Comparison of Nonheme Manganese- and Iron-Containing Flavone Synthase Mimics

Abstract

Heme and nonheme-type flavone synthase enzymes, FS I and FS II are responsible for the synthesis of flavones, which play an important role in various biological processes, and have a wide range of biomedicinal properties including antitumor, antimalarial, and antioxidant activities. To get more insight into the mechanism of this curious enzyme reaction, nonheme structural and functional models were carried out by the use of mononuclear iron, [Fe^II(CDA-BPA*)]²⁺ (6) [CDA-BPA = N,N,N',N'-tetrakis-(2-pyridylmethyl)-cyclohexanediamine], [Fe^II(CDA-BQA*)]²⁺ (5) [CDA-BQA = N,N,N',N'-tetrakis-(2-quinolilmethyl)-cyclohexanediamine], [Fe^II(Bn-TPEN)(CH₃CN)]²⁺ (3) [Bn-TPEN = N-benzyl-N,N',N'-tris(2-pyridylmethyl)-1,2-diaminoethane], [Fe^IV(O)(Bn-TPEN)]²⁺ (9), and manganese, [Mn^II(N4Py*)(CH₃CN)]²⁺ (2) [N4Py* = N,N-bis(2-pyridylmethyl)-1,2-di(2-pyridyl)ethylamine)], [Mn^II(Bn-TPEN)(CH₃CN)]²⁺ (4) complexes as catalysts, where the possible reactive intermediates, high-valent Fe^IV(O) and Mn^IV(O) are known and well characterised. The results of the catalytic and stoichiometric reactions showed that the ligand framework and the nature of the metal cofactor significantly influenced the reactivity of the catalyst and its intermediate. Comparing the reactions of [Fe^IV(O)(Bn-TPEN)]²⁺ (9) and [Mn^IV(O)(Bn-TPEN)]²⁺ (10) towards flavanone under the same conditions, a 3.5-fold difference in reaction rate was observed in favor of iron, and this value is three orders of magnitude higher than was observed for the previously published [Fe^IV(O)(N2Py2Q*)]²⁺ [N,N-bis(2-quinolylmethyl)-1,2-di(2-pyridyl)ethylamine] species.

Keywords: flavone synthase; iron(IV)-oxo; kinetic studies; manganese(IV)-oxo; oxidation.

Scheme 1

Oxidation of flavanone by heme and nonheme flavone synthases, FS I and FS II.

Scheme 2

Oxoiron(IV) and oxomanganese(IV) complexes with their iron(II) and manganese(II) precursor complexes were used in this study.

Figure 1

X-ray structure of Fe^II(±CDA-BQA*)](CF₃SO₃)₂ (5), showing a 30% probability of thermal ellipsoids.

Figure 2

Overlay of structures Fe^II(CDA-BQA*)](CF₃SO₃)₂ (5) (red) and [Fe^II(CDA-BPA*)](ClO₄)₂ (6) (blue) containing only (R,R)-enantiomers of the ligands.

Figure 3

Comparison of the flavones-synthase activity of iron(II) and manganese(II) complexes. Conditions: [M^II] = 5 mM, [FH₂] = 100 mM and [mCPBA] = 500 mM in CH₃CN at 25 °C.

Figure 4

(A) Comparison of the product formation in the [Mn^II(N4Py*)(CH₃CN)]²⁺ (2) catalysed oxidation of flavanone with mCPBA as co-oxidant and 2,6-DTBP as a radical trapping agent. (B) Comparison of the product formation in the presence of added water.

Figure 5

Dependence of the K/A ratio and the enantiomeric excess (ee%) on the oxidant concentration for the [Fe^II(CDA-BPA*)]²⁺ (6) catalysed oxidation of ethylbenzene with TBHP in CH₃CN at 0 °C.

Figure 6

(A) UV-Vis spectral changes of 9 (2 mM, red line) upon addition of flavanone (50 mM) in CH₃CN at 10 °C. The inset shows the time course of the decay of 9 monitored at 739 nm. (B) UV-Vis spectral changes of 11 (2 mM, red line) upon addition of flavanone (50 mM) in CH₃CN at 10 °C. The inset shows the time course of the decay of 11 monitored at 742 nm.

Figure 7

(A) Determination and comparison of second-order rate constants by plotting k_obs values against flavanone concentration for a series of M^IV(O) complexes in CH₃CN at 10 °C, [M]₀ = 2 mM. (B) Eyring plots of log k/T versus 1/T for 9 and 10, [9,10] = 2 mM, [FH₂] = 50 mM.

Figure 8

(A) Isokinetic plot and (B) plot of ΔG^‡ versus lnk₂ for the oxidation of flavanone with various oxomanganese(IV) and oxoiron(IV) complexes.

Figure 9

(A) UV-Vis spectral changes of 8 (2 mM, red line) upon addition of flavanone (1.8 M) in CH₃CN/TFE at 25 °C. The inset shows the time nd course of the decay of 8 monitored at 944 nm. (B) Determination and comparison of second-order rate constants by plotting k_obs values against flavanone concentration for complexes 7 and 8 in CH₃CN and CH₃CN/TFE at 25 °C, [M]₀ = 2 mM.

Scheme 3

Proposed mechanism for the C-H activation by oxoiron and oxomanganese complexes.