Biomedical subjects
Publications and source records attributed to Sylvain Hamman.
In copper(ii) complexes of tripodal ligands, the protonation state of the phenol moiety, and its position (axial vs. equatorial), are easily assessed by (19)F NMR.
Tyrosyl radicals are involved in many biologically important processes. The development of model compounds to mimic radical enzyme active sites, such as galactose oxidase (GO), has widely contributed to an enhanced understanding of their spectral properties, structural attributes and even reactivity. An emerging approach towards the synthesis of such active site mimetics is the use of peptidic ligands. The potential of cyclodecapeptides to bear phenoxyl radicals has been evaluated through three compounds. LH(4) (2+) is a cyclodecapetide containing two histidine residues (mimicking His(496) and His(581) of GO) and two tyrosine residues (mimicking Tyr(495) and the Tyr(272)* radical of GO). L(tBu)H(4) (2+) and L(OMe)H(4) (2+) incorporate 2,4,6-protected phenols in place of each tyrosine in LH(4) (2+). The deprotonation constants of each peptide determined by potentiometric titrations showed that there are some interactions between the acido-basic residues. Cyclic voltammetric studies revealed that only the peptides incorporating 2,4,6-protected phenolates exhibit reversible redox couples and are thus precursors of radicals stable enough to persist in solution. These studies also showed L(OMe2-) to possess the lower oxidation potential, indicating that this peptide, in its radical form, is the most stabilized. The electrochemically generated radical species have been characterized by EPR spectroscopy.
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Galactose oxidase (GO) is an enzyme that catalyzes two-electron oxidations. Its active site contains a copper atom coordinated to a tyrosyl radical, the biogenesis of which requires copper and dioxygen. We have recently studied the properties of electrochemically generated mononuclear Cu(II)-phenoxyl radical systems as model compounds of GO. We present here the solution chemistry of these ligands under various copper and dioxygen statuses: N(3)O ligands first chelate Cu(II), leading, in the presence of base, to [Cu(II)(ligand)(CH(3)CN)](+) complexes (ortho-tert-butylated ligands) or [(Cu(II))(2)(ligand)(2)](2+) complexes (ortho-methoxylated ligands). Excess copper(II) then oxidizes the complex to the corresponding mononuclear Cu(II)-phenoxyl radical species. N(2)O(2) tripodal ligands, in the presence of copper(II), afford directly a copper(II)-phenoxyl radical species. Addition of more than two molar equivalents of copper(II) affords a Cu(II)-bis(phenoxyl) diradical species. The donor set of the ligand directs the reaction towards comproportionation for ligands possessing an N(3)O donor set, while disproportionation is observed for ligands possessing an N(2)O(2) donor set. These results are discussed in the light of recent results concerning the self-processing of GO. A path involving copper(II) disproportionation is proposed for oxidation of the cross-linked tyrosinate of GO, supporting the fact that both copper(I) and copper(II) activate the enzyme.
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Four tripodal ligands with an N(3)O coordination sphere were synthesized: (2-hydroxy-3-tert-butyl-5-nitrobenzyl)bis(2-pyridylmethyl)amine (LNO(2)H), (2-hydroxy-3-tert-butyl-5- fluorobenzyl)bis(2-pyridylmethyl)amine (LFH), (2-hydroxy-3,5-di-tert-butylbenzyl)bis(2-pyridylmethyl)amine (LtBuH) and (2-hydroxy-3-tert-butyl-5-methoxybenzyl)bis(2-pyridylmethyl)amine (LOMeH). Their square-pyramidal copper(II) complexes, in which the phenol subunit occupies an axial position, were prepared and characterized by X-ray crystallography and UV/Vis and EPR spectroscopy. The phenolate moieties of the copper(II) complexes of LtBuH and LOMeH were electrochemically oxidized to phenoxyl radicals. These complexes are EPR-active (S=1), highly stable (k(decay)=0.008 min(-1) for [Cu(II)(LOMe(.))(CH(3)CN)](2+)) and stoichiometrically oxidise benzyl alcohol. Two additional tripodal ligands providing an N(2)O(2) coordination sphere were also studied: (2-pyridylmethyl)(2-hydroxy-3-tert-butyl-5-methoxybenzyl)(2-hydroxy-3-tert-butyl-5-nitrobenzyl)amine (L'OMeNO(2)H(2)) and (2-pyridylmethyl)bis(2-hydroxy-3-tert-butyl-5- methoxy)benzylamine (L'OMe(2)H(2)). Their copper(II) complexes were isolated as dimers ([Cu(2II)(L'OMe(2))(2)], [Cu(2II)(L'OMeNO(2))(2)]) that are converted to monomers on addition of pyridine. The complexes were investigated by X-ray crystallography and UV/Vis and EPR spectroscopy. Their one-electron electrochemical oxidation leads to copper(II)-phenoxyl systems that are less stable than those of the N(3)O complexes. The N(2)O(2) complexes are more reactive than the N(3)O analogues: they aerobically oxidize benzyl alcohol to benzaldehyde at a higher rate, as well as ethanol to acetaldehyde (40-80 turnovers).
A series of dicopper(II) complexes have been investigated as model systems for the catechol oxidase active site enzyme, regarding the binding of catechol substrate in the first step of the catalytic cycle. The [Cu(2)(L(R))(mu-OH)](ClO(4))(2) and [Cu(2)(L(R))(H(2)O)(2)](ClO(4))(3) complexes are based on the L(R) ligands (2,6-bis[(bis(2-pyridylmethyl)amino)methyl]-4-R-substituted phenol) with -R = -OCH(3), -CH(3), or -F. Binding studies of diphenol substrates were investigated using UV-vis and EPR spectroscopy, electrochemistry, and (19)F NMR (fluorinated derivatives). All the complexes are able to bind two ortho-diphenol substrates (tetrachlorocatechol and 3,5-di-tert-butylcatechol). Two successive fixation steps, respectively fast and slower, were evidenced for the mu-OH complexes (the bis(aqua) complexes are inactive in catalysis) by stopped-flow measurement and (19)F NMR. From the mu-OH species, the 1:1 complex/substrate adduct is the catalytically active form. In relation with the substrate specificity observed in the enzyme, different substrate/inhibitor combinations were also examined. These studies enabled us to propose that ortho-diphenol binds monodentately one copper(II) center with the concomitant cleavage of the OH bridge. This hydroxo ligand appears to be a key factor to achieve the complete deprotonation of the catechol, leading to a bridging catecholate.