The effect of axial ligands on the reactivity and stability of the oxoferryl moiety in model complexes of Compound I of heme-dependent enzymes

1996 ◽  
Vol 1 (4) ◽  
pp. 368-371 ◽  
Author(s):  
Z. Gross
Keyword(s):  
Compound I ◽  
Model Complexes ◽  
Axial Ligands

Proximal ligand effects on electronic structure and spectra of compound I of peroxidases

2001 ◽  
Vol 05 (03) ◽  
pp. 334-344 ◽  
Author(s):  
DANNI L. HARRIS ◽  
GILDA H. LOEW
Keyword(s):  
Electronic Structure ◽  
Density Functional ◽  
Axial Ligand ◽  
Compound I ◽  
Imidazole Ligand ◽  
Axial Ligands ◽  
Transient Spectra ◽  
Main Determinants ◽  
And Function ◽  
Optimized Geometries

Computational studies exploring the extent to which differences in proximal axial ligands modulate structure, spectra, and function of peroxidases have been performed. To this end, three heme models of compound I were characterized differing only in the axial ligand. The axial ligands considered were L = ImH , Im -, that are alternative protonation models for a typical peroxidase with an imidazole ligand such as horseradish peroxidase (HRP-I), and L = SCH - that is a model for an unsual peroxidase, chloroperoxidase (CPO-I). Density functional calculations (DFTs) were performed to determine the optimized geometries and electronic structure of each of these three species. Their electronic spectra were also calculated at the DFT optimized geometries, using the INDO/S/CI method. The results of these studies led to the following conclusions: (1) the presence of the nearby Asp in a typical peroxidase does indeed decrease the energy required to deprotonate the imidazole making the two forms essentially degenerate, (2) neither the state of protonation of the imidazole ligand nor the change in axial ligand from an imidazole in typical peroxidases such as HRP to a mercaptide in CPO significantly alters the characteristics of the lowest energy spin state or the electronic structure of compound I in a way that can obviously affect function, (3) both the Im - and ImH forms of the peroxidase compound I (HRP-I) lead to the same dramatic reduction in intensity relative to the ferric resting form observed experimentally. However, only in the ImH form of HRP-I does the calculated relative shift of one component of the Soret bands relative to CPO-I agree with that observed in the transient spectra of HRP-I compared to CPO-I. These results taken together strongly indicate that factors other than the nature of the proximal axial ligand are the main determinants of function.

Methane Hydroxylation by Axially Ligated Iron (IV)-oxo Porphyrin Cation Radical Models

2016 ◽  
Vol 1 (2) ◽  
Author(s):  
Devendra Singh ◽  
Devesh Kumar ◽  
Sam P. de Visser
Keyword(s):  
Hydrogen Atom ◽  
Cytochromes P450 ◽  
Cation Radical ◽  
Axial Ligand ◽  
Hydrogen Atom Abstraction ◽  
Energy Splitting ◽  
Compound I ◽  
Model Complexes ◽  
Mononuclear Iron ◽  
Porphyrin Cation

Methane hydroxylation is a thermochemically difficult process due to the strength of the C-H bond that needs to be broken in the process. In Nature only the methane monoxygenases have a catalytic center that is active enough to perform this task. Other metalloenzymes, such as, mononuclear iron monoxygenases and dioxygenases, including the cytochromes P450, are not known to catalyze methane hydroxylation. The cytochromes P450 contain an iron heme group that in a catalytic cycle is converted into an iron(IV)-oxo heme cation radical (Compound I). To gain insight into the features that affect methane hydroxylation by Compound I and synthetic model complexes, we have done a detailed computational study. Thus, we investigated the chemical properties of iron(IV)-oxo porphyrins with varying axial ligands, including SH<sup>−</sup>, F<sup>−</sup>, OH<sup>−</sup>, CN<sup>−</sup>, CF<sub>3</sub>COO<sup>−</sup> and CH<sub>3</sub>COO<sup>−</sup>. In addition, we calculated the methane hydroxylation pathways for a selection of these oxidants and rationalize the obtained trends with thermochemical cycles and valence bond schemes. In general, the rate determining hydrogen atom abstraction barrier is dependent on the π<sub>xz</sub>/π*<sub>xz</sub> energy splitting along the Fe−O bond, the excitation energy from π<sub>xz</sub> to a<sub>2u</sub>, as well as the bond dissociation energies of the methane C−H bond and the newly formed O−H bond. Our studies predict that iron(IV)-oxo porphyrin cation radical models with hydroxide as axial ligand should be efficient oxidants of substrate hydroxylation reactions and able to activate methane at room temperature. However, changing the axial ligand to a weaker electron donating group decreases its activity and raises the hydrogen atom abstraction barriers dramatically. These studies show that subtle modifications to the oxidant can have a great impact on the catalytic ability of the active center.

Activation of cytochrome c to a peroxidase compound I-type intermediate by H2O2: relevance to redox signalling in apoptosis

2004 ◽  
Vol 71 ◽  
pp. 97-106 ◽  
Author(s):  
Mark Burkitt ◽  
Clare Jones ◽  
Andrew Lawrence ◽  
Peter Wardman
Keyword(s):  
Cytochrome C ◽  
Hydroxyl Radical ◽  
Redox Regulation ◽  
Chemotherapeutic Agents ◽  
Tyrosyl Radical ◽  
Compound I ◽  
Definitive Evidence ◽  
Enhanced Production ◽  
Physico Chemical

The release of cytochrome c from mitochondria during apoptosis results in the enhanced production of superoxide radicals, which are converted to H2O2 by Mn-superoxide dismutase. We have been concerned with the role of cytochrome c/H2O2 in the induction of oxidative stress during apoptosis. Our initial studies showed that cytochrome c is a potent catalyst of 2′,7′-dichlorofluorescin oxidation, thereby explaining the increased rate of production of the fluorophore 2′,7′-dichlorofluorescein in apoptotic cells. Although it has been speculated that the oxidizing species may be a ferryl-haem intermediate, no definitive evidence for the formation of such a species has been reported. Alternatively, it is possible that the hydroxyl radical may be generated, as seen in the reaction of certain iron chelates with H2O2. By examining the effects of radical scavengers on 2′,7′-dichlorofluorescin oxidation by cytochrome c/H2O2, together with complementary EPR studies, we have demonstrated that the hydroxyl radical is not generated. Our findings point, instead, to the formation of a peroxidase compound I species, with one oxidizing equivalent present as an oxo-ferryl haem intermediate and the other as the tyrosyl radical identified by Barr and colleagues [Barr, Gunther, Deterding, Tomer and Mason (1996) J. Biol. Chem. 271, 15498-15503]. Studies with spin traps indicated that the oxo-ferryl haem is the active oxidant. These findings provide a physico-chemical basis for the redox changes that occur during apoptosis. Excessive changes (possibly catalysed by cytochrome c) may have implications for the redox regulation of cell death, including the sensitivity of tumour cells to chemotherapeutic agents.

Structural Study of a new Compound Based on Acid 1,4-Cyclohexanedicarboxylic (1,4-CDC)

2010 ◽  
Vol 6 (1) ◽  
pp. 891-896
Author(s):  
Manel Halouani ◽  
M. Dammak ◽  
N. Audebrand ◽  
L. Ktari
Keyword(s):  
Aqueous Solution ◽  
Water Molecules ◽  
Carboxyl Group ◽  
X Ray Diffraction ◽  
Compound I ◽  
Unit Cell Parameters ◽  
Monoclinic System ◽  
X Ray ◽  
Cell Parameters ◽  
Cyclohexanedicarboxylic Acid

One nickel 1,4-cyclohexanedicarboxylate coordination polymers, Ni2 [(O10C6H4)(COO)2].2H2O  (I), was hydrothermally synthesized from an aqueous solution of Ni (NO3)2.6H2O, (1,4-CDC) (1,4-CDC = 1,4-cyclohexanedicarboxylic acid) and tetramethylammonium nitrate. Compound (I) crystallizes in the monoclinic system with the C2/m space group. The unit cell parameters are a = 20.1160 (16) Å, b = 9.9387 (10) Å, c = 6.3672 (6) Å, β = 97.007 (3) (°), V= 1263.5 (2) (Å3) and Dx= 1.751g/cm3. The refinement converged into R= 0.036 and RW = 0.092. The structure, determined by single crystal X-ray diffraction, consists of two nickel atoms Ni (1) and Ni (2). Lots of ways of which is surrounded by six oxygen atoms, a carboxyl group and two water molecules.

Synthesis and Characterization of New Zinc Phthalocyanine - Dodecenyl Succinic Anhydride Benzoic Groups

2020 ◽  
Vol 17 (6) ◽  
pp. 488-495
Author(s):  
Hussein Ali Al-Bahrani ◽  
Mohanad Mousa Kareem ◽  
Abdul Amir Kadhum ◽  
Nour A. Alrazzak
Keyword(s):  
Salicylic Acid ◽  
Succinic Anhydride ◽  
Zinc Phthalocyanine ◽  
Central Metal ◽  
Target Compound ◽  
Compound I ◽  
Metal Phthalocyanines ◽  
Metal Atoms ◽  
Amino Salicylic Acid

Background: The phthalocyanines a series of compounds involves four iso-indole units linked by aza nitrogen atoms bonded with metal atoms that are normally located in the center a phthalocyanines ring. Some of the central metal-phthalocyanines can be excited by ultraviolet light and emit a fluorescence in far-red region. Objective: To synthesize a derivative of phthalocyanines namely 4,4',4' '-tri-(dodecenyl succinic anhydride)- 4' ' '-(5-amino salicylic acid) zinc phthalocyanine with a zinc central metal. Materials and Methods: The reaction of 4- nitro Phthalonitrile and 4- amino Phthalonitrile with ZnCl2 in the presence of dimethyl amino ethanol afforded 4,4',4' '-triamino-4' ' '-nitro zinc phthalocyanine. This product reacted with 5-amino salicylic acid to yield tetra-(5-amino salicylic acid) zinc phthalocyanine. A dodecenyl succinic anhydride was added on the amine group of benzoic rings to afford 4,4',4' '-tri-(dodecenyl succinic anhydride)-4' ' '-(5-amino salicylic acid) zinc phthalocyanine(I), the target compound. Results and Discussion: Compound I is successfully synthesized with a yield of 72% from tetra-(5-amino salicylic acid) zinc phthalocyanine with dodecenyl succinic anhydride. Conclusion: The newly synthesized molecule of 4,4',4' '-tri-(dodecenyl succinic anhydride)-4' ' '-(5-amino salicylic acid) zinc phthalocyanine (I), tetra-(5-amino salicylic acid) zinc phthalocyanine(E) and 4,4',4' '- triamino-4' ' '-nitro zinc phthalocyanine (S). The reaction of 4- nitro Phthalonitrile and 4- amino and the structure of compound I is confirmed and its formation was proven.

Pyrrolizines as Potential Anticancer Agents: Design, Synthesis, Caspase-3 activation and Micronucleus (MN) Induction

2019 ◽  
Vol 18 (15) ◽  
pp. 2124-2130
Author(s):  
Amany Belal
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Anticancer Agents ◽  
Caspase 3 ◽  
Assay Method ◽  
Breast Adenocarcinoma ◽  
Compound I ◽  
Design Synthesis ◽  
Ic50 Values ◽  
New Compounds

Background: For further exploration of the promising pyrrolizine scaffold and in continuation of our previous work, that proved the potential anticancer activity of the hit compound I, a new series of pyrrolizines 2-5 and 7-9 were designed and synthesized. Methods: Structures of the new compounds were confirmed by IR, 1H-NMR, 13C-NMR and elemental analysis. Antitumor activity for the prepared compounds against human breast adenocarcinoma (MCF-7), liver (HEPG2) and colon (HCT116) cancer cell lines was evaluated using SRB assay method. Result: Compounds 2, 3 and 5 were the most potent on colon cancer cells, their IC50 values were less than 5 µM. Compounds 2, 3 and 8 were the most potent on liver cancer cells, their IC50 values were less than 10 µM. As for MCF7, compounds 2, 7, 8 and 9 were the most active with IC50 values less than 10 µM. We can conclude that combining pyrrolizine scaffold with urea gave abroad spectrum anticancer agent 2 against the three tested cell lines. Micronucleus assays showed that compounds 2, 3, 8 are mutagenic and can induce apoptosis. In addition, caspase-3 activation was evaluated and compound 2 showed increase in the level of caspase-3 (9 folds) followed by 3 (8.28 folds) then 8 (7.89 folds). Conclusion: The obtained results encourage considering these three compounds as novel anticancer prototypes.

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