Cobalt complexes dipeptides

Complexes of cobalt with dipeptides from several laboratories led to confusion about the variety of the species formed and their structure In 1966, Gillard et al. prepar several salts of bis(glycylglycinato)cobaltate(III), [Co(glygly)2], by treating an aqueous solution (pH 6.5 9.0) containing cobalt(II) ion and glycyl-... 

Cobalt(ll) forms many complexes which can exhibit oxygen-carrying properties (2,19). Reversible oxygen uptake in solutions of cobalt (ll)-histidine (33-36), and cobalt (II) in the presence of a-amino acids and peptides (37—39) has been known for some time. The reaction of cobalt (II) with dipeptide was first observed in enzymic studies involving glycyl-glycine (40). 

Complexes of other amino acids or their derivatives with cobalt(II) that have been investigated include dipeptides (120) these complexes have long been known to absorb dioxygen. For example, the mononuclear cobalt(II) complex of N, N,N", N "-diglycylethylenediaminete-traacetic acid (121) absorbs one mole of dioxygen per two moles of complex. This system has been proposed as a simple, convenient model system for the study of dioxygen complexes of cobalt(II) peptides in solution because of its relatively slow conversion to the irreversibly formed cobalt(III) dioxygen complex. 

It has been known for many years that the rate of hydrolysis of a-amino acid esters is enhanced by a variety of metal ions such as copper(II), nickel(II), magnesium(H), manganese(II), cobalt(II) and zinc(II).338 Early studies showed that glycine ester hydrolysis can be promoted by a tridentate copper(II) complex coupled by coordination of the amino group and hydrolysis by external hydroxide ion (Scheme 88).339 Also, bis(salicylaldehyde)copper(II) promotes terminal hydrolysis of the tripeptide glycylglycylglycine (equation 73).340 In this case the iV-terminal dipeptide fragment... 

Coordinated a-amino amides can be formed by the nucleophilic addition of amines to coordinated a-amino esters (see Chapter 7.4). This reaction forms the basis of attempts to use suitable metal coordination to promote peptide synthesis. Again, studies have been carried out using coordination of several metals and an interesting early example is amide formation on an amino acid imine complex of magnesium (equation 75).355 However, cobalt(III) complexes, because of their high kinetic stability, have received most serious investigation. These studies have been closely associated with those previously described for the hydrolysis of esters, amides and peptides. Whereas hydrolysis is observed when reactions are carried out in water, reactions in dimethyl-formamide or dimethyl sulfoxide result in peptide bond formation. These comparative results are illustrated in Scheme 91.356-358 The key intermediate (126) has also been reacted with dipeptide... 

A three-site system for peptide synthesis around a cobalt(III) complex has been studied. Instead of a quadridentate ligand as used in the above experiments, Wu and Busch chose the tridentate ligand diethylenetriamine. The formation of dipeptide and tetrapeptide complexes is shown in Scheme 92.360 The ester carbonyl group in the 0-bonded amide intermediate (127) cannot be activated by coordination because it cannot reach the metal ion. Isomerization to the jV-bonded amide complex (128) occurs with base and enables coordination and therefore activation of the ester carbonyl group. 

The dependence of the principal components of the nuclear magnetic resonance (NMR) chemical shift tensor of non-hydrogen nuclei in model dipeptides is investigated. It is observed that the principal axis system of the chemical shift tensors of the carbonyl carbon and the amide nitrogen are intimately linked to the amide plane. On the other hand, there is no clear relationship between the alpha carbon chemical shift tensor and the molecular framework. However, the projection of this tensor on the C-H vector reveals interesting trends that one may use in peptide secondary structure determination. Effects of hydrogen bonding on the chemical shift tensor will also be discussed. The dependence of the chemical shift on ionic distance has also been studied in Rb halides and mixed halides. Lastly, the presence of motion can have dramatic effects on the observed NMR chemical shift tensor as illustrated by a nitrosyl meso-tetraphenyl porphinato cobalt (III) complex. 

Even though this dipeptide is turned over quite slowly, the complex examined is probably a non-productive one. Furthermore an analogous ester substrate has not been found, and it is known that carboxypeptidase behaves quite differently toward ester and peptide substrates. In particular, the kinetic parameters for peptide hydrolysis for a series of metal substituted carboxypeptidases indicate that fccat values can range from 6000 min for the cobalt enzyme down to 43 min for the cadmium enzyme 66). The values on the other hand are almost totally independent of the particular metal present. The exact opposite is true for ester hydrolysis. Km varies from 3300 M for the cobalt enzyme to 120 M for the cadmium enzyme while k<.at is essentially unchanged. 

One of the smallest naturally occurring peptides is camosine (jS-Ala-L-His) found in relatively large amounts in various animal tissues. Its exact function is not known. In the kidney an enzyme, carnosinase, hydrolyzes the peptide to its constituent amino acids. Also present in kidney is the highest in vivo concentration of cobalt, and Co complexes with carnosine are known to reversibly bind Oj. The inference is that carnosine (via its Co" complex) in kidney may control the O2 level. Further evidence is still needed for this conclusion. The extra methylene group in the -Ala moiety considerably alters the chelating properties of carnosine relative to other His-containing dipeptides (Chapter 20.2). This is particularly so with Cu" in aqueous solution where the major species is a dimer formed from the His moiety bridging the two metal centres. ... 

Boas et al. prepared and separated the meridional isomers of the [Co(ai-02)2] type complexes (oti-a2 represents the dianion of the dipeptide H2 i-a2> where ai is the N-terminal residue). Seven methods were used to prepare bis(dipeptidato)-cobaltate(III) complexes (i) by oxygenation of cobalt(II), (ii) from cobalt(II) carbonate, (iii) from sodium tricarbonatocobaltate(III), (iv) from hexaamminecobalt-(III) chloride, (v) from hexakis(urea)cobalt(III) perchlorate, (vi) from cobalt(III) hydroxide oxide, (vii) from triammine(glycylglycinato)cobalt(III). The methods starting from Co" gave more minor products, Na3[Co(C03)3] 3 H2O gave less, and cobalt(III) hydroxide oxide gave very little of these products. Thus, the method (vi) was prefered. The peptides used were gly-gly, L-ala-gly, gly-L-ala, L-leu-gly, gly-L-leu, L-phe-gly, gly-L-phe, L-ala-L-ala, L-ala-D-ala, L-leu-L-leu. 

In this scheme, the p-peroxodicobalt(III) derivative is first formed, then intramolecular oxidative dehydrogenation of a coordinated dipeptide occurs. The corresponding intermediate has been detected by polarography. Displacement of the oxidized ligand by excess free dipeptide leads to a cobalt(III) complex, which does not react with O. ... 

Dicobalt-hexacarbonyl-alkyne complexes are another class of organometallic compounds with good stability imder physiological conditions. Complexation of the alkyne proceeds smoothly under mild conditions by reaction with Co2(CO)g imder loss of two molecules of CO [79]. The applicability of this reaction to peptides was shown by Jaouen and coworkers by the reaction of Co2(CO)g with protected 2-amino-4-hexynoic acid (Aha) and dipeptides thereof (Boc-Phe-Aha-OMe and Ac-Aha-Phe-OMe) [80]. Similarly, Cp2Mo2(CO)4 complexes of these alkynes were obtained. It has been shown that the C-terminal Met" in SP can be replaced by isostere analogs without appreciable loss of physiological activity. The same is true for the C-terminal Met in neurokinin A (NKA), another tachykinin peptide hormone (Scheme 5.16). Alkyne analogs of SP and NKA were obtained by replacement of these methionines with norleucine acetylene residues. Alternatively, Lys in NKA may be replaced by an alkyne derivative which can also be complexed to Co2(CO)g as shown in Scheme 5.16. Complexation with Co2(CO)g proceeds smoothly in about 50% yield for all derivatives [81]. After HPLC purification, these cobalt alkyne peptides were comprehensively characterized spectroscopically. Most notably, they exhibit typical IR absorptions for the metal carbonyl moieties between 2000-2100 cm [3]. Recently, there is renewed interest in Co2(CO)5(alkyne) complexes because of their cytotoxicity [82-84]. 

With the complex ion catalyst cis-)5-hydroxoaquatriethylenetetramine-cobalt(III), abbreviated [Co(trien)(H20)OH], peptide bond hydrolysis of the dipeptide L-aspartylglycine takes place, but only in the productive binding mode. 

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