Synthesis and Properties of the Cytochrome P-450 Enzyme Model Compounds

Author:Wang Hai Zuo

Supervisor:wei xue hong li jian feng


Degree Year:2019





Cytochrome P-450 enzymes(P450)are b-type heme-containing monooxygenases.These enzymes are involved in a number of metabolic processes,such as steroid biosynthesis and metabolism of xenobiotics in mammals.In this paper,a series of model compounds are prepared,isolated and investigated to promote the understanding on the physiological and biochemical processes of P450.Specific research works are as follows:1.A mononuclear ferric porphyrin peroxide model compound [Fe(OEP)(O2)][Me4N] was synthesized and characterized by single crystal Xray,Fourier infrared absorption spectrum(IR),electron paramagnetic resonance(EPR)and ultraviolet visible spectrum(UV-vis).In the compound,the peroxo ligand(O22–)is coordinated to the iron in a side-on fashion and nearly eclipses the N1–Fe–N3 bonds.The Fe atom dramatically displaces from 24-atom mean plane to the ligand(0.68 ?)and the compound shows a strong Dom porphyrin core.EPR studies has confirmed the S = 5/2 high spin state.2.A variety of bis-imidazole iron porphyrin compounds,[Fe(TFPP)(1-Me Im)2],[Fe(TFPP)(1-Vinyl Im)2],[Fe(TFPP)(4-Me HIm)2]Cl and [Fe(TFPP)(1-Et Im)2]BF4,were synthesized and characterized by UV-vis and single crystal X-ray.UV-vis titration suggested that [Fe(TFPP)Cl] can be reduced to ferrous bis-imidazole product with the addition of 1-methyl imidazole.The bis-imidazole ferrous porphyrin compounds,[FeII(Por)(Im)2](Im = 1-Me Im or 4-Me HIm),showed a negative correlation between the axial Fe–NIm distance and φ angle(the dihedral angle between the axial ligand’s mean plane and the closest Nax–Fe–Np plane)that the smaller φ angle correspond to a longer Fe–NIm distance.The negative correlation demonstrated that nonbonded interactions between the imidazole and porphyrin plane have stretched the axial Fe–NIm distances.In addition,studies on crystal structures of bis-(hindered imidazole)analogues,suggested that the steric hindrance can induce strong porphyrin distortion or even isomerization.3.Two six-coordination ferrous porphyrin carbene compounds,[Fe(TFPP)(CPh2)(1-Et Im)] and [Fe(TFPP)(CPh2)(1,2-Me2Im)],have been characterized by single crystal X-ray and M?ssbauer.The crystal structure studies have revealed several noteworthy features including shorter Fe–C bonds(1.810(4)~1.843(4)?),larger iron displacements(0.07~0.16 ?)toward carbene ligand and longer Fe–NIm bonds(2.134(3)~2.231(3)?).The M?ssbauer spectra suggested that the bonding of trans imidazole ligands only induced small decreases on ΔEQ(~0.5 mm/s)than the [Fe(TFPP)(CPh2)] precursor.These features are well consistent with the stronger π bonding of CPh2 carbene.We also isolated the ferric porphyrin carbene compound,[Fe(TFPP)(CPh2)(NO)][BF4],which has been characterized by IR,single crystal X-ray and EPR spectra.It is seen that Fe and the pyrrole nitrogen N3 atoms are bridged by the carbene carbon(C23),and the Fe appears sixcoordinated.EPR has suggested a high spin state(S = 5/2)for the compound.Interestingly,a six-coordinate [FeIII(TFPP)(THF)2][BF4] with slightly saddled porphyrin conformation(C24 = 0.15 ?)was isolated when [Fe(TFPP)(CPh2)(NO)][BF4] was dissolved in THF solution.The crystal structure and electron spectroscopic investigations on the model compounds have deepened our understanding on the P450 intermediates and reaction mechanisms it catalyzes.