药学学报

Compd.	Yield /%	Property	mp/℃	¹H NMR (600 MHz, DMSO-d₆)	¹³C NMR (151 MHz, DMSO-d₆)	ESI⁺-MS (m/z) [M+H]⁺
4a	83	Yellow powder	212.0-213.1	12.41 (s, 1H), 9.08 (s, 1H), 8.73 (s, 1H), 7.71 (d, J = 7.3 Hz, 1H), 7.43 (t, J = 7.3 Hz, 1H), 7.21 (d, J = 7.9 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 3.87 (t, J = 6.4 Hz, 2H), 3.51 (t, J = 4.5 Hz, 4H), 2.57 (t, J = 6.4 Hz, 2H), 2.44 (t, J = 4.5 Hz, 4H).	178.8, 160.8, 142.9, 131.1, 131.0, 122.7, 120.7, 119.3, 110.1, 66.1, 54.9, 53.1, 36.6.	334.133 2
4b	70	Yellow powder	232.3-233.5	12.36 (s, 1H), 9.08 (s, 1H), 8.73 (s, 1H), 7.72 (d, J = 7.4 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 3.98 (t, J = 7.3 Hz, 2H), 3.19 (t, J = 7.4 Hz, 2H), 2.88 (m, 2H), 2.73 (m, 1H), 1.62 (m, 2H), 1.52 (m, 2H), 1.34 (m, 2H), 1.07 (d, J = 7.1 Hz, 3H).	178.7, 160.9, 142.0, 131.5, 131.1, 123.1, 120.8, 119.7, 110.0, 59.2, 50.9, 48.1, 33.6, 30.7, 22.3, 21.5, 17.1.	346.169 6
4c	80	Yellow powder	230.0-231.5	12.41 (s, 1H), 9.07 (s, 1H), 8.73 (s, 1H), 7.72 (d, J = 7.4 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 3.82 (t, J = 6.6 Hz, 2H), 3.62 (t, J = 7.8 Hz, 4H), 2.80 (t, J = 7.1 Hz, 2H), 2.72 (t, J = 7.7 Hz, 4H), 1.91 (m, 2H).	178.7, 160.9, 142.8, 131.2, 131.1, 122.8, 120.7, 119.4, 109.9, 64.7, 54.5, 52.2, 37.1, 22.6.	348.148 9
4d	87	Yellow powder	217.3-218.9	12.37 (s, 1H), 9.06 (s, 1H), 8.73 (s, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 3.85 (t, J = 6.8 Hz, 2H), 3.40 (m, 1H), 3.18 (m, 2H), 2.97 (t, J = 6.3 Hz, 2H), 2.03 (t, J = 7.5 Hz, 2H), 1.82 (m, 2H), 1.67 (m, 2H), 1.54 (m, 2H), 1.25 (d, J = 7.9 Hz, 3H).	178.7, 160.9, 142.6, 131.2, 131.1, 122.9, 120.8, 119.5, 109.9, 58.3, 51.1, 49.5, 36.7, 31.1, 30.7, 22.5, 21.0, 17.3.	360.185 8
4e	76	Yellow powder	231.2-232.5	12.38 (s, 1H), 9.08 (s, 1H), 8.74 (s, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 7.26 (d, J = 7.9 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 3.84 (t, J = 6.8 Hz, 2H), 3.09 (t, J = 7.1 Hz, 2H), 3.04 (m, 4H), 1.98 (m, 2H), 1.14 (t, J = 7.3 Hz, 6H).	178.7, 160.8, 142.8, 131.2, 131.1, 122.8, 120.7, 119.4, 109.9, 49.1, 46.2, 37.1, 23.2, 9.9.	334.170 2
4f	87	Yellow powder	225.8-226.5	12.42 (s, 1H), 9.05 (s, 1H), 8.70 (s, 1H), 7.71 (d, J = 7.5 Hz, 1H), 7.44 (t, J = 7.7 Hz, 1H), 7.21 (d, J = 7.9 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 3.77 (t, J = 6.8 Hz, 2H), 3.66 (t, J = 7.4 Hz, 4H), 2.74 (t, J = 7.2 Hz, 4H), 2.69 (t, J = 6.9 Hz, 2H), 1.66 (m, 2H), 1.57 (m, 2H).	178.7, 160.8, 142.7, 131.2, 131.1, 122.8, 120.7, 119.4, 110.0, 64.7, 56.6, 56.0, 52.2, 24.4, 21.7.	362.165 1
4g	84	Yellow powder	217.3-218.9	12.42 (s, 1H), 9.03 (s, 1H), 8.69 (s, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.42 (t, J = 7.7 Hz, 1H), 7.20 (d, J = 7.9 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 3.76 (t, J = 6.9 Hz, 2H), 3.43 (t, J = 7.0 Hz, 2H), 3.02 (m, 1H), 2.87 (m, 2H), 1.67 (t, J = 7.6 Hz, 2H), 1.62 (m, 2H), 1.57 (m, 2H), 1.53 (m, 2H), 1.35 (m, 2H), 1.11 (d, J = 6.3 Hz, 3H).	178.6, 160.7, 142.7, 131.2, 131.1, 122.8, 120.7, 119.3, 110.0, 56.4, 56.0, 51.6, 50.4, 48.5, 31.8, 24.5, 23.71, 21.4, 18.5.	374.201 5
4h	64	Yellow powder	297.5-298.5	12.42 (s, 1H), 9.08 (s, 1H), 8.73 (s, 1H), 7.71 (d, J = 7.1 Hz, 1H), 7.44 (t, J = 7.8, 1.0 Hz, 1H), 7.21 (d, J = 7.9 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 3.77 (t, J = 6.9 Hz, 2H), 2.73 (t, J = 7.9 Hz, 2H), 2.64 (m, 4H), 1.66 (m, 2H), 1.50 (m, 2H), 1.01 (t, J = 6.8 Hz, 6H).	178.7, 160.7, 142.7, 131.2, 131.1, 122.8, 120.7, 119.4, 110.0, 51.1, 48.5, 46.33, 38.8, 24.5, 10.1.	347.178 0
5a	77	Yellow powder	216.1-217.9	12.43 (s, 1H), 7.54 (d, J = 7.4 Hz, 1H), 7.42 (t, J = 7.7 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H), 7.03 (t, J = 7.7 Hz, 1H), 3.94 (s, 2H, S-CH₂), 3.82 (t, J = 6.4 Hz, 2H), 3.51 (t, J = 4.6 Hz, 4H), 2.55 (t, J = 6.5 Hz, 2H), 2.45 (t, J = 4.8 Hz, 4H).	184.3, 175.1, 157.2, 143.7, 143.5, 132.0, 122.3, 120.8, 120.1, 109.4, 66.0, 54.9, 53.1, 36.4, 33.4.	372.112 5
5b	70	Yellow powder	265.0-266.3	11.52 (s, 1H), 7.55 (d, J = 7.2 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.25 (d, J = 6.9 Hz, 1H), 7.10 (t, J = 6.7 Hz, 1H), 4.02 (s, 2H, S-CH₂), 3.96 (t, J = 7.2 Hz, 2H), 3.26 (t, J = 6.0 Hz, 2H), 3.12 (m, 1H), 2.93 (t, J = 7.0 Hz, 2H), 1.76 (m, 2H), 1.46 (m, 2H), 1.17 (d, J = 6.3 Hz, 3H).	186.2, 178.7, 160.9, 142.5, 131.1, 131.0, 122.9, 120.7, 119.5, 110.1, 56.3, 50.6, 50.4, 48.9, 35.1, 31.8, 24.3, 22.2, 17.2.	384.148 9
5c	76	Yellow powder	210.5-211.4	12.44 (s, 1H), 7.54 (d, J = 7.3 Hz, 1H), 7.42 (t, J = 7.7 Hz, 1H), 7.11 (d, J = 7.9 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 3.93 (s, 2H, S-CH₂), 3.74 (t, J = 6.7 Hz, 2H), 3.49 (t, J = 4.7 Hz, 4H), 2.34 (t, J = 7.3 Hz, 2H), 2.30 (t, J = 4.9 Hz, 4H), 1.76 (m, 2H).	186.8, 178.7, 160.9, 142.8, 131.2, 131.1, 122.8, 120.7, 119.4, 109.9, 64.7, 54.5, 52.2, 37.1, 27.4, 22.6.	386.128 7
5d	72	Yellow powder	200.2-203.0	12.42 (s, 1H), 7.53 (d, J = 7.3 Hz, 1H), 7.40 (t, J = 7.5 Hz, 1H), 7.11 (d, J = 7.4 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 3.91 (s, 2H, S-CH₂), 3.70 (t, J = 7.1 Hz, 2H), 3.55 (t, J = 4.1 Hz, 4H), 2.37 (t, J = 4.3 Hz, 4H), 2.33 (t, J = 7.3 Hz, 2H), 1.61 (m, 2H), 1.46 (m, 2H).	187.5, 178.7, 160.7, 142.7, 131.2, 131.1, 122.8, 120.7, 119.4, 110.0, 64.7, 56.5, 52.2, 38.8, 24.4, 21.7, 18.5.	402.160 0

Compd.	Yield /%	Property	mp/℃	¹H NMR (600 MHz, DMSO-d₆)	¹³C NMR (151 MHz, DMSO-d₆)	ESI⁺-MS (m/z) [M+H]⁺
4a	83	Yellow powder	212.0-213.1	12.41 (s, 1H), 9.08 (s, 1H), 8.73 (s, 1H), 7.71 (d, J = 7.3 Hz, 1H), 7.43 (t, J = 7.3 Hz, 1H), 7.21 (d, J = 7.9 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 3.87 (t, J = 6.4 Hz, 2H), 3.51 (t, J = 4.5 Hz, 4H), 2.57 (t, J = 6.4 Hz, 2H), 2.44 (t, J = 4.5 Hz, 4H).	178.8, 160.8, 142.9, 131.1, 131.0, 122.7, 120.7, 119.3, 110.1, 66.1, 54.9, 53.1, 36.6.	334.133 2
4b	70	Yellow powder	232.3-233.5	12.36 (s, 1H), 9.08 (s, 1H), 8.73 (s, 1H), 7.72 (d, J = 7.4 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 3.98 (t, J = 7.3 Hz, 2H), 3.19 (t, J = 7.4 Hz, 2H), 2.88 (m, 2H), 2.73 (m, 1H), 1.62 (m, 2H), 1.52 (m, 2H), 1.34 (m, 2H), 1.07 (d, J = 7.1 Hz, 3H).	178.7, 160.9, 142.0, 131.5, 131.1, 123.1, 120.8, 119.7, 110.0, 59.2, 50.9, 48.1, 33.6, 30.7, 22.3, 21.5, 17.1.	346.169 6
4c	80	Yellow powder	230.0-231.5	12.41 (s, 1H), 9.07 (s, 1H), 8.73 (s, 1H), 7.72 (d, J = 7.4 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 3.82 (t, J = 6.6 Hz, 2H), 3.62 (t, J = 7.8 Hz, 4H), 2.80 (t, J = 7.1 Hz, 2H), 2.72 (t, J = 7.7 Hz, 4H), 1.91 (m, 2H).	178.7, 160.9, 142.8, 131.2, 131.1, 122.8, 120.7, 119.4, 109.9, 64.7, 54.5, 52.2, 37.1, 22.6.	348.148 9
4d	87	Yellow powder	217.3-218.9	12.37 (s, 1H), 9.06 (s, 1H), 8.73 (s, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 3.85 (t, J = 6.8 Hz, 2H), 3.40 (m, 1H), 3.18 (m, 2H), 2.97 (t, J = 6.3 Hz, 2H), 2.03 (t, J = 7.5 Hz, 2H), 1.82 (m, 2H), 1.67 (m, 2H), 1.54 (m, 2H), 1.25 (d, J = 7.9 Hz, 3H).	178.7, 160.9, 142.6, 131.2, 131.1, 122.9, 120.8, 119.5, 109.9, 58.3, 51.1, 49.5, 36.7, 31.1, 30.7, 22.5, 21.0, 17.3.	360.185 8
4e	76	Yellow powder	231.2-232.5	12.38 (s, 1H), 9.08 (s, 1H), 8.74 (s, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 7.26 (d, J = 7.9 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 3.84 (t, J = 6.8 Hz, 2H), 3.09 (t, J = 7.1 Hz, 2H), 3.04 (m, 4H), 1.98 (m, 2H), 1.14 (t, J = 7.3 Hz, 6H).	178.7, 160.8, 142.8, 131.2, 131.1, 122.8, 120.7, 119.4, 109.9, 49.1, 46.2, 37.1, 23.2, 9.9.	334.170 2
4f	87	Yellow powder	225.8-226.5	12.42 (s, 1H), 9.05 (s, 1H), 8.70 (s, 1H), 7.71 (d, J = 7.5 Hz, 1H), 7.44 (t, J = 7.7 Hz, 1H), 7.21 (d, J = 7.9 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 3.77 (t, J = 6.8 Hz, 2H), 3.66 (t, J = 7.4 Hz, 4H), 2.74 (t, J = 7.2 Hz, 4H), 2.69 (t, J = 6.9 Hz, 2H), 1.66 (m, 2H), 1.57 (m, 2H).	178.7, 160.8, 142.7, 131.2, 131.1, 122.8, 120.7, 119.4, 110.0, 64.7, 56.6, 56.0, 52.2, 24.4, 21.7.	362.165 1
4g	84	Yellow powder	217.3-218.9	12.42 (s, 1H), 9.03 (s, 1H), 8.69 (s, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.42 (t, J = 7.7 Hz, 1H), 7.20 (d, J = 7.9 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 3.76 (t, J = 6.9 Hz, 2H), 3.43 (t, J = 7.0 Hz, 2H), 3.02 (m, 1H), 2.87 (m, 2H), 1.67 (t, J = 7.6 Hz, 2H), 1.62 (m, 2H), 1.57 (m, 2H), 1.53 (m, 2H), 1.35 (m, 2H), 1.11 (d, J = 6.3 Hz, 3H).	178.6, 160.7, 142.7, 131.2, 131.1, 122.8, 120.7, 119.3, 110.0, 56.4, 56.0, 51.6, 50.4, 48.5, 31.8, 24.5, 23.71, 21.4, 18.5.	374.201 5
4h	64	Yellow powder	297.5-298.5	12.42 (s, 1H), 9.08 (s, 1H), 8.73 (s, 1H), 7.71 (d, J = 7.1 Hz, 1H), 7.44 (t, J = 7.8, 1.0 Hz, 1H), 7.21 (d, J = 7.9 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 3.77 (t, J = 6.9 Hz, 2H), 2.73 (t, J = 7.9 Hz, 2H), 2.64 (m, 4H), 1.66 (m, 2H), 1.50 (m, 2H), 1.01 (t, J = 6.8 Hz, 6H).	178.7, 160.7, 142.7, 131.2, 131.1, 122.8, 120.7, 119.4, 110.0, 51.1, 48.5, 46.33, 38.8, 24.5, 10.1.	347.178 0
5a	77	Yellow powder	216.1-217.9	12.43 (s, 1H), 7.54 (d, J = 7.4 Hz, 1H), 7.42 (t, J = 7.7 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H), 7.03 (t, J = 7.7 Hz, 1H), 3.94 (s, 2H, S-CH₂), 3.82 (t, J = 6.4 Hz, 2H), 3.51 (t, J = 4.6 Hz, 4H), 2.55 (t, J = 6.5 Hz, 2H), 2.45 (t, J = 4.8 Hz, 4H).	184.3, 175.1, 157.2, 143.7, 143.5, 132.0, 122.3, 120.8, 120.1, 109.4, 66.0, 54.9, 53.1, 36.4, 33.4.	372.112 5
5b	70	Yellow powder	265.0-266.3	11.52 (s, 1H), 7.55 (d, J = 7.2 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.25 (d, J = 6.9 Hz, 1H), 7.10 (t, J = 6.7 Hz, 1H), 4.02 (s, 2H, S-CH₂), 3.96 (t, J = 7.2 Hz, 2H), 3.26 (t, J = 6.0 Hz, 2H), 3.12 (m, 1H), 2.93 (t, J = 7.0 Hz, 2H), 1.76 (m, 2H), 1.46 (m, 2H), 1.17 (d, J = 6.3 Hz, 3H).	186.2, 178.7, 160.9, 142.5, 131.1, 131.0, 122.9, 120.7, 119.5, 110.1, 56.3, 50.6, 50.4, 48.9, 35.1, 31.8, 24.3, 22.2, 17.2.	384.148 9
5c	76	Yellow powder	210.5-211.4	12.44 (s, 1H), 7.54 (d, J = 7.3 Hz, 1H), 7.42 (t, J = 7.7 Hz, 1H), 7.11 (d, J = 7.9 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 3.93 (s, 2H, S-CH₂), 3.74 (t, J = 6.7 Hz, 2H), 3.49 (t, J = 4.7 Hz, 4H), 2.34 (t, J = 7.3 Hz, 2H), 2.30 (t, J = 4.9 Hz, 4H), 1.76 (m, 2H).	186.8, 178.7, 160.9, 142.8, 131.2, 131.1, 122.8, 120.7, 119.4, 109.9, 64.7, 54.5, 52.2, 37.1, 27.4, 22.6.	386.128 7
5d	72	Yellow powder	200.2-203.0	12.42 (s, 1H), 7.53 (d, J = 7.3 Hz, 1H), 7.40 (t, J = 7.5 Hz, 1H), 7.11 (d, J = 7.4 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 3.91 (s, 2H, S-CH₂), 3.70 (t, J = 7.1 Hz, 2H), 3.55 (t, J = 4.1 Hz, 4H), 2.37 (t, J = 4.3 Hz, 4H), 2.33 (t, J = 7.3 Hz, 2H), 1.61 (m, 2H), 1.46 (m, 2H).	187.5, 178.7, 160.7, 142.7, 131.2, 131.1, 122.8, 120.7, 119.4, 110.0, 64.7, 56.5, 52.2, 38.8, 24.4, 21.7, 18.5.	402.160 0

Compd.	IC₅₀/μmol·L^-1
4a	38.7 ± 1.4	49.6 ± 8.6	82.6 ± 1.9	54.2 ± 1.2	39.7 ± 2.0
4b	8.1 ± 2.0	47.6 ± 5.1	24.5 ± 4.6	58.5 ± 7.8	53.2 ± 5.9
4c	22.6 ± 1.3	62.7 ± 2.4	41.3 ± 5.2	47.2 ± 1.1	46.4 ± 3.2
4d	14.7 ± 5.2	39.4 ± 3.4	28.0 ± 1.2	31.4 ± 5.6	61.6 ± 2.4
4e	49.6 ± 1.1	50.9 ± 1.0	35.6 ± 3.4	39.9 ± 5.1	82.1 ± 2.1
4f	72.3 ± 1.3	50.7 ± 8.7	45.5 ± 1.2	69.3 ± 7.2	11.5 ± 1.1
4g	44.0 ± 2.2	76.7 ± 1.2	81.4 ± 5.9	59.2 ± 8.1	54.6 ± 4.2
4h	83.7 ± 1.9	63.1 ± 9.4	67.2 ± 2.6	81.6 ± 3.4	45.0 ± 1.1
5a	33.0 ± 4.0	49.9 ± 6.6	15.2 ± 3.6	51.6 ± 7.2	39.7 ± 6.3
5b	12.6 ± 2.9	16.4 ± 1.8	12.0 ± 1.3	36.8 ± 1.9	74.4 ± 1.6
5c	43.4 ± 1.6	44.7 ± 6.7	44.9 ± 5.0	70.9 ± 1.5	79.2 ± 1.2
5d	82.4 ± 1.9	62.6 ± 1.0	81.3 ± 1.9	82.3 ± 3.0	47.4 ± 1.7
Cisplatin	40.1 ± 4.1	66.6 ± 6.8	8.4 ± 2.0	49.8 ± 6.7	52.0 ± 8.7

Compd.	IC₅₀/μmol·L^-1
4a	38.7 ± 1.4	49.6 ± 8.6	82.6 ± 1.9	54.2 ± 1.2	39.7 ± 2.0
4b	8.1 ± 2.0	47.6 ± 5.1	24.5 ± 4.6	58.5 ± 7.8	53.2 ± 5.9
4c	22.6 ± 1.3	62.7 ± 2.4	41.3 ± 5.2	47.2 ± 1.1	46.4 ± 3.2
4d	14.7 ± 5.2	39.4 ± 3.4	28.0 ± 1.2	31.4 ± 5.6	61.6 ± 2.4
4e	49.6 ± 1.1	50.9 ± 1.0	35.6 ± 3.4	39.9 ± 5.1	82.1 ± 2.1
4f	72.3 ± 1.3	50.7 ± 8.7	45.5 ± 1.2	69.3 ± 7.2	11.5 ± 1.1
4g	44.0 ± 2.2	76.7 ± 1.2	81.4 ± 5.9	59.2 ± 8.1	54.6 ± 4.2
4h	83.7 ± 1.9	63.1 ± 9.4	67.2 ± 2.6	81.6 ± 3.4	45.0 ± 1.1
5a	33.0 ± 4.0	49.9 ± 6.6	15.2 ± 3.6	51.6 ± 7.2	39.7 ± 6.3
5b	12.6 ± 2.9	16.4 ± 1.8	12.0 ± 1.3	36.8 ± 1.9	74.4 ± 1.6
5c	43.4 ± 1.6	44.7 ± 6.7	44.9 ± 5.0	70.9 ± 1.5	79.2 ± 1.2
5d	82.4 ± 1.9	62.6 ± 1.0	81.3 ± 1.9	82.3 ± 3.0	47.4 ± 1.7
Cisplatin	40.1 ± 4.1	66.6 ± 6.8	8.4 ± 2.0	49.8 ± 6.7	52.0 ± 8.7

Compd.	H-Bonds interaction	p-π conjugation
4a	Ser143; His155	-
4b	Ser143	-
4c	Ser143; His155	-
4d	Ser143; Arg246	-
4e	Ser143; His141	-
4f	Ser143; His154; His155	-
4g	Ser143; His154	-
4h	His155; His141	-
5a	Lys130; His140	Lys135
5b	Ser143; His141; Lys135	-
5c	Lys130; Lys135; Ser143	-
5d	Ser143; His155	-
PAP	His141; His140; Ser143; Lys135	-

Compd.	H-Bonds interaction	p-π conjugation
4a	Ser143; His155	-
4b	Ser143	-
4c	Ser143; His155	-
4d	Ser143; Arg246	-
4e	Ser143; His141	-
4f	Ser143; His154; His155	-
4g	Ser143; His154	-
4h	His155; His141	-
5a	Lys130; His140	Lys135
5b	Ser143; His141; Lys135	-
5c	Lys130; Lys135; Ser143	-
5d	Ser143; His155	-
PAP	His141; His140; Ser143; Lys135	-

靛红衍生物类棕榈酰基转移酶抑制剂的设计、合成及抗肿瘤活性研究

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余伟 ¹ , 董金娇 ¹ , 朱昕悦 ¹ , 杨侃 ¹ , 刘振明 ² , 乔晓强 ¹^,³ , 宋亚丽 ¹^,^*

药学学报 | 研究论文 2022,57(4): 1073-1079

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药学学报 | 研究论文 2022, 57(4): 1073-1079

靛红衍生物类棕榈酰基转移酶抑制剂的设计、合成及抗肿瘤活性研究

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余伟¹, 董金娇¹, 朱昕悦¹, 杨侃¹, 刘振明², 乔晓强¹^,³, 宋亚丽¹^,^*

作者信息

1.河北大学药学院, 河北省药物质量分析控制重点实验室, 河北保定 071002

2.北京大学, 天然药物及仿生药物国家重点实验室, 北京 100191

3.河北大学, 药物化学与分子诊断教育部重点实验室, 河北保定 071002

通讯作者:

*宋亚丽, E-mail: yalisong@hbu.edu.cn

Design, synthesis and antitumor activity of isatin derivatives as palmitoyl transferase inhibitors

Wei YU¹, Jin-jiao DONG¹, Xin-yue ZHU¹, Kan YANG¹, Zhen-ming LIU², Xiao-qiang QIAO¹^,³, Ya-li SONG¹^,^*

Affiliations

1. College of Pharmaceutical Sciences, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, Hebei University, Baoding 071002, China

2. State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China

3. Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Hebei University, Baoding 071002, China

出版时间: 2022-04-12 doi: 10.16438/j.0513-4870.2021-1389

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摘要

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基于已知化合物的化学结构, 利用生物电子等排体原理, 结合分子对接技术设计合成了12个靛红衍生物类棕榈酰基转移酶抑制剂, 测定了其体外抗肿瘤活性并进行了分子对接研究。目标化合物结构均已由核磁共振氢谱(¹H NMR)、核磁共振碳谱(¹³C NMR) 和高分辨质谱(HR-MS) 进行了确证。体外抗肿瘤实验结果表明, 化合物5b对棕榈酰基转移酶高表达的MCF-7细胞表现出的抑制活性与对照药(IC₅₀ = 8.4 μmol·L^-1) 相当, IC₅₀为12.0 μmol·L^-1。化合物4b对HeLa细胞(IC₅₀ = 8.1 μmol·L^-1) 的抑制活性优于顺铂(IC₅₀ = 40.1 μmol·L^-1)。同时分子对接结果表明, 化合物均能完全进入3'-磷酸腺苷-5'-二磷酸(PAP) 活性口袋内, 且5b打分值最好, 具有进一步的研究价值。

关键词

靛红衍生物 / 棕榈酰基转移酶 / 合成 / 分子对接 / 抗肿瘤活性

Abstract

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Based on the chemical structure of known compound, 12 isatin derivatives palmitoyl transferase inhibitors are designed and synthesized using bioisosterism and molecular docking, while their anti-tumor activities in vitro are determined. The structures of the target compounds are confirmed by ¹H NMR, ¹³C NMR and HR-MS. In vitro anti-tumor assay illustrates that compound 5b exhibits similar anti-tumor activity to the control (IC₅₀ = 8.4 μmol·L^-1), with IC₅₀ value of 12.0 μmol·L^-1 against MCF-7 in which palmitoyl transferase is highly expressed. Compound 4b shows higher inhibitory activity against HeLa (IC₅₀ = 8.1 μmol·L^-1) than cisplatin (IC₅₀ = 40.1 μmol·L^-1). The molecular docking demonstrates that all compounds could completely enter the site of 3'-adenosine monophosphate-5'-diphosphate (PAP). Taken together, isatin derivatives represent promising compounds for the discovery of novel anti-tumor agents.

Key words

isatin derivative / palmitoyl transferase / synthesis / molecular docking / anti-tumor activity

引用本文

余伟, 董金娇, 朱昕悦, 杨侃, 刘振明, 乔晓强, 宋亚丽. 靛红衍生物类棕榈酰基转移酶抑制剂的设计、合成及抗肿瘤活性研究. 药学学报, 2022 , 57 (4) : 1073 -1079 . DOI: 10.16438/j.0513-4870.2021-1389

Wei YU, Jin-jiao DONG, Xin-yue ZHU, Kan YANG, Zhen-ming LIU, Xiao-qiang QIAO, Ya-li SONG. Design, synthesis and antitumor activity of isatin derivatives as palmitoyl transferase inhibitors[J]. Acta Pharmaceutica Sinica, 2022 , 57 (4) : 1073 -1079 . DOI: 10.16438/j.0513-4870.2021-1389

正文

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靛红即二氢吲哚-2, 3-二酮, 在多种植物中广泛分布, 是一类重要的氮杂环化合物^[1]。其衍生物具有多种生物活性, 在抗肿瘤、抗病毒、神经保护等方面具有重要的意义, 其中最突出的作用是抗肿瘤活性^{[2, 3]}。最近几年研究表明, 靛红衍生物在体内体外均具有良好的抗肿瘤活性, Fares等^[4]将靛红与喹唑啉结构进行杂合, 制备了一系列新颖的靛红衍生物, 实验结果表明化合物1具有较强的体外抗肿瘤活性。Solomon等^[5]将靛红与苯并噻唑进行缀合, 合成了新型的希夫碱类衍生物2, 对人体的乳腺癌细胞具有一定程度的抑制活性。Eldehna等^[6]利用药效团杂合的原理, 将靛红与吡啶基团进行杂合得到化合物3, 对肿瘤细胞也有一定的细胞毒活性。有些靛红衍生物已经用于临床, 例如辉瑞制药研发的多靶点小分子酪氨酸激酶抑制剂舒尼替尼(sunitinib) 于2006年被FDA批准上市, 用于治疗晚期肾细胞癌等疾病; 勃林格殷格翰公司研发的三联血管生成抑制剂尼达尼布(nintedanib) 于2014年11月在德国获批上市, 用于治疗特定类型的晚期肺癌。因此, 设计以不同片段修饰的靛红衍生物, 合成了具有代表性的抗肿瘤化合物, 具体结构如图 1所示^[7]。

棕榈酰化修饰是一种广泛存在并且可逆的蛋白质翻译后脂质修饰, 对蛋白质的定位、扩散和稳定性的动态调控至关重要。多种癌细胞的增殖、迁移和侵袭都依赖于癌症相关蛋白的棕榈酰化, 大量数据证明, 与正常细胞比较, 在卵巢癌、乳腺癌、结肠癌、肾癌和前列腺癌中DHHC20表达水平均上调^[8]。人类棕榈酰基转移酶家族的23个成员多数都参与肿瘤的调节, 使得靶向棕榈酰基转移酶成为潜在的肿瘤治疗策略。Ducker等^[9]发现了5个棕榈酰基转移酶抑制剂, 其结构如图 2所示。Jennings等^[10]对5个化合物进行的棕榈酰基转移酶抑制活性实验显示, 所有化合物对棕榈酰基转移酶均有不同程度的抑制作用, 其中化合物Ⅴ的抑制作用最强。进一步的作用机制研究显示, 化合物Ⅴ对酶的抑制作用是可逆的, 且安全性更高。分子对接分析其与棕榈酰基转移酶的作用方式, 发现这5个化合物均可进入3'-磷酸腺苷-5'-二磷酸(PAP) 结合位点, Ⅰ、Ⅲ仅与His155有氢键作用; Ⅱ仅与Ser143有氢键作用; Ⅳ仅与His154有π-π共轭作用; Ⅴ与Lys135、His140、His141、Ser143有氢键作用且打分值最高, 同时也与PAP作用方式更为接近, 因此, 以化合物Ⅴ的结构为基础, 通过生物电子等排的方法将苯并氢化噻吩酮骨架替换成靛红结构, 并围绕此结构进行修饰, 有可能寻找到特异性更好、抑制作用可逆的棕榈酰基转移酶抑制剂。

结果与讨论

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1 化合物的设计

2018年Rana等^[11]报道了棕榈酰基转移酶的结构, 其蛋白晶体结构(PDB ID: 6BML) 中的配体小分子PAP所处的活性口袋是棕榈酰CoA的结合位点。本项目以配体小分子PAP所处的口袋作为活性位点, 利用生物电子等排理论, 将化合物Ⅴ的苯并氢化噻吩酮骨架替换为生物电子等排体靛红, 根据PAP的结构及其与氨基酸残基的相互作用特点, 在靛红的1位引入碱性基团二级胺结构; PAP所在口袋含有多种极性氨基酸(如组氨酸、丝氨酸、精氨酸等), 氨基硫脲带有1个硫原子和3个氮原子, 可以与周围的氨基酸残基形成良好的相互作用, 如氢键、p-π共轭等, 分子对接结果也进一步验证了这一猜想: 3位引入氨基硫脲结构可以增加与PAP结合位点Ser143、His141等极性氨基酸的相互作用。再在此结构基础上利用分子对接对其进行结构优化, 将3位氨基硫脲的部分结构环化形成噻唑烷酮, 增加的羰基氧原子还可以和PAP结合位点的氨基酸残基形成氢键, 增强与靶蛋白的相互作用, 设计了的靛红衍生物类棕榈酰基转移酶抑制剂。结构如图 3所示。

2 化合物的合成

目标化合物4a~4h、5a~5d的合成路线如图 4所示。中间体2、3的合成采用文献报道的方法进行^{[12, 13]}。以靛红为原料, 在碱性条件下, 分别与1, 2-二溴乙烷、1, 3-二溴丙烷或1, 4-二溴丁烷发生取代反应, 得到中间产物2; 再在碱性条件下引入吗啉环等二级胺得到中间产物3; 中间产物3与氨基硫脲经过缩合反应得到目标化合物4; 化合物4与2-溴乙酸乙酯在碱性条件下环合生成化合物5。目标化合物4a~4h、5a~5d的结构经¹H NMR、¹³C NMR和HR-MS进行了确证, 其收率、性状、熔点及波谱数据见表 1。

3 活性评价

3.1 体外抗增殖活性实验

本部分实验以顺铂为阳性对照药物, 选取MGC-803、HeLa、MCF-7、RBL-2H3和L-929细胞对目标化合物进行细胞毒性实验, 结果见表 2。抗增殖结果表明, 目标化合物对所测试的细胞具有不同程度的抑制活性, 其中化合物5a、5b对MCF-7细胞表现出较好的抗增殖活性, IC₅₀值分别为15.2和12.0 μmol·L^-1; 化合物4b、4d、5b对HeLa细胞表现出较好的抑制活性, IC₅₀值分别为8.1、14.7和12.6 μmol·L^-1; 化合物4f对L-929细胞体现出一定程度的毒性, 其IC₅₀值为11.5 μmol·L^-1, 遗憾的是目标化合物对RBL-2H3细胞的抑制活性都比较差。目标化合物中5b对MCF-7细胞抑制活性最好, 其IC₅₀为12.0 μmol·L^-1, 与阳性对照相当。它对棕榈酰基转移酶高表达的癌细胞具有较好的活性, 因此具有成为棕榈酰基转移酶抑制剂先导化合物的潜质。

3.2 AO/EB染色实验

本实验选择化合物5b来评估它对MCF-7癌细胞的影响, 如图 5所示。由图可知, 在30 μmol·L^-1浓度下, 化合物5b能明显引起视野内MCF-7癌细胞的减少, 一定程度上促进其凋亡, 且化合物5b的对MCF-7细胞的IC₅₀为12.0 μmol·L^-1, 其结果与抗增殖活性结果一致。

3.3 划痕实验

在抗增殖活性实验中, 化合物5b表现出较好的抗癌活性, 故本实验选择化合物5b来评估其对MCF-7癌细胞迁移的影响, 如图 6所示。与阴性对照相比, 化合物5b在15 μmol·L^-1浓度下能明显抑制MCF-7癌细胞的迁移, 并且相同浓度下化合物5b对MCF-7细胞的抑制作用比顺铂效果好, 与实验预期的结果一致。

4 分子对接实验

目标化合物的分子对接结果如表 3、图 7所示。由表中数据可知, 化合物均能进入PAP活性口袋内, 并且能与周围氨基酸残基产生相互作用力。从图 7可知, 化合物4b靛红结构上的羰基、侧链取代基上的两个氨基都可与氨基酸残基Ser143形成氢键, 将其线性结构进一步改造成环时, 化合物5b母核结构上的羰基保持着与氨基酸残基Ser143的氢键作用, 并且其噻唑烷酮结构上的硫原子可与氨基酸残基His141形成氢键, 羰基可与Lys135形成氢键。与化合物4b相比, 化合物5b与6BML的相互作用和PAP与6BML的相互作用(PAP与氨基酸残基His141、Lys135、Ser143等形成氢键) 更加吻合, 这可能是化合物5b对MCF-7细胞的抗增殖活性强于化合物4b的原因。

5 小结

基于化合物Ⅴ的化学结构, 利用生物电子等排体原理, 结合分子对接技术设计合成了12个靛红衍生物类棕榈酰基转移酶抑制剂, 测定了其体外抗肿瘤活性并进行了分子对接研究。采用MTT法对该类化合物进行抗肿瘤活性测试, 结果表明, 大部分化合物具有中等的抗肿瘤活性, 其中化合物5b对MCF-7的IC₅₀值小于15 μmol·L^-1, 和顺铂抑制活性相当。细胞划痕实验表明, 在15 μmol·L^-1浓度下, 化合物5b能明显抑制MCF-7癌细胞的迁移。AO/EB染色实验表明, 化合物5b的浓度为30 μmol·L^-1时能显著引起MCF-7癌细胞的凋亡。分子对接结果表明, 化合物均能完全进入PAP活性口袋内, 且生物活性结果越好的化合物, 其作用方式与配体PAP与棕榈酰基转移酶的相互作用方式越吻合, 这为后续研究设计更高效的棕榈酰基转移酶抑制剂提供了思路。

实验部分

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SGW X-4显微熔点仪(上海精密仪器科技有限公司, 未校正); Bruker AVIII-600 MHz核磁共振波谱仪(Bruker); QEXACTIVE高分辨质谱分析仪(Thermo Fisher Scientific); LDZX-30KBS立式压力蒸汽灭菌器(上海申安医疗器厂); W-CJ-ZDF型超净台(上海贺德实验设备厂); 其他试剂和溶剂未经特别说明均为国产或进口分析纯与生物级, 无水试剂均按常规方法处理。

1 化合物合成

1.1 N-(2-溴乙基) 靛红(2)

向250 mL圆底烧瓶中加入7.36 g (50 mmol) 化合物1, 用50 mL的N, N-二甲基甲酰胺溶解后, 加入8.29 g (60 mmol) K₂CO₃, 室温搅拌10 min, 再加入60 mmol 1, 2-二溴乙烷(1, 3-二溴丙烷或1, 4-二溴丁烷), 室温反应, TLC监测反应进程^[12]。反应完全后向反应液里倒入100 mL水, 静置过夜, 析出沉淀, 抽滤得粗品。粗品用200目硅胶色谱[V (乙酸乙酯)∶V (石油醚) = 1∶5] 纯化得化合物2。收率54%~75%。

1.2 N-(4-吗啉乙基) 靛红(3)

将5 mmol化合物2、6 mmol Na₂CO₃和6 mmol二级胺置于50 mL圆底烧瓶中, 加入10 mL无水乙腈, 室温反应, TLC监测反应进程^[13]。反应完全后抽滤除去固体, 滤液减压蒸馏, 除去溶剂得粗品。粗品用200目硅胶色谱[V (乙酸乙酯)∶V(石油醚) = 1∶2] 纯化得化合物3。产率60%~65%。

1.3 N-(4-吗啉乙基) 靛红-3-缩氨基硫脲(4a)

将1 mmol化合物3、1 mmol氨基硫脲置于25 mL圆底烧瓶中, 加入5 mL无水乙醇溶解, 搅拌下滴加5滴冰醋酸, 滴加完毕后升温至80 ℃反应, TLC监测反应进程。反应完全后趁热过滤, 热乙醇洗涤, 得粗品。粗品用200目硅胶色谱[V (二氯甲烷)∶V (甲醇) = 100∶1] 纯化得化合物4a。化合物4b~4h参照此法合成, 收率60%~90%。

1.4 2-(N-(4-吗啉乙基) 靛红-3-二亚甲基肼) 噻唑烷-4-酮(5a)

向25 mL圆底烧瓶中加入0.5 mmol化合物4、0.5 mmol无水乙酸钠、5 mL甲醇, 搅拌下滴加0.6 mmol溴乙酸乙酯, 室温反应, TLC监测反应进程, 反应结束后将反应体系倒入冰水中, 二氯甲烷萃取3次, 合并有机相, 无水硫酸钠干燥后回收溶剂, 经200目硅胶色谱[V (二氯甲烷)∶V (甲醇) = 100∶1] 纯化得化合物5a。化合物5b~5d参照此法合成, 收率60%~80%。

2 化合物活性评价

2.1 体外抗增殖活性

采用MTT法进行体外抗增殖活性研究^{[14, 15]}。选取人胃癌细胞(MGC-803)、人宫颈癌细胞(HeLa)、人乳腺癌细胞(MCF-7) 和大鼠嗜碱性白血病细胞(RBL-2H3) 4种肿瘤细胞进行抗肿瘤活性实验和小鼠成纤维细胞(L-929) 对目标化合物进行细胞毒性实验。将细胞悬液(每毫升4×10⁴个) 接种到96孔板中, 每孔90 μL。在37 ℃、CO₂相对浓度为5%、相对湿度为95%的培养箱中培养, 当显微镜观察到细胞单层铺满96孔板底部时, 每孔加入10 μL的不同浓度的化合物。将96孔板放置于培养箱中, 显微镜观察细胞形态, 培养48 h后, 每孔加入10 μL浓度为5 mg·mL^-1的MTT的PBS溶液(现配现用, 避光), 继续培养4 h。4 h后, 弃掉96孔板内的培养基, 每孔加入100 μL的DMSO后, 置于摇床轻摇20 min使结晶充分溶解。待结晶溶解, 把96孔板放置在酶标仪上, 设置波长为490 nm, 测定吸光度, 重复测定4次。使用软件GraphPad Prism 8.3计算每个化合物的IC₅₀值。

2.2 AO/EB染色实验

将细胞悬液接种到12孔板中, 每孔900 μL。将12孔板置于CO₂恒温培养箱中, 37 ℃、CO₂相对浓度为5%、相对湿度为95%的条件下培养细胞。12 h后每孔加入100 μL不同浓度的化合物, 孵育48 h。弃掉上层培养基, PBS清洗细胞2次, 使用1×Buffer重悬细胞。避光, 加入等量混合均匀的AO/EB染色液, 轻轻混合均匀后室温孵育5 min, 使用荧光倒置显微镜观察拍照^[16]。

2.3 划痕实验

将6孔板置于CO₂恒温培养箱中, 37 ℃、CO₂相对浓度为5%、相对湿度为95%的条件下培养细胞。直至观察细胞密度达到90%左右后。事先用Marker笔在6孔板底部均匀的划3条平行直线, 用200 μL枪头在与标记线垂直的地方划3条平行线, 划后除去培养基, 用PBS清洗3次, 加入无血清培养基和药物(空白组加入DMSO)。将其放入37 ℃、CO₂相对浓度为5%、相对湿度为95%的培养箱中, 按0、12、24、48 h观察结果并拍照。

3 分子对接研究

分子对接使用Maestro 11.9版本的Schrödinger Suite软件。选取DHHC20晶体结构(Protein Data Bank, ID: 6BML) 作为受体, 与目标化合物进行分子对接研究。首先利用Schrödinger Suite软件中的LigPrep模块对目标化合物进行准备优化; 然后, 利用Schrödinger Suite软件中的Protein Preparation Wizard模块对受体蛋白进行能量优化、修复丢失的氨基酸残基和loop区、加氢、删除水分子; 再利用Schrödinger Suite软件中的Glide模块进行受体格点设置; 最后, 利用Glide模块中的Ligand Docking工具进行Glide-XP模式的分子对接。选取打分值最高的构象用PyMoL软件(http://www.pymol.org/) 进行作图^[17]。

作者贡献: 余伟、董金娇、朱昕悦、宋亚丽负责化合物的设计合成、活性研究及稿件撰写与修改, 杨侃、刘振明和乔晓强参与化合物的合成及分子对接分析。

利益冲突: 本文作者声明无任何利益冲突。

基金

收起

河北省高等学校科学技术研究项目(ZD2019060)
国家自然科学基金资助项目(82003597)
河北省自然科学基金资助项目(B2019201359)
河北省青年拔尖人才、河北大学自然科学多学科交叉研究计划资助项目(DXK201912)
河北省硕士研究生创新资助项目(CXZZSS2021012)
大学生创新创业训练项目(2021193)

参考文献

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https://doi.org/10.6023/cjoc202101056

2022年第57卷第4期

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doi: 10.16438/j.0513-4870.2021-1389

接收时间：2021-09-22
首发时间：2025-12-22
出版时间：2022-04-12

补充材料

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收稿日期：2021-09-22
修回日期：2021-10-13

基金

河北省高等学校科学技术研究项目(ZD2019060)

国家自然科学基金资助项目(82003597)

河北省自然科学基金资助项目(B2019201359)

河北省青年拔尖人才、河北大学自然科学多学科交叉研究计划资助项目(DXK201912)

河北省硕士研究生创新资助项目(CXZZSS2021012)

大学生创新创业训练项目(2021193)

作者信息

1.河北大学药学院, 河北省药物质量分析控制重点实验室, 河北保定 071002

2.北京大学, 天然药物及仿生药物国家重点实验室, 北京 100191

3.河北大学, 药物化学与分子诊断教育部重点实验室, 河北保定 071002

通讯作者:

*宋亚丽, E-mail: yalisong@hbu.edu.cn

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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Compd.	Yield /%	Property	mp/℃	¹H NMR (600 MHz, DMSO-d₆)	¹³C NMR (151 MHz, DMSO-d₆)	ESI⁺-MS (m/z) [M+H]⁺
4a	83	Yellow powder	212.0-213.1	12.41 (s, 1H), 9.08 (s, 1H), 8.73 (s, 1H), 7.71 (d, J = 7.3 Hz, 1H), 7.43 (t, J = 7.3 Hz, 1H), 7.21 (d, J = 7.9 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 3.87 (t, J = 6.4 Hz, 2H), 3.51 (t, J = 4.5 Hz, 4H), 2.57 (t, J = 6.4 Hz, 2H), 2.44 (t, J = 4.5 Hz, 4H).	178.8, 160.8, 142.9, 131.1, 131.0, 122.7, 120.7, 119.3, 110.1, 66.1, 54.9, 53.1, 36.6.	334.133 2
4b	70	Yellow powder	232.3-233.5	12.36 (s, 1H), 9.08 (s, 1H), 8.73 (s, 1H), 7.72 (d, J = 7.4 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 3.98 (t, J = 7.3 Hz, 2H), 3.19 (t, J = 7.4 Hz, 2H), 2.88 (m, 2H), 2.73 (m, 1H), 1.62 (m, 2H), 1.52 (m, 2H), 1.34 (m, 2H), 1.07 (d, J = 7.1 Hz, 3H).	178.7, 160.9, 142.0, 131.5, 131.1, 123.1, 120.8, 119.7, 110.0, 59.2, 50.9, 48.1, 33.6, 30.7, 22.3, 21.5, 17.1.	346.169 6
4c	80	Yellow powder	230.0-231.5	12.41 (s, 1H), 9.07 (s, 1H), 8.73 (s, 1H), 7.72 (d, J = 7.4 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 3.82 (t, J = 6.6 Hz, 2H), 3.62 (t, J = 7.8 Hz, 4H), 2.80 (t, J = 7.1 Hz, 2H), 2.72 (t, J = 7.7 Hz, 4H), 1.91 (m, 2H).	178.7, 160.9, 142.8, 131.2, 131.1, 122.8, 120.7, 119.4, 109.9, 64.7, 54.5, 52.2, 37.1, 22.6.	348.148 9
4d	87	Yellow powder	217.3-218.9	12.37 (s, 1H), 9.06 (s, 1H), 8.73 (s, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 3.85 (t, J = 6.8 Hz, 2H), 3.40 (m, 1H), 3.18 (m, 2H), 2.97 (t, J = 6.3 Hz, 2H), 2.03 (t, J = 7.5 Hz, 2H), 1.82 (m, 2H), 1.67 (m, 2H), 1.54 (m, 2H), 1.25 (d, J = 7.9 Hz, 3H).	178.7, 160.9, 142.6, 131.2, 131.1, 122.9, 120.8, 119.5, 109.9, 58.3, 51.1, 49.5, 36.7, 31.1, 30.7, 22.5, 21.0, 17.3.	360.185 8
4e	76	Yellow powder	231.2-232.5	12.38 (s, 1H), 9.08 (s, 1H), 8.74 (s, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 7.26 (d, J = 7.9 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 3.84 (t, J = 6.8 Hz, 2H), 3.09 (t, J = 7.1 Hz, 2H), 3.04 (m, 4H), 1.98 (m, 2H), 1.14 (t, J = 7.3 Hz, 6H).	178.7, 160.8, 142.8, 131.2, 131.1, 122.8, 120.7, 119.4, 109.9, 49.1, 46.2, 37.1, 23.2, 9.9.	334.170 2
4f	87	Yellow powder	225.8-226.5	12.42 (s, 1H), 9.05 (s, 1H), 8.70 (s, 1H), 7.71 (d, J = 7.5 Hz, 1H), 7.44 (t, J = 7.7 Hz, 1H), 7.21 (d, J = 7.9 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 3.77 (t, J = 6.8 Hz, 2H), 3.66 (t, J = 7.4 Hz, 4H), 2.74 (t, J = 7.2 Hz, 4H), 2.69 (t, J = 6.9 Hz, 2H), 1.66 (m, 2H), 1.57 (m, 2H).	178.7, 160.8, 142.7, 131.2, 131.1, 122.8, 120.7, 119.4, 110.0, 64.7, 56.6, 56.0, 52.2, 24.4, 21.7.	362.165 1
4g	84	Yellow powder	217.3-218.9	12.42 (s, 1H), 9.03 (s, 1H), 8.69 (s, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.42 (t, J = 7.7 Hz, 1H), 7.20 (d, J = 7.9 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 3.76 (t, J = 6.9 Hz, 2H), 3.43 (t, J = 7.0 Hz, 2H), 3.02 (m, 1H), 2.87 (m, 2H), 1.67 (t, J = 7.6 Hz, 2H), 1.62 (m, 2H), 1.57 (m, 2H), 1.53 (m, 2H), 1.35 (m, 2H), 1.11 (d, J = 6.3 Hz, 3H).	178.6, 160.7, 142.7, 131.2, 131.1, 122.8, 120.7, 119.3, 110.0, 56.4, 56.0, 51.6, 50.4, 48.5, 31.8, 24.5, 23.71, 21.4, 18.5.	374.201 5
4h	64	Yellow powder	297.5-298.5	12.42 (s, 1H), 9.08 (s, 1H), 8.73 (s, 1H), 7.71 (d, J = 7.1 Hz, 1H), 7.44 (t, J = 7.8, 1.0 Hz, 1H), 7.21 (d, J = 7.9 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 3.77 (t, J = 6.9 Hz, 2H), 2.73 (t, J = 7.9 Hz, 2H), 2.64 (m, 4H), 1.66 (m, 2H), 1.50 (m, 2H), 1.01 (t, J = 6.8 Hz, 6H).	178.7, 160.7, 142.7, 131.2, 131.1, 122.8, 120.7, 119.4, 110.0, 51.1, 48.5, 46.33, 38.8, 24.5, 10.1.	347.178 0
5a	77	Yellow powder	216.1-217.9	12.43 (s, 1H), 7.54 (d, J = 7.4 Hz, 1H), 7.42 (t, J = 7.7 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H), 7.03 (t, J = 7.7 Hz, 1H), 3.94 (s, 2H, S-CH₂), 3.82 (t, J = 6.4 Hz, 2H), 3.51 (t, J = 4.6 Hz, 4H), 2.55 (t, J = 6.5 Hz, 2H), 2.45 (t, J = 4.8 Hz, 4H).	184.3, 175.1, 157.2, 143.7, 143.5, 132.0, 122.3, 120.8, 120.1, 109.4, 66.0, 54.9, 53.1, 36.4, 33.4.	372.112 5
5b	70	Yellow powder	265.0-266.3	11.52 (s, 1H), 7.55 (d, J = 7.2 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.25 (d, J = 6.9 Hz, 1H), 7.10 (t, J = 6.7 Hz, 1H), 4.02 (s, 2H, S-CH₂), 3.96 (t, J = 7.2 Hz, 2H), 3.26 (t, J = 6.0 Hz, 2H), 3.12 (m, 1H), 2.93 (t, J = 7.0 Hz, 2H), 1.76 (m, 2H), 1.46 (m, 2H), 1.17 (d, J = 6.3 Hz, 3H).	186.2, 178.7, 160.9, 142.5, 131.1, 131.0, 122.9, 120.7, 119.5, 110.1, 56.3, 50.6, 50.4, 48.9, 35.1, 31.8, 24.3, 22.2, 17.2.	384.148 9
5c	76	Yellow powder	210.5-211.4	12.44 (s, 1H), 7.54 (d, J = 7.3 Hz, 1H), 7.42 (t, J = 7.7 Hz, 1H), 7.11 (d, J = 7.9 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 3.93 (s, 2H, S-CH₂), 3.74 (t, J = 6.7 Hz, 2H), 3.49 (t, J = 4.7 Hz, 4H), 2.34 (t, J = 7.3 Hz, 2H), 2.30 (t, J = 4.9 Hz, 4H), 1.76 (m, 2H).	186.8, 178.7, 160.9, 142.8, 131.2, 131.1, 122.8, 120.7, 119.4, 109.9, 64.7, 54.5, 52.2, 37.1, 27.4, 22.6.	386.128 7
5d	72	Yellow powder	200.2-203.0	12.42 (s, 1H), 7.53 (d, J = 7.3 Hz, 1H), 7.40 (t, J = 7.5 Hz, 1H), 7.11 (d, J = 7.4 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 3.91 (s, 2H, S-CH₂), 3.70 (t, J = 7.1 Hz, 2H), 3.55 (t, J = 4.1 Hz, 4H), 2.37 (t, J = 4.3 Hz, 4H), 2.33 (t, J = 7.3 Hz, 2H), 1.61 (m, 2H), 1.46 (m, 2H).	187.5, 178.7, 160.7, 142.7, 131.2, 131.1, 122.8, 120.7, 119.4, 110.0, 64.7, 56.5, 52.2, 38.8, 24.4, 21.7, 18.5.	402.160 0

Compd.

Yield /%

Property

mp/℃

¹H NMR (600 MHz, DMSO-d₆)

¹³C NMR (151 MHz, DMSO-d₆)

ESI⁺-MS (m/z) [M+H]⁺

Yellow powder

212.0-213.1

12.41 (s, 1H), 9.08 (s, 1H), 8.73 (s, 1H), 7.71 (d, J = 7.3 Hz, 1H), 7.43 (t, J = 7.3 Hz, 1H), 7.21 (d, J = 7.9 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 3.87 (t, J = 6.4 Hz, 2H), 3.51 (t, J = 4.5 Hz, 4H), 2.57 (t, J = 6.4 Hz, 2H), 2.44 (t, J = 4.5 Hz, 4H).

178.8, 160.8, 142.9, 131.1, 131.0, 122.7, 120.7, 119.3, 110.1, 66.1, 54.9, 53.1, 36.6.

334.133 2

Yellow powder

232.3-233.5

12.36 (s, 1H), 9.08 (s, 1H), 8.73 (s, 1H), 7.72 (d, J = 7.4 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 3.98 (t, J = 7.3 Hz, 2H), 3.19 (t, J = 7.4 Hz, 2H), 2.88 (m, 2H), 2.73 (m, 1H), 1.62 (m, 2H), 1.52 (m, 2H), 1.34 (m, 2H), 1.07 (d, J = 7.1 Hz, 3H).

178.7, 160.9, 142.0, 131.5, 131.1, 123.1, 120.8, 119.7, 110.0, 59.2, 50.9, 48.1, 33.6, 30.7, 22.3, 21.5, 17.1.

346.169 6

Yellow powder

230.0-231.5

12.41 (s, 1H), 9.07 (s, 1H), 8.73 (s, 1H), 7.72 (d, J = 7.4 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 3.82 (t, J = 6.6 Hz, 2H), 3.62 (t, J = 7.8 Hz, 4H), 2.80 (t, J = 7.1 Hz, 2H), 2.72 (t, J = 7.7 Hz, 4H), 1.91 (m, 2H).

178.7, 160.9, 142.8, 131.2, 131.1, 122.8, 120.7, 119.4, 109.9, 64.7, 54.5, 52.2, 37.1, 22.6.

348.148 9

Yellow powder

217.3-218.9

12.37 (s, 1H), 9.06 (s, 1H), 8.73 (s, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 3.85 (t, J = 6.8 Hz, 2H), 3.40 (m, 1H), 3.18 (m, 2H), 2.97 (t, J = 6.3 Hz, 2H), 2.03 (t, J = 7.5 Hz, 2H), 1.82 (m, 2H), 1.67 (m, 2H), 1.54 (m, 2H), 1.25 (d, J = 7.9 Hz, 3H).

178.7, 160.9, 142.6, 131.2, 131.1, 122.9, 120.8, 119.5, 109.9, 58.3, 51.1, 49.5, 36.7, 31.1, 30.7, 22.5, 21.0, 17.3.

360.185 8

Yellow powder

231.2-232.5

12.38 (s, 1H), 9.08 (s, 1H), 8.74 (s, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 7.26 (d, J = 7.9 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 3.84 (t, J = 6.8 Hz, 2H), 3.09 (t, J = 7.1 Hz, 2H), 3.04 (m, 4H), 1.98 (m, 2H), 1.14 (t, J = 7.3 Hz, 6H).

178.7, 160.8, 142.8, 131.2, 131.1, 122.8, 120.7, 119.4, 109.9, 49.1, 46.2, 37.1, 23.2, 9.9.

334.170 2

Yellow powder

225.8-226.5

12.42 (s, 1H), 9.05 (s, 1H), 8.70 (s, 1H), 7.71 (d, J = 7.5 Hz, 1H), 7.44 (t, J = 7.7 Hz, 1H), 7.21 (d, J = 7.9 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 3.77 (t, J = 6.8 Hz, 2H), 3.66 (t, J = 7.4 Hz, 4H), 2.74 (t, J = 7.2 Hz, 4H), 2.69 (t, J = 6.9 Hz, 2H), 1.66 (m, 2H), 1.57 (m, 2H).

178.7, 160.8, 142.7, 131.2, 131.1, 122.8, 120.7, 119.4, 110.0, 64.7, 56.6, 56.0, 52.2, 24.4, 21.7.

362.165 1

Yellow powder

217.3-218.9

12.42 (s, 1H), 9.03 (s, 1H), 8.69 (s, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.42 (t, J = 7.7 Hz, 1H), 7.20 (d, J = 7.9 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 3.76 (t, J = 6.9 Hz, 2H), 3.43 (t, J = 7.0 Hz, 2H), 3.02 (m, 1H), 2.87 (m, 2H), 1.67 (t, J = 7.6 Hz, 2H), 1.62 (m, 2H), 1.57 (m, 2H), 1.53 (m, 2H), 1.35 (m, 2H), 1.11 (d, J = 6.3 Hz, 3H).

178.6, 160.7, 142.7, 131.2, 131.1, 122.8, 120.7, 119.3, 110.0, 56.4, 56.0, 51.6, 50.4, 48.5, 31.8, 24.5, 23.71, 21.4, 18.5.

374.201 5

Yellow powder

297.5-298.5

12.42 (s, 1H), 9.08 (s, 1H), 8.73 (s, 1H), 7.71 (d, J = 7.1 Hz, 1H), 7.44 (t, J = 7.8, 1.0 Hz, 1H), 7.21 (d, J = 7.9 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 3.77 (t, J = 6.9 Hz, 2H), 2.73 (t, J = 7.9 Hz, 2H), 2.64 (m, 4H), 1.66 (m, 2H), 1.50 (m, 2H), 1.01 (t, J = 6.8 Hz, 6H).

178.7, 160.7, 142.7, 131.2, 131.1, 122.8, 120.7, 119.4, 110.0, 51.1, 48.5, 46.33, 38.8, 24.5, 10.1.

347.178 0

Yellow powder

216.1-217.9

12.43 (s, 1H), 7.54 (d, J = 7.4 Hz, 1H), 7.42 (t, J = 7.7 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H), 7.03 (t, J = 7.7 Hz, 1H), 3.94 (s, 2H, S-CH₂), 3.82 (t, J = 6.4 Hz, 2H), 3.51 (t, J = 4.6 Hz, 4H), 2.55 (t, J = 6.5 Hz, 2H), 2.45 (t, J = 4.8 Hz, 4H).

184.3, 175.1, 157.2, 143.7, 143.5, 132.0, 122.3, 120.8, 120.1, 109.4, 66.0, 54.9, 53.1, 36.4, 33.4.

372.112 5

Yellow powder

265.0-266.3

11.52 (s, 1H), 7.55 (d, J = 7.2 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.25 (d, J = 6.9 Hz, 1H), 7.10 (t, J = 6.7 Hz, 1H), 4.02 (s, 2H, S-CH₂), 3.96 (t, J = 7.2 Hz, 2H), 3.26 (t, J = 6.0 Hz, 2H), 3.12 (m, 1H), 2.93 (t, J = 7.0 Hz, 2H), 1.76 (m, 2H), 1.46 (m, 2H), 1.17 (d, J = 6.3 Hz, 3H).

186.2, 178.7, 160.9, 142.5, 131.1, 131.0, 122.9, 120.7, 119.5, 110.1, 56.3, 50.6, 50.4, 48.9, 35.1, 31.8, 24.3, 22.2, 17.2.

384.148 9

Yellow powder

210.5-211.4

12.44 (s, 1H), 7.54 (d, J = 7.3 Hz, 1H), 7.42 (t, J = 7.7 Hz, 1H), 7.11 (d, J = 7.9 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 3.93 (s, 2H, S-CH₂), 3.74 (t, J = 6.7 Hz, 2H), 3.49 (t, J = 4.7 Hz, 4H), 2.34 (t, J = 7.3 Hz, 2H), 2.30 (t, J = 4.9 Hz, 4H), 1.76 (m, 2H).

186.8, 178.7, 160.9, 142.8, 131.2, 131.1, 122.8, 120.7, 119.4, 109.9, 64.7, 54.5, 52.2, 37.1, 27.4, 22.6.

386.128 7

Yellow powder

200.2-203.0

12.42 (s, 1H), 7.53 (d, J = 7.3 Hz, 1H), 7.40 (t, J = 7.5 Hz, 1H), 7.11 (d, J = 7.4 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 3.91 (s, 2H, S-CH₂), 3.70 (t, J = 7.1 Hz, 2H), 3.55 (t, J = 4.1 Hz, 4H), 2.37 (t, J = 4.3 Hz, 4H), 2.33 (t, J = 7.3 Hz, 2H), 1.61 (m, 2H), 1.46 (m, 2H).

187.5, 178.7, 160.7, 142.7, 131.2, 131.1, 122.8, 120.7, 119.4, 110.0, 64.7, 56.5, 52.2, 38.8, 24.4, 21.7, 18.5.

402.160 0

Compd.	IC₅₀/μmol·L^-1
4a	38.7 ± 1.4	49.6 ± 8.6	82.6 ± 1.9	54.2 ± 1.2	39.7 ± 2.0
4b	8.1 ± 2.0	47.6 ± 5.1	24.5 ± 4.6	58.5 ± 7.8	53.2 ± 5.9
4c	22.6 ± 1.3	62.7 ± 2.4	41.3 ± 5.2	47.2 ± 1.1	46.4 ± 3.2
4d	14.7 ± 5.2	39.4 ± 3.4	28.0 ± 1.2	31.4 ± 5.6	61.6 ± 2.4
4e	49.6 ± 1.1	50.9 ± 1.0	35.6 ± 3.4	39.9 ± 5.1	82.1 ± 2.1
4f	72.3 ± 1.3	50.7 ± 8.7	45.5 ± 1.2	69.3 ± 7.2	11.5 ± 1.1
4g	44.0 ± 2.2	76.7 ± 1.2	81.4 ± 5.9	59.2 ± 8.1	54.6 ± 4.2
4h	83.7 ± 1.9	63.1 ± 9.4	67.2 ± 2.6	81.6 ± 3.4	45.0 ± 1.1
5a	33.0 ± 4.0	49.9 ± 6.6	15.2 ± 3.6	51.6 ± 7.2	39.7 ± 6.3
5b	12.6 ± 2.9	16.4 ± 1.8	12.0 ± 1.3	36.8 ± 1.9	74.4 ± 1.6
5c	43.4 ± 1.6	44.7 ± 6.7	44.9 ± 5.0	70.9 ± 1.5	79.2 ± 1.2
5d	82.4 ± 1.9	62.6 ± 1.0	81.3 ± 1.9	82.3 ± 3.0	47.4 ± 1.7
Cisplatin	40.1 ± 4.1	66.6 ± 6.8	8.4 ± 2.0	49.8 ± 6.7	52.0 ± 8.7

Compd.

IC₅₀/μmol·L^-1

HeLa

MGC-803

MCF-7

RBL-2H3

L-929

38.7 ± 1.4

49.6 ± 8.6

82.6 ± 1.9

54.2 ± 1.2

39.7 ± 2.0

8.1 ± 2.0

47.6 ± 5.1

24.5 ± 4.6

58.5 ± 7.8

53.2 ± 5.9

22.6 ± 1.3

62.7 ± 2.4

41.3 ± 5.2

47.2 ± 1.1

46.4 ± 3.2

14.7 ± 5.2

39.4 ± 3.4

28.0 ± 1.2

31.4 ± 5.6

61.6 ± 2.4

49.6 ± 1.1

50.9 ± 1.0

35.6 ± 3.4

39.9 ± 5.1

82.1 ± 2.1

72.3 ± 1.3

50.7 ± 8.7

45.5 ± 1.2

69.3 ± 7.2

11.5 ± 1.1

44.0 ± 2.2

76.7 ± 1.2

81.4 ± 5.9

59.2 ± 8.1

54.6 ± 4.2

83.7 ± 1.9

63.1 ± 9.4

67.2 ± 2.6

81.6 ± 3.4

45.0 ± 1.1

33.0 ± 4.0

49.9 ± 6.6

15.2 ± 3.6

51.6 ± 7.2

39.7 ± 6.3

12.6 ± 2.9

16.4 ± 1.8

12.0 ± 1.3

36.8 ± 1.9

74.4 ± 1.6

43.4 ± 1.6

44.7 ± 6.7

44.9 ± 5.0

70.9 ± 1.5

79.2 ± 1.2

82.4 ± 1.9

62.6 ± 1.0

81.3 ± 1.9

82.3 ± 3.0

47.4 ± 1.7

Cisplatin

40.1 ± 4.1

66.6 ± 6.8

8.4 ± 2.0

49.8 ± 6.7

52.0 ± 8.7

Compd.	H-Bonds interaction	p-π conjugation
4a	Ser143; His155	-
4b	Ser143	-
4c	Ser143; His155	-
4d	Ser143; Arg246	-
4e	Ser143; His141	-
4f	Ser143; His154; His155	-
4g	Ser143; His154	-
4h	His155; His141	-
5a	Lys130; His140	Lys135
5b	Ser143; His141; Lys135	-
5c	Lys130; Lys135; Ser143	-
5d	Ser143; His155	-
PAP	His141; His140; Ser143; Lys135	-

Compd.

H-Bonds interaction

p-π conjugation

Ser143; His155

Ser143

Ser143; His155

Ser143; Arg246

Ser143; His141

Ser143; His154; His155

Ser143; His154

His155; His141

Lys130; His140

Lys135

Ser143; His141; Lys135

Lys130; Lys135; Ser143

Ser143; His155

PAP

His141; His140; Ser143; Lys135