Catechol-based matrix metalloproteinase inhibitors with additional antioxidative activity

Figures & data

Figure 1. Catechol-based MMP inhibitors.

Figure 2. Catechol-based MMP inhibitors.

Table 1. MMP activity values expressed as IC₅₀ (μM) and antioxidant activity values expressed as EC₅₀ in DPPH assay and ARP.

Compounds	n	R	R^1	MMP-2	MMP-8	MMP-9	EC50^a	ARP^b
Gallic acid							0.065 ± 0.012	15.4
1	0	H	H	>100	>100	>100	0.130 ± 0.041	7.7
2	0	C6H5	H	34 ± 6	>100	>100	0.163 ± 0.012	6.1
3	1	C6H5	H	4.0 ± 1.4	25 ± 4	56 ± 8	0.099 ± 0.009	10.1
4	1	C6H5	CH3	>100	>100	>100	0.112 ± 0.021	8.9
5	0	C6H5O	H	6.6 ± 1.2	26 ± 5	33 ± 5	0.104 ± 0.044	9.6
6	1	C6H5O	H	4.2 ± 0.9	94 ± 4	95 ± 5	0.119 ± 0.009	8.4
7	0	CH3O	H	12 ± 4	16 ± 3	19 ± 3	0.128 ± 0.013	7.8
8	0	C6H5	H	12 ± 3	8.7 ± 2.0	6.2 ± 0.4	0.101 ± 0.001	9.9
9	0	C6H5O	H	6.3 ± 2.3	6.2 ± 1.5	6.5 ± 2.0	0.112 ± 0.012	8.9
10	0	C6H5	CH3	9.5 ± 2.5	>100	>100	0.133 ± 0.023	7.5
11	0	C6H5O	CH3	17.5 ± 2.1	33.5 ± 0.7	29 ± 4	0.138 ± 0.004	7.2
12	1	C6H5	H	7 ± 2	2.5 ± 0.9	2.1 ± 1.0	0.166 ± 0.011	6.0
13	1	Br	H	4.4 ± 0.5	1.9 ± 0.4	2.0 ± 0.5	0.172 ± 0.025	5.8
14	0	C6H5	H	7.0 ± 0.2	3.1 ± 1.1	2.7 ± 0.8	0.143 ± 0.020	7.0
15	0	Br	H	5.6 ± 1.5	6 ± 2	5.5 ± 2.0	0.192 ± 0.042	5.2
16	1	C6H5	H	12 ± 2	6 ± 1	7.5 ± 1.5	0.167 ± 0.023	6.0
17	1	Br	H	10 ± 1	4.4 ± 0.3	2.5 ± 0.1	0.188 ± 0.002	5.3

^aμmol of antioxidant/μmol of DPPH. ^bAntiradical power (ARP) = 1/EC₅₀.

Table 2. MMP activity values expressed as IC₅₀ (μM) and antioxidant activity values expressed as EC₅₀ in DPPH assay and ARP.

Compounds	n	R^1	R^2	R^3	MMP-2	MMP-8	MMP-9	EC50^a	ARP^b
18	0	H	H	H	>100	>100	>100	>1	<1
19	1	H	H	H	>100	>100	>100	>1	<1
20	0	H	H	OH	>100	>100	>100	0.37 ± 0.09	2.7
21	0	H	OH	H	>100	>100	>100	>1	<1
22	0	OH	H	H	>100	>100	>100	0.15 ± 0.03	6.6

^aμmole of antioxidant/μmol of DPPH. ^bAntiradical power (ARP) = 1/EC₅₀.

Scheme 1. Reagents and conditions: (a) anhydrous THF, r.t. or DMAP, DCC, CH₂Cl₂, r.t.; (b) dry DMF, NaH, CH₃I, 0 °C; (c) H₂, 10% Pd-C, CH₃OH/THF 2:5, r.t.

Figure 3. Hydrogen bond network of the catechol form (A) and the oxidized quinone form (B) of 14 (distances in Å).

Figure 4. Pharmacophore model on the reference structure 15.

Figure 5. QSAR models for MMP-8 (A), MMP-9 (B), and MMP-2 (C) (test set + training set molecules).

Figure 6. (A) MMP-8:14 X-ray complex (IC₅₀: 3.1 μM, predicted total energy −395 kJ/mol), (B) MMP-2:14 modeled complex (IC₅₀: 7.0 μM, predicted total energy −379 kJ/mol), and (C) MMP-9:14 modeled complex (IC₅₀: 2.7 μM, predicted total energy −405 kJ/mol). The ligand is represented as sticks and the water molecules as spheres. The network of water molecules is depicted with H-bonds reported as dashed lines and water clusters are encircled.

Figure 7. ROC curves (A) MMP-8:14 – AUC: 0.855. (B) MMP-2:14 – AUC: 0.790. (C) MMP-9:14 – AUC: 0.829.

Scheme 2. Reagents and conditions: (a) Et₃N, CH₂Cl₂, reflux; (b) dry DMF, NaH, CH₃I, 0 °C; (c) THF/MeOH, 10% Pd/C, H₂, r.t. or BBr₃, CH₂Cl₂, 0 °C 1 h.

Scheme 3. Reagents and conditions: (a) Et₃N, CH₂Cl₂, reflux.

Scheme 4. Reagents and conditions: (a) Et₃N, CH₂Cl₂, reflux; (b) BBr₃, CH₂Cl₂, 0 °C 1 h.