Supporting Information

Supporting Information Structure-Activity and Structure-Property Relationship and Exploratory in vivo Evaluation of the Nanomolar Keap1-Nrf2 Protein-Protein Interaction Inhibitor Zheng-Yu Jiang, a,b Li-Li Xu, a,b Meng-Chen Lu, a,b Zhi-Yun Chen, a,b Zhen-Wei Yuan, a,b Xiao-Li Xu, a,b,c Xiao-Ke Guo, a,b,c Xiao-Jin Zhang, a,b,d Hao-Peng Sun, a,b,c* Qi-Dong You a,b* a State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China b Jiang Su Key Laboratory of Drug Design and ptimization, China Pharmaceutical University, Nanjing 210009, China c Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China d Department of rganic Chemistry, School of Science, China Pharmaceutical University, Nanjing 210009, China 1

Table of contents: S1. Characterization of the other intermediates. p3-p9 S2. Binding mode comparison of 8 and 15. p10 S3. Detailed results of the ligand efficiency (LE), ligand efficiency dependent lipophilicity (LELP) and lipophilic efficiency (LipE). p11-p12 S4. Body weight of mice during the experiment. p13 S5. The comparison of in vivo effects between 8 and 18e. p14 S6. Primers used for qrt-pcr. p15 2

S1. Characterization of the other intermediates N,N'-(1,4-phenylene)bis(4-methylbenzenesulfonamide) (10b) 10b was synthesized according to the procedure of 10a, light pink powder, yield 74%; m.p.: 256 258 C; 1 H-NMR (300 MHz, DMS, δ) 9.99 (s, 2H) 7.52 (d, 4H, J=8.22 Hz) 7.28 (d, 4H, J=8.10 Hz) 6.88 (s, 4H) 2.32 (s, 6H); HRMS (ESI): found 434.1223 (C 20 H 24 N 3 4 S 2, [M+NH 4 ] +, requires 434.1203). N,N'-(2-methyl-1,4-phenylene)bis(4-methoxybenzenesulfonamide) (10C): 10c was synthesized according to the procedure of 10a, gray solid, yield 86%; m.p.: 199-201 C; 1 H-NMR (300 MHz, DMS, δ) 10.08 (s, 1H), 9.23 (s, 1H), 7.65 (d, 2H, J=8.82 Hz), 7.46 (d, 2H, J=8.82 Hz), 7.07 6.99 (m, 4H), 6.80 6.79 (m,3h), 3.81 (s, 3H), 3.80(s, 3H), 1.83 (s,3h); HRMS (ESI): found 485.0801 (C 21 H 22 N 2 Na 6 S 2, [M+Na] +, requires 485.0811). N,N'-(2,5-dimethyl-1,4-phenylene)bis(4-methoxybenzenesulfonamide) (10d): 10d was synthesized according to the procedure of 10a, white solid, yield 82%; m.p.: 255-256 C; 1 H-NMR (300 MHz, DMS, δ) 9.29 (s, 2H), 7.52 (d, 4H, J=8.91 Hz), 7.04 (d, 4H, J=8.94), 6.72 (s, 2H), 3.81 (s, 6H), 1.77 (s, 6H); HRMS (ESI): found 499.0948 (C 22 H 24 N 2 Na 6 S 2, [M+Na] +, requires 499.0968). N,N'-(2-methoxy-1,4-phenylene)bis(4-methoxybenzenesulfonamide) (10e): To a solution of 2-Methoxy-4-nitroaniline (1.68 g, 10 mmol) in THF was added Pd/C. The reaction mixture was stirred under hydrogen for 4h. The solution was filtered to remove the catalyst. The filtrate was concentrated under reduced pressure to give the light yellow oil. The crude product, 2-Methoxyl-1, 4-diaminobenzene, was used without further purification, and the 10e was synthesized according to the procedure of 10a, light brown solid, yield 58%;.m.p.: 177-179 C; 1 H-NMR (300 MHz, DMS, δ) 10.07 (s, 1H) 9.13 (s, 1H) 7.66 (d, 2H, J=8.85 Hz), 7.50 (d, 2H, J=8.82 Hz), 7.06 6.96 (m, 5H), 6.58(s, 1H), 6.55(s, 1H), 3.80(s, 6H), 3.44 (s, 3H); HRMS (ESI): found 501.0734 (C 21 H 22 N 2 Na 7 S 2, [M+Na] +, requires 501.0761). Diethyl 2,2'-(1,4-phenylenebis(tosylazanediyl))diacetate (11b): 11b was synthesized according to the procedure of 11a, pink solid, yield 68%; m.p.:146-148 C; 1 H-NMR (300 MHz, DMS, δ) 7.49 (d, 4H, J=8.19 Hz) 7.36 (d, 4H, J=8.16 Hz) 7.11 (s, 4H), 4.48 (s, 4H), 4.06 (q, 4H, J=7.08 Hz), 2.40 (s, 6H), 1.11(t, 6H, J=7.08 Hz); HRMS (ESI): found 611.1511 (C 28 H 32 N 2 Na 8 S 2, [M+Na] +, requires 611.1492). 3

Dimethyl 2,2'-((2-methyl-1,4-phenylene)bis(((4-methoxyphenyl) sulfonyl)azanediyl))diacetate (11c): To a solution of 10c (924 mg, 2 mmol) in DMF (5ml) was added K 2 C 3 (830 mg, 6 mmol) followed by methyl bromoacetate (765 mg, 5 mmol). After 3h stirring at room temperature, the reaction mixture was then diluted in 30 ml water and quenched with 2 M hydrochloric acid to ph 5. The crude product was obtained through filtration. Recrystallization from ethyl acetate/ n-hexane give the 11c, gray solid, yield 74%; m.p.: 103-105 C; 1 H-NMR (300 MHz, DMS, δ) 7.56 (d, 2H, J=8.88 Hz) 7.51 (d, 2H, J=8.91 Hz), 7.09 7.05 (m, 5H), 6.82 6.79 (m, 2H), 4.47 (s, 2H), 4.32 (s, 2H), 3.86 (s, 6H), 3.61 (s, 3H), 3.57(s, 3H), 2.14(s, 3H); HRMS (ESI): found 629.1201 (C 27 H 30 N 2 Na 10 S 2, [M+Na] +, requires 629.1234). Dimethyl 2,2'-((2,5-dimethyl-1,4-phenylene)bis(((4-methoxyphenyl) sulfonyl)azanediyl))diacetate (11d): 11d was synthesized according to the procedure of 11c, gray solid, yield 77%; m.p.: 174-176 C; 1 H-NMR (300 MHz, DMS, δ) 8.43 8.31 (m, 1H), 8.14 8.07 (m, 1H), 7.55 7.46 (m, 4H), 7.07 6.99 (m, 4H), 5.04 4.88 (m, 4H), 3.87(s, 3H), 3.80 (s, 3H), 3.68 3.59 (m, 6H), 2.89 (s, 3H), 2.73 (s, 3H); HRMS (ESI): found 643.1368 (C 28 H 32 N 2 Na 10 S 2, [M+Na] +, requires 643.1391). Dimethyl 2,2'-((2-methoxy-1,4-phenylene)bis(((4-methoxyphenyl) sulfonyl)azanediyl))diacetate (11e): 11e was synthesized according to the procedure of 11c, gray solid, yield 58%; m.p.:83-85 C; 1 H NMR (300 MHz, DMS, δ) 7.61 (d, 2H, J=8.91Hz), 7.50 (d, 2H, J=8.91Hz), 7.29 (d, 1H, J=8.43Hz), 7.11 7.03 (m,4h), 6.84 6.77(m, 1H), 6.60 6.59 (m,1h), 4.52 (s, 2H), 4.30 (s, 2H), 3.85 (s, 6H), 3.64(s, 3H), 3.60(s, 3H), 3.18(s,3H); HRMS (ESI): found 640.1601 (C 27 H 34 N 3 11 S 2, [M+NH 4 ] +, requires 640.1629). N,N'-(naphthalene-1,4-diyl)bis(4-fluorobenzenesulfonamide) (16b): 16b was synthesized according to the procedure of 16a, gray solid, yield 59%; 235-237 C; 1 H-NMR (300 MHz, DMS, δ) 10.26 (s, 2H), 7.96 7.88 (m, 2H), 7.72 7.68 (m, 4H), 7.35 7.32 (m, 6H) 7.04 (s, 2H); HRMS (ESI): found 492.0891 (C 22 H 20 F 2 N 3 4 S 2, [M+NH 4 ] +, requires 492.0858). N,N'-(naphthalene-1,4-diyl)bis(4-chlorobenzenesulfonamide) (16c): 16c was synthesized according to the procedure of 16a, orange solid, yield 59%; m.p.: 210-212 C; 1 H-NMR (300 MHz, DMS, δ) 10.30 (s, 1H), 10.10 (s, 1H), 7.98 7.92 (m, 2H), 7.65 7.50 (m, 8H), 7.48 7.37 (m, 2H), 6.97 (s, 2H); HRMS (ESI): found 524.0298 (C 22 H 20 Cl 2 N 3 4 S 2, [M+NH 4 ] +, requires 524.0267). N,N'-(naphthalene-1,4-diyl)bis(4-bromobenzenesulfonamide) (16d): 16d was synthesized according to the procedure of 16a, light brown solid, yield 76%; 4

m.p.: 228-230 C; 1 H-NMR (300 MHz, DMS, δ) 10.32 (s, 2H), 7.93 7.90 (m, 2H), 7.69 (d, 4H, J=8.66 Hz), 7.53 (d, 4H, J=8.66 Hz), 7.41 7.38 (m, 2H), 7.02 (s, 2H); HRMS (ESI): found 616.8801 (C 22 H 16 Br 2 N 2 Na 4 S 2, [M+Na] +, requires 616.8810). N,N'-((((4-(hydrosulfonylamino)naphthalen-1-yl)amino)sulfonyl)bis(4,1- phenylene))diacetamide (16e): 16e was synthesized according to the procedure of 16a, pink solid, yield 76%; m.p.: 200-201 C; 1 H-NMR (300 MHz, DMS, δ) 10.34 (s, 2H), 10.05 (s, 2H), 7.99 7.97 (m, 2H), 7.69 7.66 (m, 4H), 7.56 7.53 (m, 4H), 7.41 7.38 (m, 2H), 7.00 (s, 2H), 2.07 (s, 6H); HRMS (ESI): found 570.1491 (C 26 H 28 N 5 6 S 2, [M+NH 4 ] +, requires 570.1476). N,N'-(naphthalene-1,4-diyl)bis(4-(tert-butyl)benzenesulfonamide) (16f): 16f was synthesized according to the procedure of 16a, gray solid, yield 79%; m.p.: 200-201 C m.p.: 197-199 C; 1 H-NMR (300 MHz, DMS, δ) 10.12 (s, 2H), 7.88 7.83 (m, 2H), 7.58-7.53 (m, 4H), 7.51 7.47 (m, 4H), 7.35 7.28 (m, 2H), 7.09 (s, 2H), 1.27 1.24 (m, 18H); HRMS (ESI): found 573.1874 (C 30 H 34 N 2 Na 4 S 2, [M+Na] +, requires 573.1852). N,N'-(naphthalene-1,4-diyl)bis(2,4,6-trimethylbenzenesulfonamide) (16g): 16g was synthesized according to the procedure of 16a, white solid, yield 64%; m.p.: 219-220 C; 1 H-NMR (300 MHz, DMS, δ) 10.02 (s, 2H), 8.03 (dd, 2H, J=6.45,3.21 Hz), 7.44 (dd, 2H, J=6.49,3.15 Hz), 6.93 (s, 4H), 6.89 (s,2h), 2.32 (s,12h), 2.22 (s,6h); HRMS (ESI): found 540.1962 (C 30 H 34 N 2 Na 4 S 2, [M+Na] +, requires 540.1985). N,N'-(naphthalene-1,4-diyl)dibenzenesulfonamide (16h): 16h was synthesized according to the procedure of 16a, gray solid, yield 58%; m.p.: 248-250 C; 1 H-NMR (300 MHz, DMS, δ) 10.20 (s, 2H), 7.90 (dd, 2H, J=6.51, 3.24 Hz), 7.63 7.55 (m, 6H), 7.49 7.46 (m, 4H), 7.38 7.33 (m, 2H), 7.03 (s, 2H); HRMS (ESI): found 461.0571 (C 22 H 18 N 2 Na 4 S 2, [M+Na] +, requires 461.0600). N,N'-(naphthalene-1,4-diyl)bis(4-(trifluoromethoxy) benzenesulfonamide) (16i): 16i was synthesized according to the procedure of 16a, light brown solid, yield 55%; m.p.: 108-110 C; 1 H-NMR (300 MHz, DMS, δ) 10.28 (br, 2H), 7.84 7.81 (m, 2H), 7.71 (d, 4H, J=8.85 Hz), 7.43 (d, 4H, J=8.34 Hz), 7.29 7.27 (m, 2H), 7.05 (s, 2H); HRMS (ESI): found 624.0702 (C 24 H 20 F 6 N 3 6 S 2, [M+NH 4 ] +, requires 624.0692). 5

N,N'-(naphthalene-1,4-diyl)bis(naphthalene-2-sulfonamide) (16j): 16j was synthesized according to the procedure of 16a, white solid, yield 78%; m.p.: 208-210 C; 1 H-NMR (300 MHz, DMS, δ) 10.27 (s, 2H), 8.24 (s, 2H), 8.00 7.94 (m, 8H), 7.70 7.59 (m, 6H), 7.32 7.29 (m, 2H), 6.96 (s, 2H); HRMS (ESI): found 561.0944 (C 30 H 22 N 2 Na 4 S 2, [M+Na] +, requires 561.0913). N,N'-(naphthalene-1,4-diyl)bis(4-(trifluoromethyl) benzenesulfonamide) (16k): 16k was synthesized according to the procedure of 16a, light pink solid, yield 47%; m.p.: 262-263 C; 1 H-NMR (300 MHz, DMS, δ) 10.49 (s, 2H), 7.92-7.78 (m, 10H), 7.32 (dd, 2H, J=6.54, 3.18 Hz), 7.08 (s, 2H); HRMS (ESI): found 592.0788 (C 24 H 20 F 6 N 3 4 S 2, [M+NH 4 ] +, requires 592.0794). N,N'-(naphthalene-1,4-diyl)bis(3-methoxybenzenesulfonamide) (16l): 16l was synthesized according to the procedure of 16a, gray solid, yield 61%; m.p.: 194-196 C; 1 H-NMR (300 MHz, DMS, δ) 10.22 (s, 2H), 7.94 (dd, 2H, J=6.47, 3.18 Hz), 7.41 7.36 (m, 4H), 7.18 7.12 (m, 6H), 7.06 (s, 2H), 3.67 (s, 6H); HRMS (ESI): found 521.0814 (C 24 H 22 N 2 Na 6 S 2, [M+Na] +, requires 521.0811). N,N'-(naphthalene-1,4-diyl)bis(4-cyanobenzenesulfonamide) (16m): 16g was synthesized according to the procedure of 16a, gray solid, yield 74%; m.p.: 294-295 C; 1 H-NMR (300 MHz, DMS, δ) 10.56 (s, 2H), 8.18 7.98 (m, 4H), 7.91 7.88 (m, 2H), 7.81 7.78 (m, 4H), 7.44 7.42 (m, 2H), 7.05 (s, 2H); HRMS (ESI): found 506.0957 (C 24 H 20 N 5 4 S 2, [M+NH 4 ] +, requires 506.0951). N,N'-(naphthalene-1,4-diyl)bis(4-butoxybenzenesulfonamide) (16n): 16g was synthesized according to the procedure of 16a, gray solid, yield 74%; m.p.:146-148 C; 1 H-NMR (300 MHz, DMS, δ) 9.87 (s, 2H), 7.99 (dd, 2H, J=6.48, 3.21 Hz), 7.54 7.48 (m, 4H), 7.33 (dd, 2H, J=6.50, 3.27 Hz), 6.95 6.90 (m, 5H), 6.83 (d, 1H, J=8.80 Hz), 3.99 3.94 (m, 4H), 1.71 1.62 (m, 4H), 1.46 1.36 (m, 4H), 0.95 0.88 (m, 6H); HRMS (ESI): found 605.1774 (C 30 H 34 N 2 Na 6 S 2, [M+Na] +, requires 605.1750). diethyl 2,2'-(naphthalene-1,4-diylbis(((4-fluorophenyl)sulfonyl) azanediyl))diacetate (17b): 17b was synthesized according to the procedure of 17a, gray solid, yield 65%; m.p.: 150-152 C; 1 H-NMR (300 MHz, DMS, δ) 8.24-8.22 (m, 1H), 8.18-8.14 (m, 1H) 7.78 7.70 (m, 4H) 7.60 7.59 (m, 2H) 7.48 7.36(m, 6H), 7.15 (s, 1H), 6.97 (s, 1H), 4.60 4.54 (m, 4H), 4.06 3.99 (m, 4H) 1.11 1.04 (m, 6H); HRMS (ESI): found 664.1582 (C 30 H 32 F 2 N 3 8 S 2, [M+NH 4 ] +, requires 664.1593). diethyl 2,2'-(naphthalene-1,4-diylbis(((4-chlorophenyl)sulfonyl) 6

azanediyl))diacetate (17c): 17c was synthesized according to the procedure of 17a, brown solid, yield 48%; m.p.: 165-168 C; 1 H-NMR (300 MHz, DMS, δ) 8.32 8. 29 (m, 1H), 8.15 8.11 (m, 1H) 7.94 7.64 (m, 10H) 7.16 (s, 1H) 6.92 (s, 1H) 4.68 4.45 (m, 4H), 4.15 3.95 (m, 4H) 1.18 1.07 (m, 6H); HRMS (ESI): found 701.0549 (C 30 H 28 Cl 2 N 2 Na 8 S 2, [M+Na] +, requires 701.0556). diethyl 2,2'-(naphthalene-1,4-diylbis(((4-bromophenyl)sulfonyl) azanediyl))diacetate (17d): 17d was synthesized according to the procedure of 17a, light pink solid, yield 57%; m.p.: 182-184 C; 1 H-NMR (300 MHz, DMS, δ) 8.28 8.27 (m, 1H), 8.16 8.13 (m, 1H), 7.84 (d, 2H, J=8.43), 7.75 (d, 2H, J=8.43), 7.63 7.55 (m, 6H), 7.15 (s, 1H), 6.89 (s, 1H), 4.62 4.53 (m, 4H), 4.05-3.95 (m, 4H), 1.10 1.02 (m, 6H) ; HRMS (ESI): found 766.9724 (C 30 H 29 Br 2 N 2 8 S 2, [M+H] +, requires 766.9727). diethyl 2,2'-(naphthalene-1,4-diylbis(((4-acetamidophenyl) sulfonyl)azanediyl))diacetate (17e): 17e was synthesized according to the procedure of 17a, light brown solid, yield 42%; m.p.: 231-233 C; 1 H-NMR (300 MHz, DMS, δ) 10.35 (d, 2H, J=9.45), 8.28 8.26 (m, 1H), 8.19 8.18 (m, 1H), 7.80 (d, 2H, J=8.73), 7.73(d, 2H, J=8.88), 7.61 7.55 (m, 6H), 7.07 (s, 1H), 6.93(s, 1H), 4.53 4.47 (m, 4H), 4.07 3.95 (m, 4H), 2.15 (s, 3H), 2.09 (s, 3H), 1.10 1.02 (m, 6H) ; HRMS (ESI): found 747.1758 (C 34 H 36 N 4 Na 10 S 2, [M+Na] +, requires 747.1765). diethyl 2,2'-(naphthalene-1,4-diylbis(((4-(tert-butyl)phenyl)sulfonyl) azanediyl))diacetate (17f): 17f was synthesized according to the procedure of 17a, gray solid, yield 72%; m.p.: 165-167 C; 1 H-NMR (300 MHz, DMS, δ) 8.07 8.05 (m, 1H), 8.04 8.00 (m, 1H), 7.64 7.62 (m, 4H), 7.60 7.58 (m, 4H), 7.54 7.51 (m, 2H), 7.20 (s, 1H), 7.09 (s, 1H), 4.66 4.41 (m, 4H), 4.04 3.97 (m, 4H), 1.34 1.30 (m, 18H), 1.09 1.02 (m, 6H) ; HRMS (ESI): found 745.2579 (C 38 H 46 N 2Na 8 S 2, [M+Na] +, requires 745.2588). diethyl 2,2'-(naphthalene-1,4-diylbis((mesitylsulfonyl) azanediyl))diacetate (17g): 17g was synthesized according to the procedure of 17a, gray solid, yield 75%; m.p.: 142-144 C; 1 H-NMR (300 MHz, DMS, δ) 7.87 (s, 2H) 7.55 7.40 (m, 4H), 6.97 6.91 (m, 4H), 4.75 4.69 (m, 2H), 4.53 4.39 (m, 2H), 4.01 3.99 (m, 4H), 2.25 2.16 (m, 18H), 1.17 1.04 (m, 6H) ; HRMS (ESI): found 712.2714 (C 36 H 46 F 2 N 3 8 S 2, [M+NH 4 ] +, requires 712.2721). Diethyl 2,2'-(naphthalene-1,4-diylbis((phenylsulfonyl) azanediyl)) diacetate (17h): 17h was synthesized according to the procedure of 17a, light brown solid, yield 51%; m.p.: 131-133 C; 1 H-NMR (300 MHz, DMS, δ) 8.25 8.22 (m, 1H), 8.12 8.09 (m, 1H), 7.77 7.55 (m, 12H), 7.12 (s, 1H), 6.89 (s, 1H), 4.60 4.48 (m, 4H), 4.07 3.96 (m, 4H), 1.10 1.03 (m, 6H) ; HRMS (ESI): found 628.1782 (C 30 H 34 N 3 8 S 2, [M+NH 4 ] +, requires 628.1782). 7

Dibenzyl 2,2'-(naphthalene-1,4-diylbis(((4-(trifluoromethoxy) phenyl)sulfonyl)azanediyl))diacetate (17i): 17i was synthesized according to the similar procedure of 17a, the ethyl bromoacetate was replaced by the Benzyl 2-bromoacetate, gray solid, yield 47%; m.p.: 109-111 C; 1 H-NMR (300 MHz, DMS, δ) 8.16 8.13 (m, 1H), 8.05 8.03 (m, 1H), 7.81 7.75 (m, 4H), 7.57 7.46 (m, 4H), 7.37 7.25 (m, 13H), 6.88 (s, 1H), 5.16 5.07 (m, 4H), 4.76 4.65 (m, 4H) ; HRMS (ESI): found 920.1745 (C 42 H 36 F 6 N 3 8 S 2, [M+NH 4 ] +, requires 920.1741). Diethyl 2,2'-(naphthalene-1,4-diylbis((naphthalen-2-ylsulfonyl) azanediyl))diacetate (17j): 17j was synthesized according to the procedure of 17a, gray solid, yield 69%; m.p.: 92-94 C; 1 H-NMR (300 MHz, DMS, δ) 8.45 8.33 (m, 3H), 8.20 8.16 (m, 2H), 8.08 7.98 (m, 5H), 7.80 7.62 (m, 8H), 7.07 (s, 1H), 6.80 (s, 1H), 4.65 4.52 (m, 4H), 4.02 3.93 (m, 4H), 1.05 0.99 (m, 6H) ; HRMS (ESI): found 728.2095 (C 38 H 38 N 3 8 S 2, [M+NH 4 ] +, requires 728.2095). F 3 C N S N S CF 3 Dibenzyl 2,2'-(naphthalene-1,4-diylbis(((4-(trifluoromethyl)phenyl) sulfonyl)azanediyl))diacetate (17k): 17k was synthesized according to the procedure of 17i, purified by column chromatography (silica gel; hexanes/etac; 4:1 to 2:1) to give the light yellow oil, yield 81%; 1 H NMR (300 MHz, DMS, δ) 8.24 8.23 (m, 1H), 8.11 8.09 (m, 1H), 7.98 7.7.87 (m, 8H), 7.53 7.49 (m, 2H), 7.38 7.26 (m, 10H), 7.14 (s,1h), 6.80(s, 1H), 5.19 5.07 (m, 4H), 4.78 4.46 (m, 4H) ; HRMS (ESI): found 888.1837 (C 42 H 36 F 6 N 3 8 S 2, [M+NH 4 ] +, requires 888.1843). S N N S Dibenzyl 2,2'-(naphthalene-1,4-diylbis(((3-methoxyphenyl)sulfonyl) azanediyl))diacetate (17l): 17l was synthesized according to the procedure of 17i, purified by column chromatography (silica gel; hexanes/etac; 4:1 to 2:1) to give light yellow oil, yield 77%; 1 H NMR (300 MHz, DMS, δ) 8.10(s, 1H), 7.93(s, 1H), 7.47 7.40 (m, 4H), 7.32 7.11 (m, 14H), 7.06 7.00 (m, 4H), 5.11 5.03 (m, 4H), 4.73 4.48 (m, 4H), 3.75(s, 3H), 3.59(s, 3H); HRMS (ESI): found 795.2027 (C 42 H 39 N 2 10 S 2, [M+H] +, requires 795.2041). Dimethyl 2,2'-(naphthalene-1,4-diylbis(((4-cyanophenyl)sulfonyl) azanediyl))diacetate (17m): 17m was synthesized according to the procedure of 11c, light pink solid, yield 61%; m.p.: 173-175 C; 1 H NMR (300 MHz, DMS, δ) 8.19 8.02 (m, 6H), 7.89 7.80 (m, 4H), 7.63 7.58 (m, 2H), 7.18 (s, 1H), 7.03(s, 1H), 4.76 4.55 (m, 4H), 3.62(s, 3H), 3.56(s, 3H); HRMS (ESI): found 650.1392 (C 30 H 28 N 5 8 S 2, [M+NH 4 ] +, requires 650.1374). 8

Dibenzyl 2,2'-(naphthalene-1,4-diylbis(((4-butoxyphenyl)sulfonyl) azanediyl))diacetate (17n): 17n was synthesized according to the procedure of 17i, purified by column chromatography (silica gel; hexanes/etac; 8:1 to 2:1) to give the gray solid, yield 53%; m.p.: 239-241 C; 1 H-NMR (300 MHz, DMS, δ) 8.17 8.13 (m, 2H), 7.67 7.65 (m, 4H), 7.39 7.26 (m, 16H), 6.94 6.88 (m, 2H), 5.17 5.11 (m, 4H), 4.62 4.58 (m, 4H), 4.01 3.93 (m, 4H), 1.87 1.83 (m, 4H), 1.62 1.58 (m, 4H), 1.10 1.07 (m, 6H) ; HRMS (ESI): found 901.2808 (C 48 H 50 N 2 Na 10 S 2, [M+Na] +, requires 901.2799). N,N'-(naphthalene-1,5-diyl)bis(4-methoxybenzenesulfonamide) (13): 13 was synthezied according to the procedures of 16a, grap solid, yield 73%; m.p.: 266-268 C; 1 H-NMR (300 MHz, DMS) 10.03 (s, 2H), 7.88 (d, 2H, J=8.49), 7.56 (d, 4H, J=8.61), 7.32-7.27 (m, 2H), 7.07 (d, 2H, J=7.26), 6.98 (d, 4H, J=8.67), 3.76(s, 6H); HRMS (ESI): found 516.1258 (C 24 H 26 N 3 6 S 2, [M+NH 4 ] +, requires 516.1258). dimethyl 2,2'-(naphthalene-1,5-diylbis(((4-methoxyphenyl)sulfonyl) azanediyl))diacetate (14): 14 was synthezied according to the procedures of 17m, light brown solid, yield 66%; m.p.: 180-182 C; 1 H-NMR (300 MHz, DMS) 8.33 8.27 (m, 2H), 7.65 7.57 (m, 4H), 7.51 7.47 (m, 2H), 7.14 7.09 (m, 6H), 4.55(s, 2H), 4.51 (s, 2H), 3.88(s, 3H), 3.86(s, 3H), 3.59 (s, 3H), 3.55(s, 3H); HRMS (ESI): found 665.1214 (C 30 H 30 N 2 Na 10 S 2, [M+Na] +, requires 665.1234). 9

S2. Binding mode comparison of 8 and 15. Figure S1. Binding mode comparison between 8 and 15. The hydrogen bonds were represented as green dashed lines and the electrostatic interactions were represented as yellow dashed lines. The carbon atoms of ligands and Keap1 residues were colored as cyan and purple respectively 10

S3. Detailed results of the ligand efficiency (LE), ligand efficiency dependent lipophilicity (LELP) and lipophilic efficiency (LipE). a Compd. R 1 IC 50 (nm) 95% CI MW the number of non-hydrogen atoms pic 50 LE LELP LipE 8 4-CH 3 30.8 27.6-34.4 614.6 1.71 42 7.511449 0.250382 6.829574 5.801449 18a 4-CH 3 18.1 15.0-21.8 582.6 0.93 40 7.742321 0.270981 3.431972 6.812321 18b 4-F 54.3 49.9-59.1 590.6 1.16 40 7.2652 0.254282 4.561864 6.1052 18c 4-Cl 42.3 34.8-51.4 623.5 2.11 40 7.37366 0.258078 8.17582 5.26366 18d 4-Br 36.5 29.7-44.8 712.4 4.29 40 7.437707 0.26032 16.47973 3.147707 18e 4-acetamido 14.4 12.4 to 16.7 668.7 1.02 46 7.841638 0.238659 4.273889 6.821638 18f 4-C(CH 3 ) 3 50.2 42.8-58.9 666.8 5.2 46 7.299296 0.222152 23.40734 2.099296 18g 2,4,6-trimethyl 979 672-1425 638.8 3.44 44 6.009217 0.191202 17.99141 2.569217 18h H 34.3 30.3-38.9 554.6 0.45 38 7.464706 0.275015 1.636272 7.014706 18i 4-CF 3 179 144-222 722.6 0.93 48 6.747147 0.196792 4.725807 5.817147 11

18j 5,6-C 4 H 4 47.4 37.9-59.2 654.7 3.9 46 7.324222 0.222911 17.49576 3.424222 18k 4-CF 3 122 98.1-151 690.6 2.81 46 6.91364 0.210415 13.35455 4.10364 18l 3-CH 3 66.1 55.9-78.3 614.6 0.89 42 7.179799 0.239327 3.718767 6.289799 18m 4-CN 118 84.0-165 604.6 0.65 42 6.928118 0.230937 2.814617 6.278118 18n 4-n-butyl 42.2 37.5-47.4 698.2 1.89 48 7.374688 0.215095 8.786813 5.484688 a LE = 1.4pIC50/HAC (heavy atom count HAC); LipE = pic50-logp; LELP = logp/le 12

S4. Body weight of the mice during the experiment Figure S2. Body weight of C57BL/6 female mice in different groups (n = 10 mice per group) during the experiment. 13

S5. The comparison of in vivo effects between 8 and 18e. Figure S3. Quantification of various inflammatory cytokines including IL-6, Il-12, IL-17, TNF-α and IFN-γ in the blood serum of C57BL/6 female mice after 5h of LPS challenge. Dexamethasone (10 mg/kg) was used as positive control. 14

S6. Primers used for qrt-pcr Primers are shown as follows: Nrf2 Sense primer: AACCACCCTGAAAGCACGC Antisense primer: TGAAATGCCGGAGTCAGAATC H-1 Sense primer: ATGGCCTCCCTGTACCACATC Antisense primer: TGTTGCGCTCAATCTCCTCCT NQ-1 Sense primer: CGCAGACCTTGTGATATTCCAG Antisense primer: CGTTTCTTCCATCCTTCCAGG GCLM-1 Sense primer: TTGGAGTTGCACAGCTGGATTC Antisense primer: TGGTTTTACCTGTGCCCACTG 15