Paramagnetic moieties

The noncovalent approach is based on the use of complexes containing suitable moieties which are able to recognize specific proteins, primarily human serum albumin (HSA). When the targeting protein is confined in the blood, the adduct between the serum albumin and the functionalized complex may function as a blood pool agent. Due to the reversible nature of binding between the protein and the paramagnetic chelate, these adducts maintain excretory pathways typical of small complexes which, from the pharmacological point of view, favors them over covalently bound macromolecules. 

The one-electron oxidation of enol silyl ether donor (as described above) generates a paramagnetic cation radical of greatly enhanced homolytic and electrophilic reactivity. It is the unique dual reactivity of enol silyl ether cation radicals that provides the rich chemistry exploitable for organic synthesis. For example, Snider and coworkers42 showed the facile homolytic capture of the cation radical moiety by a tethered olefinic group in a citronellal derivative to a novel multicyclic derivative from an acyclic precursor (Scheme 8). 

The donor is covalently linked to the paramagnetic moiety and then stronger interactions are expected between the organic centered radicals and the paramagnetic centers. Of course, this statement is true only if the functionalized donors are fully conjugated, or, in other words, if the TTF radicals spread over the chelating site(s). 

Radicals have been known for many years to form organic paramagnetic materials with numerous magnetic properties (ferro- or ferri-magnetism, spin Peierls transition, spin frustration, spin ladder systems) (see [51-60] for verdazyl radicals, [61-68] for thiazyl radicals, [69] for nitronyl nitroxide and [70-78] for Tempo radicals) (Fig. 6). When they are in their cationic form, they are valuable candidates for an association with the M(dmit)2 systems they will then provide the magnetic properties thanks to their free electron(s), whereas the M(dmit)2 moieties will provide the electrical properties. 

Electron paramagnetic resonance (EPR) yields the location of unpaired electron density from hyperfine splitting by metals or atoms with nuclear spin.21 The S = 0 Fe(III)—O 2 state of oxy-Mb or Hb would be indicated by the absence of an EPR signal, although other results such as the IR or resonance Raman absorption of the O2 moiety would be needed for positive confirmation. 

One of the earliest reports of LO inhibition concerned the effects of ortho-dihydroxybenzene (catechol) derivatives on soybean 15-LO [58]. Lipophilic catechols, notably nordihydroguaiaretic acid (NDGA) (19), were more potent (10 /zM) than pyrocatechol itself. The inactivation was, under some conditions, irreversible, and was accompanied by oxidation of the phenolic compound. The orfAo-dihydroxyphenyl moiety was required for the best potency, and potency also correlated with overall lipophilicity of the inhibitor [61]. NDGA and other phenolic compounds have been shown by electron paramagnetic resonance spectroscopy to reduce the active-site iron from Fe(III) to Fe(II) [62] one-electron oxidation of the phenols occurs to yield detectable free radicals [63]. Electron-poor, less easily oxidized catechols form stable complexes with the active-site iron atom [64]. 

Scheme 8.15 compels attention to the following features of the resulting species Complexation of the cation-radical with parent neutral counterparts enhances mobility of an unpaired electron. Introduction of selenium (heavier and bulkier atom) increases the overlap among donor planes due to the better chalcogen-chalcogen intermolecular contacts. The presence of the paramagnetic nitroxyl moiety is decisive for magnetism of the product. 

The latter point is rather critical. In fact, whereas long xr values can be easily attained through a proper choice of the macromolecular system and the binding modality, it may not be an easy task to keep the relaxometric properties of the paramagnetic moiety unaltered, upon formation of the macromolecular adduct. In fact, this may result in a reduced hydration of the Gd(III) ion as donor groups such as aspartate or glutamate on the surface of a protein can replace coordinated water molecules (103 104). When the hydration state is maintained, the occurrence of a marked reduction of the exchange rate of inner-sphere water is very common (see next Section). 

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