost all environmental and pathogenic bacteria. 8À12 Siderophores have diverse structures and have been classified according to the metal ion-binding functional group as catechol-, hydroxamic acid-or citric acid-based compounds. 13 Clinical applications of hydroxamic acid-based siderophores include the mesylate salt of desferrioxamine B for the treatment of iron-overload disease in patients undergoing frequent blood transfusions and suberoylanilide hydroxamic acid, which acts as an anticancer agent via the inhibition of Zn(II) containing histone deacetylases. 14À18 While siderophores have evolved as high-affinity Fe(III) complexing agents, these ligands have a rich coordination chemistry with other transition-metal ions in the first and second row of the Periodic Table. 19 Siderophores excreted by marine bacteria compete for Fe(III) and other transition-metal ions present in greater abundance in the ocean, such as Mo(VI) and V(V). 20 Nitrogen fixing Azotobacter vinelandii produces a suite of siderophores that bind Fe(III) and V in order to meet its V requirement for the biosynthesis of V-containing nitrogenase. 21 Desferrioxamine B reactivated V(V)-inhibited enzymes by sequestering the V(V) ion at the active site 22 and the V(V)hydroxamic acid complexes inhibited the β-lactamase of Enterobacter cloacae P99. 23 Complexes between V(IV) or V(V) and hydroxamic acids lowered blood glucose levels in rat adipocytes 24 and streptozotocin-induced diabetic mice 25 and are under
Adamantyl-based compounds are used clinically for the treatment of neurological conditions, as an... more Adamantyl-based compounds are used clinically for the treatment of neurological conditions, as antiviral agents and as agents against type 2 diabetes. The value of the adamantyl group in drug design is multidimensional. The hydrophobic substituent constant for the adamantyl group has been estimated from the calculated partition coefficients (clogP values) of 31 adamantyl-bearing compounds in the clinic or in development as p adamantyl ¼ 3.1, which indicates that the logP value of a compound with high water solubility (logP < < 0) could be moved with an adamantyl-based modification to a region that is more clinically useful. The steric bulk of the adamantyl group can: (i) restrict or modulate intramolecular reactivity; and (ii) impede the access of hydrolytic enzymes, thereby increasing drug stability and plasma half life. The value of the adamantyl group in drug design has been recognized most recently in the design of agents to treat iron overload disease (in development), malaria (in clinical trials) and type 2 diabetes (in the clinic).
The reaction between Zr(IV) and the forward endo-hydroxamic acid monomer 4-[(5-aminopentyl)-(hydr... more The reaction between Zr(IV) and the forward endo-hydroxamic acid monomer 4-[(5-aminopentyl)-(hydroxy)amino]-4-oxobutanoic acid (for-PBH) in a 1:4 stoichiometry in the presence of diphenylphosphoryl azide and triethylamine gave the octadentate Zr(IV)-loaded tetrameric hydroxamic acid macrocycle for-[Zr(DFOT 1)] ([M + H] + calc 887.3, obs 887.2). In this metal-templated synthesis (MTS) approach, the coordination preferences of Zr(IV) directed the preorganization of four oxygen-rich bidentate for-PBH ligands about the metal ion prior to ring closure under peptide coupling conditions. The replacement of for-PBH with 5-[(5-aminopentyl) (hydroxy)amino]-5-oxopentanoic acid (for-PPH), which contained an additional methylene group in the dicarboxylic acid region of the monomer, gave the analogous Zr(IV)-loaded macrocycle for-[Zr(PPDFOT 1)] ([M + H] + calc 943.4, obs 943.1). A second, well-resolved peak in the liquid chromatogram from the for-PPH MTS system also characterized as a species with [M + H] + 943.3, and was identified as the octadentate complex between Zr(IV) and two dimeric tetradentate hydroxamic acid macrocycles for-[Zr(PPDFOT 1D) 2 ]. Treatment of for-[Zr(PPDFOT 1)] or for-[Zr(PPDFOT 1D) 2 ] with EDTA at pH 4.0 gave the respective hydroxamic acid macrocycles as free ligands: octadentate PPDFOT 1 or two equivalents of tetradentate PPDFOT 1D (homobisucaberin, HBC). At pH values closer to physiological, EDTA treatment of for-[Zr(DFOT 1)], for-[Zr(PPDFOT 1)], or Zr(IV) complexes with related linear tri-or tetrameric hydroxamic acid ligands showed the macrocycles were more resistant to the release of Zr(IV), which has implications for the design of ligands optimized for the use of Zr(IV)-89 in positron emission tomography (PET) imaging of cancer.
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