A macrocyclic quinol-containing ligand enables high catalase activity even with a redox-inactive metal at the expense of the ability to mimic superoxide dismutase

Previously, we found that linear quinol-containing ligands could allow manganese complexes to act as functional mimics of superoxide dismutase (SOD). The redox activity of the quinol enables even Zn(ii) complexes with these ligands to catalyze superoxide degradation. As we were investigating the abilities of manganese and iron complexes with 1,8-bis(2,5-dihydroxybenzyl)-1,4,8,11-tetraazacyclotetradecane (H4qp4) to act as redox-responsive contrast agents for magnetic resonance imaging (MRI), we found evidence that they could also catalyze the dismutation of H2O2. Here, we investigate the antioxidant behavior of Mn(ii), Fe(ii), and Zn(ii) complexes with H4qp4. Although the H4qp4 complexes are relatively poor mimetics of SOD, with only the manganese complex displaying above-baseline catalysis, all three display extremely potent catalase activity. The ability of the Zn(ii) complex to catalyze the degradation of H2O2 demonstrates that the use of a redox-active ligand can enable redox-inactive metals to catalyze the decomposition of reactive oxygen species (ROS) besides superoxide. The results also demonstrate that the ligand framework can tune antioxidant activity towards specific ROS.


A
b Metal complex pK a values:  Table S3.Parameters for the Michaelis-Menten models that were fitted to the oxygraphy data displayed in Figure 3.  , where [M] is the concentration of the tested H 4 qp4 complex.The v o corresponds to the decomposition of H 2 O 2 , which was measured through UV/vis.All reactions were performed in 25 °C 200 mM phosphate buffered to pH 7.0.100 nM of each coordination complex was present as a catalyst.Five data points were taken for each shown data point.A) Data for 1. k cat = 9.8 × 10 3 s -1 , k on = 1.3 × 10 6 M -1 s -1 .B) Data for 2. k cat = 2.8 × 10 4 s -1 , k on = 5.5 × 10 5 M -1 s -1 .C) Data for 3. k cat = 4.5 × 10 3 s -1 , k on = 2.0 × 10 5 M -1 s -1 .
Table S4.Parameters for the Michaelis-Menten models that were fitted to the UV/vis data displayed in Figure S13.

Figure S2 .
Figure S2.IR spectrum of 3. The 3404 cm -1 feature is assigned to the O-H stretches associated with the quinol groups of the H 3 qp4 -ligand.

Figure S5 .
Figure S5.UV/vis data for a 0.10 mM solution of 3 in 294 K water.The major band at 299 nm ( = 7000 M -1 cm -1 ) is attributed to an intraligand transition associated with the quinol.

Figure S6 .
Figure S6.Cyclic voltammogram of 1.0 mM 3 in aqueous phosphate solution buffered to pH 7.2.An irreversible feature is observed with E pa = 225 mV vs. Ag/AgCl and E pc = -10 mV vs. Ag/AgCl.Another feature with E pc = 5 mV vs. Ag/AgCl may be attributable to the acid/base behavior of either the quinol or the semiquinone oxidation product.The scan rate was 100 mV s -1 , and the scan commenced at -1.0 V.

Figure S11 .
Figure S11.Mass spectrometry (ESI) of the reaction between 20 equiv.KO 2 and 3 in water at RT.The sample was analyzed 15 min after the beginning of the reaction.The 505.2291 m/z feature is assigned to the Zn(II) complex with the singly deprotonated form of the monoquinolate/monopara-quinone H 2 qp4 ligand: [Zn(Hqp4)] + (calculated m/z = 505.1866).The appearance of many other peaks is consistent with the degradation of the complex.

a 1 )Figure S13 .
Figure S13.Plots of v o /[M] vs. the concentration of H 2 O 2, where [M] is the concentration of the tested H 4 qp4 complex.The v o corresponds to the decomposition of H 2 O 2 , which was measured through UV/vis.All reactions were performed in 25 °C 200 mM phosphate buffered to pH 7.0.100 nM of each coordination complex was present as a catalyst.Five data points were taken for each shown data point.A) Data for 1. k cat = 9.8 × 10 3 s -1 , k on = 1.3 × 10 6 M -1 s -1 .B) Data for 2. k cat = 2.8 × 10 4 s -1 , k on = 5.5 × 10 5 M -1 s -1 .C) Data for 3. k cat = 4.5 × 10 3 s -1 , k on = 2.0 × 10 5 M -1 s -1 .

1 )Figure S14 .
Figure S14.Peroxidase activity for complexes 1 and 2 as assessed by their ability to catalyze the reaction between H 2 O 2 and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonate) (ABTS).Each v o corresponds to the initial rate of formation of ABTS .+, as measured through UV/vis.All reactions were run in RT 50 mM acetate solution buffered to pH 5.0 with 0.10 mM of the tested catalyst.All kinetic runs were performed in triplicate.A) Plot of v o /[M] vs. the concentration of H 2 O 2 , where [M] is the concentration of 1. 10 mM ABTS was initially present.B) Plot of v o /[M] vs. the concentration of H 2 O 2 , where [M] is the concentration of 2. 10 mM ABTS was initially present.C) Plot of v o vs. the concentration of [ABTS] for 1. 10 mM H 2 O 2 was initially present.The k 3 rate constant was determined from the slope of the plot.D) Plot of v o vs. the concentration of [ABTS] for 2. 10 mM H 2 O 2 was initially present.The k 3 rate constant was determined from the slope of the plot.

Figure S17 .
Figure S17.Mass spectrometry (ESI) of the reaction between 10 mM H 2 O 2 and 1 in MeCN at RT.The sample was analyzed 30 s after the beginning of the reaction.The 497.1944 m/z feature is assigned to the Mn(III) complex with the doubly protonated H 4 qp4 ligand, H 2 qp4 2-: [Mn III (H 2 qp4)] + (calculated m/z = 497.1955).

Figure S18 .
Figure S18.Mass spectrometry (ESI) of the reaction between 10 mM H 2 O 2 and 2 in MeCN at RT.The sample was analyzed 30 s after the beginning of the reaction.The 498.1912 m/z feature is assigned to the Fe(III) complex with the doubly protonated form of the H 4 qp4 ligand, H 2 qp4 2-: [Fe III (H 2 qp4)] + (calculated m/z = 498.1929).

Figure S19 .
Figure S19.Mass spectrometry (ESI) of the reaction between 10 mM H 2 O 2 and 3 in MeCN at RT.The sample was analyzed 30 s after the beginning of the reaction.The 505.1789 m/z feature is assigned to the Zn(II) complex with the singly deprotonated form of the monoquinolate/monopara-quinone H 2 qp4 ligand: [Zn(Hqp4)] + (calculated m/z = 505.1794).The 507.1942 m/z feature is assigned to the Zn(II) with the singly deprotonated form of the diquinol H 4 qp4 ligand: [Zn II (H 3 qp4)] + (calculated m/z = 507.1951).

Figure S20 .
Figure S20.Expansion of the data in Figure S19, showing the new feature with m/z = 539.1395,which is consistent with the addition of two O atoms to [Zn(H 3 qp4)] + .The m/z may be consistent with [Zn II (H 2 qp4)(OOH)] + , where H 2 qp4 is the monoquinol/mono-para-quinone form of the ligand (calculated m/z = 539.1848).

Figure S21 .
Figure S21.Mass spectrometry (ESI) of the reaction between 10 mM H 2 O 2 and 3 in MeCN at RT.The data were acquired 60 s after the beginning of the reaction.Oxygenated products become more prominent.

Figure S22 .
Figure S22.Mass spectrometry (ESI) of the reaction between 300 equivalents of H 2 O 2 and 1 in water at RT.The sample was analyzed 60 min after the beginning of the reaction.The 496.1888 m/z feature is assigned to the Mn(II) complex with the singly deprotonated form of the monoquinolate/mono-para-quinone H 2 qp4 ligand: [Mn II (Hqp4)] + (calculated m/z = 496.1882).The 512.1841 m/z peak is assigned to the Mn(II) complex with the singly deprotonated and singly oxygenated form of the mono-quinolate/mono-para-quinone form of the ligand: [Mn II (Hqp4+O)] + (calculated m/z = 512.1832).The 375.1570 m/z feature is assigned to the Mn(II) complex with a mono-quinone ligand missing the other 2,5-dihydroxybenzyl group: [Mn II (H 2 qp4-C 7 H 7 O 2 +H) (calculated m/z =375.1593).

Figure S23 .
Figure S23.Mass spectrometry (ESI) of the reaction between 300 equivalents of H 2 O 2 and 2 in water at RT.The sample was analyzed 60 min after the beginning of the reaction.The 497.1948 m/z feature is assigned to the Fe(III) complex with the singly deprotonated form of the monoquinolate/monopara-quinone H 2 qp4 ligand: [Fe(Hqp4)] + (calculated m/z = 497.1851).New prominent m/z peaks are seen at 362.9261, 430.9135, and 566.8880.

Table S2 .
Parameters for the Hyperquad model for the potentiometric pH titration data.
a Ligand log(β) and derived pK a values from reference 1: