Substitution-inert complexes

In the cases of substitution-inert complexes of Fe(ni) it is envisaged that R-forms a temporary bond with the ligand through which the electron transport takes place. 

Substitution-inert complexes have also recently been introduced into DNA as modified-base phosphoramidites. Interest here is generally focused on photo- and redox-active metal species for use as probes for sensing applications (165) and in studies on DNA-mediated electron... 

Such reactions are observed in electron transfer reactions of substitutionally inert complexes. The mechanism involves three steps. 

A major compilation of solvolytic data for octahedral complexes up to 1976 can be found in the review by Edwards et a/.126 and an extensive review by House127 covers the acido—pentaamine complexes of Co(III) and Cr(III). Both are limited to substitutionally inert complexes and this section of the chapter will also be so restricted in order to allow an independent examination of the variables, in so far as they can be conveniently separated. 

It is generally believed that the oxidation of thiourea and related compounds by aqua-metal ions involves an inner-sphere electron-transfer process, whereas an outer-sphere mechanism is more commonly associated with substitution-inert complexes. The stoichiometry of redox reactions with one-electron oxidizing agents is different for acid and alkaline media. The oxidation of both thiourea and thioacetamide by [Mo(CN)g] in the range 0.02 < [HCIO4] < 0.08 M proceeds in a 1 1 ratio, yielding the disulfide as a product (108) ... 

Szilard-Chalmers reactions are applicable to elements existing in different stable oxidation states or forming substitution-inert complexes. Exchange reactions between the oxidation states or with the complexes should not take place during irradiation and chemical separation, because they would cause a decrease of the specific activity. Therefore, substitution-labile complexes are not suitable. 

The EPR silent metalloporphyrins are considered to be low-spin Mm (S = 1 /2) coupled to NO (S=l/2), as suggested by Mossbauer spectroscopy.19,20 The first characterized iron derivative [Fe(OEP)(NO)(OH2)]+15 and other related complexes have short Fe—N(NO) lengths (ca. 1.65 A), consistent with a strong bond (one a and two ir). The iron is located on the center, close to the porphyrin plane. Interestingly, NO is labile in the porphyrin-Fem systems, in contrast with the substitution-inert complexes with classical coligands, as nitroprusside (NP). Although these ferriheme derivatives are difficult to isolate because of reductive nitrosylation (see Section 1.31.1.5), some [Fe(OEP)(NO)(L)]+ complexes have been characterized. Figure 2 shows the structure of the L= l-Melm derivative. 

Tris(phenanthroline) complexes of ruthenium(II), cobalt(III), and rhodium(III) are octahedral, substitutionally inert complexes, and as a result of this coordina-tive saturation the complexes bind to double-helical DNA through a mixture of noncovalent interactions. Tris(phenanthroline) metal complexes bind to the double helix both by intercalation in the major groove and through hydrophobic association in the minor groove. " " Intercalation and minor groove-binding are, in fact, the two most common modes of noncovalent association of small molecules with nucleic acids. In addition, as with other small molecules, a nonspecific electrostatic interaction between the cationic complexes and the DNA polyanion serves to stabilize association. Overall binding of the tris(phenanthroline) complexes to DNA is moderate (log K = 4)." ... 

The importance of a nonadiabatic path for outer-sphere electron transfer reactions of Eu(III)/Eu(Il) was again examined by Yee et al. (1983) via a study of a series of reactions with Eu(III)/(II) cryptates (table 12). The cryptate (polyoxadiazamacrobi-cyclic) ligands form thermodynamically stable and substitution inert complexes with both Eu(lll) and Eu(ll), markedly changing the primary coordination spheres of the Eu ions. The dramatic variation in the values for the Eu exchange reactions with such a change is demonstrated by the respective calculated values for EUavalues calculated from the cross reactions are consistent with the values of the Franck-Condon barriers estimated from structural data. 

Tissues. Profiles of the distribution of chloroammlneplatlnum(II) complexes as a function of time (for periods up to 7 d) in four specific tissues are shown in Figure 3. The distribution patterns are distinct and presumably reflect the unique chemical behavior expected for discrete substitution-inert complexes, l.e., these complexes appear to retain sufficient identity in vivo to exhibit characteristic distribution patterns. This can be contrasted with the behavior of simple binary metal salts, which exist as labile cations in solution, and whose distribution properties show little or no difference from one salt to another. All compounds are cleared relatively rapidly from the blood (panel A), especially the cationic species, [Pt(NH3)3d] and [Pt(NH3) ] , for which the levels are on the order of 0.1% and 0.02%, respectively after 4 h. The [Pt(NH3)Cl3] ion shows the highest level after 7 d (-v-U). 

Tissue distribution patterns are well-defined and reflect the unique chemistry of these substitution-inert complexes. 

We should note the fact that in the bacterial systems, the substitutionally inert complexes which are mutagenic and active in the repair assay all have effects similar to those of the platinum complexes known to be anti-tumor drugs. Since repair effects are closely correlated with activity of the platinum compounds (17), then the anti-tumor activity could be related to the substitutional inertness of our complexes. We have noted that many of the complexes we have studied are far less bacteriocidal than the platinum compounds, and yet comparable in repair activity. This suggests that further study of substitutionally inert metal complexes may yield anti-tumor drugs which are as effective as the platinum compounds, and yet lack their undesirable toxic side effects. 

An outer sphere mechanism involves electron transfer from reductant to oxidant with the inner coordination spheres of each remaining intact. That is, one reactant becomes involved in the outer or second coordination sphere of the other reactant, and an electron flows from reductant to oxidant. Such a mechanism is established when rapid electron transfer occurs between two substitution inert complexes. A typical example of this type of process is the reaction between [FeCCNj ] and [IrCy ... 

Mn -ATP (from a folded chelate to an extended outer-sphere complex) when the nucleotide binds to pyruvate kinase. It has also been established that the substitution-inert complex Cr iL-ATP binds at the ATP binding site of the pyruvate kinase-M + complex, and studies with this magnetic probe have led to the construction of molecular models for composite complexes of this important enzyme. Steady-state kinetic studies on the Mn +-, Ni +-, and Co +-activated systems suggest that the substrates of pyruvate kinase are PEP, uncomplexed ADP, and free bivalent cations. Magnesium-complexed ADP and ATP bind at the same site on yeast phosphoglycerate kinase, as do the uncomplexed nucleotides. 

The more recent results on the interaction of these substitution inert complexes with DNA (see Chapter 1), and especially the photosensitized cleavage of DNA by Co(III) complexes [46], may well be relevant to these biological results, especially as a 1,10-phenanthroline chelate, cis-[Co(phen)2(N02)2], is also claimed to be an efficient sensitizer. Differing activities have been observed in isomeric forms of [Co(NH3)4X2], X = Cl, NO2. Abrams et al. [40] have observed that all active complexes show a reduction potential of < 260 mV, which represents a cut-off point as there is no strict correspondence between reduction potential and OER. No selectivity is apparent for these complexes in hypoxic cells. The hexam-mine and pentammine complexes originally reported [36] are essentially... 

The approach we have introduced is based on the chemistry that Cleland and co-workers have described for the preparation of Co(III) substitution inert complexes of nucleoside di- and triphosphates (Cornelius et ai, 1977). For example, when dADP is reacted with Co(NH3)4(H20)2, a diastereo-meric mixture of o ,y -substitution inert complexes is formed because the reaction involves complex formation with the diastereotopic oc-phosphoryl oxygens of the nucleotide this reaction is illustrated in Fig. 10 using the diastereomers of [a- 0, 0]dADP as the nucleotide reactants. The complexes formed from dADP (and ADP) can be separated by chromatography... 

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