Additions to Metal-Activated Organonitriles†

Cu and Zn have been shown to accumulate in the brains of Alzheimer's disease patients. We have previously reported that Cu(2+) and Zn(2+) bind amyloid beta (Abeta), explaining their enrichment in plaque pathology. Here we detail the stoichiometries and binding affinities of multiple cooperative Cu(2+)-binding sites on synthetic Abeta1-40 and Abeta1-42. We have developed a ligand displacement technique (competitive metal capture analysis) that uses metal-chelator complexes to evaluate metal ion binding to Abeta, a notoriously self-aggregating peptide. This analysis indicated that there is a very-high-affinity Cu(2+)-binding site on Abeta1-42 (log K(app) = 17.2) that mediates peptide precipitation and that the tendency of this peptide to self-aggregate in aqueous solutions is due to the presence of trace Cu(2+) contamination (customarily approximately 0.1 microM). In contrast, Abeta1-40 has much lower affinity for Cu(2+) at this site (estimated log K(app) = 10.3), explaining why this peptide is less self-aggregating. The greater Cu(2+)-binding affinity of Abeta1-42 compared with Abeta1-40 is associated with significantly diminished negative cooperativity. The role of trace metal contamination in inducing Abeta precipitation was confirmed by the demonstration that Abeta peptide (10 microM) remained soluble for 5 days only in the presence of high-affinity Cu(2+)-selective chelators.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1471-4159.2000.0751219.x

Characterization of copper interactions with alzheimer amyloid beta peptides: identification of an attomolar-affinity copper binding site on amyloid beta1-42.

The crystal structure of biotin synthase from Escherichia coli in complex with S-adenosyl-L-methionine and dethiobiotin has been determined to 3.4 angstrom resolution. This structure addresses how "AdoMet radical" or "radical SAM" enzymes use Fe4S4 clusters and S-adenosyl-L-methionine to generate organic radicals. Biotin synthase catalyzes the radical-mediated insertion of sulfur into dethiobiotin to form biotin. The structure places the substrates between the Fe4S4 cluster, essential for radical generation, and the Fe2S2 cluster, postulated to be the source of sulfur, with both clusters in unprecedented coordination environments.

/pdf/crystal-structure-of-biotin-synthase-an-s-adenosylmethionine-3sganq2qon.pdf

Crystal structure of biotin synthase, an S-adenosylmethionine-dependent radical enzyme.

Metal-mediated and metal-catalyzed hydrolysis of nitriles

The aim of this perspective is to highlight the continued development and application of amidines and guanidines as neutral, N-based donor ligands in coordination chemistry. From a sporadic interest dating back to the 1980s, work on these two closely related classes of compounds has steadily grown, with examples of evermore sophisticated substitution about the common ligand framework being developed to address specific problems in a number of fields of chemistry. These compounds have shown varied coordination modes at metals from across the periodic table, and examples of their application in a number of catalytic processes are emerging as the field matures.

Application of neutral amidines and guanidines in coordination chemistry

Dimethylcyanamide (N identical withCNMe(2)) has been coordinated to both hard and soft electrophiles ((NH(3))(5)Co(3+), (NH(3))(5)Os(3+), (dien)Pt(2+)) which activate ( approximately x10(6)) the nitrile toward attack by nucleophiles such as ammonia and hydroxide. Amination with liquid ammonia gave a rare coordinated guanidine (N,N-dimethylguanidine) ligand, which NMR spectra and X-ray crystal structures show to be charge neutral rather than anionic. Crystals of [(NH(3))(5)CoNH=C(NH(2))NMe(2)](S(2)O(6))(3/2).H(2)O, CoC(3)H(26)N(8)O(10)S(3), were triclinic, space group Po, a = 11.565(2) A, b = 10.629(5) A, c = 8.026(1) A, alpha = 84.93(3) degrees, beta = 76.01(1) degrees, gamma = 73.82(3) degrees, V = 919.2(5) A(3), Z = 2, and R(F)() (R(w)(F)()) = 0.038 (0.047) for 3262 observed reflections (I > 3.0 sigma(I)). Crystals of [(dien)PtNH=C(NH(2))NMe(2)](CF(3)SO(3))(2), PtC(9)H(22)N(6)O(6) S(2)F(6), are monoclinic, space group P2(1)/c, a = 13.857(4), b = 14.748(4) A, c = 22.092(4) A, beta = 105.38(2) degrees, V = 4353(2) A(3), Z = 8, and R(F)() (R(w)(F)()) = 0.034 (0.038) for 6778 reflections. Coordination geometries around the metals are octahedral and square planar, respectively, the guanidine skeletons being planar with bond angles and lengths characteristic of the metal-imino (rather than metal-amino) tautomer. The complexes are very stable in coordinating solvents (DMSO; water, pH 3-11) indicating high affinity of guanidine ligands for metal ions. Hydration of the dimethylcyanamide ligand is base-catalyzed, and first-order in [OH(-)] (0.05-0.5 M NaOH; k = k(s) + k(OH)[OH(-)], k(OH) = 2-5 M(-)(1) s(-)(1), 25 degrees C), in each case producing coordinated N,N-dimethylurea ([dienPtNHCONMe(2)](+), [(NH(3))(5)CoNHCONMe(2)](2+), [(NH(3))(5)OsNHCONMe(2)](2+)). Hydration rates are surprizingly similar despite differing radial extensions of the metal d-orbitals, a finding consistent with their comparable polarizing powers but contrary to expectation from other work. The relevance of metal activation of nitriles to biological systems is discussed.

Models for Arginine-Metal Binding. Synthesis of Guanidine and Urea Ligands through Amination and Hydration of a Cyanamide Ligand Bound to Platinum(II), Osmium(III), and Cobalt(III).

Amide-Iminol Tautomerism: Effect of Metalation

The coordination of acetamide and formamide to dienPtII is described. Both O- and N-bonded amide complexes are stable and have been isolated. As oxygen donor ligands for dienPtII, the binding affinity of amides lies between water and the very weakly coordinating acetone. The O-bonded amide complexes [dienPtOC(R)NH2]2+ are the kinetically preferred isomers in acetone but they rearrange very slowly (t1/2 ∼ 30 h, 20°C) and intramolecularly to the thermodynamically more stable N-bonded amide complexes (K = [N]/[O] ∼ 30). This is the reverse of relative amide affinities for harder metal ions (e.g. (NH3)5M3+, M = Co(III), Cr(III), Ru(III)) despite comparable polarizing power for dienPtII. The N-bonded amide isomers exist in solution (acetone, DMSO, water) as the imidol, [dienPtNH=C(OH)R]2+, rather than the amide tautomer, [dienPtNH2COR]2+, whereas the opposite has been observed for N-bonded ureas. The N-bonded amides adopt only one of the two possible geometric isomers which could result from restricted rotation about the amide N=C bond, and they are appreciably acidic (pKa 3.8, 20°C, H2O, I = 0.1 M; R = Me). Complexes of both O- and N-bonded amides are unstable in coordinating solvents (f1/2 40 h, N-isomers; 20°C, H2O), but no decomposition of the amide ligands was detected during solvolysis (amide release) in either DMSO or water, nor was the Pt(II) susceptible to aerial oxidation as reported for mixtures of amides with cis-diammineplatinum(II). Coordination preferences of amides to "soft" versus "hard" metals are compared.

Amide complexes of (diethylenetriamine)platinum(II)

Syntheses and properties of isomeric(diethylenetriamine)platinum(II) complexes of 1,1-dimethylurea (DMU)bound through oxygen or nitrogen are reported. Isomers were distinguished by a combination of NMR (H-1, C-13) and IR spectroscopy, acidity and reactivity measurements, and an isomer selective synthetic route. The oxygen-bonded DMU compound, [dienPtOC(NH2)NMe2]2+, is the kinetically preferred product from the stoichiometric reaction of DMU with [dienPtOH2]2+ in acetone. This oxygen-bonded form then rearranges (t1/2 approximately 18 min, 22-degrees-C) to the slightly more thermodynamically stable nitrogen-bonded linkage isomer (K(NO) = [N-isomer]/[0-isomer] approximately 3). The reverse isomerization from N-bonding to O-bonding was also detected. NMR(H-1, C-13) and IR spectroscopy proved that the N-bonded DMU complex, which was also independently and selectively synthesized through base hydrolysis of the cyanamide precursor [dienPtN = CNMe2]2+, exists in solution and in the solid state as the unusual amide tautomer [dienPtNH2COR]2+ (R = NMe2), rather than the imidol tautomer [dienPtNH:C(OH)R]2+ observed for acetamide (R = Me). The N-bonded DMU ligand was much more acidic (pK(a) 5.6, H20,20-degrees-C) than the 0-bonded DMU linkage isomer (pK(a) greater-than-or-equal-to 11 (est)), indicating greater resonance stabilization for the deprotonated urea of [dienPtNHCONMe2]+ versus [dienPtOC(NMe2)NH]+, but less acidic than the N-bonded acetamide of [dienPtNH: C(OH)Me]2+ (pK(a) 3.8), where the acidic proton is on oxygen instead of nitrogen. Both the approximately 50-fold faster solvolysis of the N-bonded DMU versus the N-bonded acetamide (R = NMe2, k = 5 x 10(-4) S-1; R = Me, k = 1 X 10(-5) S-1; H2O, pH 2.5, 40.0-degrees-C) and the approximately 100-fold rate difference in linkage isomerization from O-bonding to N-bonding DMU (R = NMe2, k = 6.4 x 10(-4) s-1; R = Me, k = 6.8 x 10(-6) s-1; acetone, 22-degrees-C) are attributed to the requirement for proton migration between imidol and amide tautomers of the N-bonded form. Both isomerization and solvolysis likely proceed via the amide tautomer only. The O-bonded DMU ligand is displaced much faster (water, DMSO; t1/2 < 1 min, 22-degrees-C) than the N-bonded DMU ligand from platinum by coordinating solvents.

Tai Chin Woon

Papers

Models for Arginine-Metal Binding. Synthesis of Guanidine and Urea Ligands through Amination and Hydration of a Cyanamide Ligand Bound to Platinum(II), Osmium(III), and Cobalt(III).

Amide-Iminol Tautomerism: Effect of Metalation

Amide complexes of (diethylenetriamine)platinum(II)

Oxygen versus nitrogen coordination of a urea to (diethylenetriamine)platinum(II)

Inhibition of HIV-1 proteinase by non-peptide carboxylates