Macrocycles modulators

One of the structures present in many enzymes is the corrinoid structure. It consists of a tetrapyrrolic macrocycle, where a direct link between two pyrrole rings exists. Such a direct link and the different degrees of unsaturation that can be introduced into the macrocycle modulate its chelating properties towards metal ions and its reactivity. 

Macrocyclic modulators of the p-opioid reeeptor inelude cyclic p-casomor-phin- and enkephalin- analogs as well as so ealled atypical cyclic peptides derived from endomorphin-1. 

Meso substitution of porphyrines to give tetraazaporphyrines, so-called porphyrazines, modulates the electronic character of the macrocycle. While porphyrazines have received considerably less attention than porphyrines over many years, this has changed due to the development of efficient syntheses of soluble derivatives.1 6-1809 Also, various porphyrazines (and phtalocyanines) with peripheral groups for metal ion coordination have been prepared and used for the construction of multimetallic complexes.1806 Ni porphyrazines (695) typically show absorptions spectra with a strong Q band at around 615nm. 

As with any metalloprotein, the chemical and physical properties of the metal ion in cytochromes are determined by the both the primary and secondary coordination spheres (58-60). The primary coordination sphere has two components, the heme macrocycle and the axial ligands, which directly affect the bound metal ion. The pyrrole nitrogen donors of the heme macrocycle that are influenced by the substitutents on the heme periphery establish the base heme properties. These properties are directly modulated by the number and type of axial ligands derived from the protein amino acids. Typical heme proteins utilize histidine, methionine, tyrosinate, and cysteinate ligands to affect five or six coordination at the metal center. 

Nitrenium ions have been applied to the synthesis of macrocycles and other medicinally interesting compounds. The most successful reactions have been in cases where the nitrenium ion is covalently tethered to its intended target. Further efforts aimed at modulating the selectivity of these intermediates would increase their synthetic utility. 

Despite the similarities existing among natural tetrapyrrolic macrocycles, e.g. they are all tetradentate equatorial N4 ligands, structural variations cause a fine modulation of the reactivity of the central metal atom. Thus it is most probably the corrin skeleton that enables the cobalt atom of vitamin B12 to carry out reactions impossible for a similar cobalt porphyrinate. 

In the case of porphyrins different substitution patterns induce relevant electronic variations the energy level of the two HOMOs of the porphyrin n system (a/u and a2u) are in fact reversed in going from a meso-substituted porphyrin, such as tetraphenylporphyrin, to a -substituted one, such as octaethylporphyrin [44]. Electronic variations may also derive from conformational changes Smith and coworkers have reported hybrid compounds substituted both at meso and P positions, the Zn2+ complexes of 2,3,7,8,12,13,17,18-octaethyl- and 2,3,7,8,12,13,17,18-octamethyl-5,10,15,20-tetraphenylporphyrin [46] (see Sect. 3.3). These complexes have a nonplanar conformation caused by the steric interactions of the substituents. Theoretical calculations indicate that such conformational changes cause a differential shift in the energies of the HOMO and LUMO and so modulate the electronic structure of the macrocycles. 

Lowe, M. P., Parker, D., Reany, O., Aime, S., Botta, M., Castellano, G., Gianolio, E., Pagliarin, R. pH-dependent modulation of relaxivity and luminescence in macrocyclic gadolinium and europium complexes based on reversible intramolecular sulfonamide ligation, J. Am. Chem. Soc. 123 (2001), 7601... 

This reaction was followed by a second slower reaction that was not characterized in the report. An analysis of the overall results showed that the influence of steric or electrostatic effects on kinetic parameters is not necessarily minor. The dynamics of binding of NO to the diaqua species is mainly tuned by modulation of electron density on the iron center by the porphyrin macrocycle. A volume profile for NO binding based on values ofAV on and A V 0ff of + 1.5 and + 9.3 cm3/mol, respectively, maybe interpreted as an interchange mechanism for the on reaction, as the Fenl-H20 bond is decidedly stabilized (see Figure 7.15a). The volume of activation for the off reaction indicates a less dissociative mode of activation compared with NO release from other porphyrins. 

Photochemical host-guest systems on the basis of photoswitchable macrocycles have also been investigated most recently in a number of publications. Schafer et al.23 and Anselmetti et al.24 modified a bifunctional resorcin[4]arene with two anthracene units and proved its switching function in photochemical induction and heating cycles. Moreover, they modified the lower rim of the resorcin[4]arene with four 10-(decylthio)decyl linkers for an oriented surface immobilization on gold via molecular self-assembly (Fig. 15.7). The affinity modulation of this optical switch was... 

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