The coordination of imidazole and substituted pyridines by the hemeoctapeptide N-acetyl-ferromicroperoxidase-8 (FeIINAcMP8)

“…histidine. Nevertheless pyridine is generally considered to be a better ligand of ferrous heme iron 40, 41 , the active form of IDO, than imidazole, which is a considered a stronger ligand for ferric heme iron 16 . However, none of the compounds containing pyridine demonstrated activity better than 4-PI.…”

Section: Resultsmentioning

confidence: 99%

Structure Based Development of Phenylimidazole-Derived Inhibitors of Indoleamine 2,3-Dioxygenase

et al. 2008

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Indoleamine 2,3-dioxygenase (IDO) is emerging as an important new therapeutic target for the treatment of cancer, chronic viral infections, and other diseases characterized by pathological immune suppression. With the goal of developing more potent IDO inhibitors, a systematic study of 4-phenyl-imidazole (4-PI) derivatives was undertaken. Computational docking experiments guided design and synthesis efforts with analogs of 4-PI. In particular, three interactions of 4-PI analogs with IDO were studied: the active site entrance, the interior of the active site and the heme iron binding. The three most potent inhibitors (1, 17 and 18) appear to exploit interactions with C129 and S167 in the interior of the active site. All three inhibitors are approximately ten-fold more potent than 4-PI. The study represents the first example of enzyme inhibitor development with the recently reported crystal structure of IDO and offers important lessons in the search for more potent inhibitors.

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“…[61] The effect of differing trans bond distances is likely the difference that imidazoles are modest π-electron-donors compared to the modest π-accepting character of pyridine. [62,63] Clearly, one can expect that the cyanide and pyridine will compete for the same iron π density whereas the imidazole can π-donate and hence form a stronger bond.…”

Section: Discussionmentioning

confidence: 99%

New Insights on the Electronic and Molecular Structure of Cyanide-Ligated Iron(III) Porphyrinates

Noll

Schulz

et al. 2007

Inorg. Chem.

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The preparation and characterization of several new cyanoligated six-coordinate low-spin iron(III) porphyrinates are reported. The synthesis and structure of the new bis(cyanide) derivative K(222)] [Fe(TMP)(CN) 2 ] (TMP= tetramesitylporphyrinate) is described. Three mixed-ligand species of the general form [Fe(Porph)(CN)(L)], where L = 1-methylimidazole or pyridine, have also been prepared and structurally characterized. All complexes have been studied with EPR spectroscopy in frozen solution and in microcrystalline form. In some cases, especially those of the bis(cyanide) derivative above and the previously reported [Fe(TPP)(CN) 2 ] − , there are significant differences in the EPR spectra as a result of the state change. These spectral differences can be correlated with changes in the electron configuration that are the likely result of a differing environment of the coordinated cyanide ligands; core conformation and electronic structure of the porphyrin ligand are unlikely to play a role. All four new complexes and [Fe(TPP)(CN) 2 ] − have been studied by Mössbauer spectroscopy with variable temperature and applied magnetic field measurements. The sign of the quadrupole splitting value has been established as negative. These measurements have allowed us to give estimates of the energy difference between the two close-lying d π (d xz and d yz ) orbitals. These splitting values range from ∼267 cm −1 for [Fe(TPP)(CN) 2 ] − to ∼614 cm −1 for [Fe(TPP)(CN)(Py)].

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The coordination of imidazole and substituted pyridines by the hemeoctapeptide N-acetyl-ferromicroperoxidase-8 (FeIINAcMP8)

Cited by 26 publications

References 74 publications

Probing the nature of the Co(III) ion in cobalamins: The reactions of aquacobalamin (vitamin B12a), aqua-10-chlorocobalamin and aqua-10-bromocobalamin with anionic and neutral ligands

Probing the nature of the Co(III) ion in cobalamins: The reactions of aquacobalamin (vitamin B12a), aqua-10-chlorocobalamin and aqua-10-bromocobalamin with anionic and neutral ligands

Structure Based Development of Phenylimidazole-Derived Inhibitors of Indoleamine 2,3-Dioxygenase

New Insights on the Electronic and Molecular Structure of Cyanide-Ligated Iron(III) Porphyrinates

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