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Compd.	ESI-MS (m/z) [M+H]⁺	Elemental analysis/found (Calcd.)
3	618.2	75.62 (75.74)	8.43 (8.46)	2.27 (2.26)
4	618.4	75.73 (75.76)	8.49 (8.48)	2.26 (2.27)
5	632.4	75.86 (75.98)	8.64 (8.61)	2.23 (2.22)
6	632.3	75.89 (75.95)	9.06 (9.02)	2.17 (2.16)
7	646.5	76.28 (76.19)	8.72 (8.73)	2.18 (2.17)
8	660.4	76.45 (76.39)	8.83 (8.85)	2.13 (2.12)
11	619.4	73.57 (73.70)	8.33 (8.30)	4.54 (4.52)
12	633.4	73.99 (73.96)	8.47 (8.44)	4.43 (4.42)
13	633.1	73.83 (73.97)	8.38 (8.40)	4.41 (4.40)
14	681.4	75.92 (75.80)	7.83 (7.84)	4.10 (4.11)

Compd.

ESI-MS (m/z) [M+H]⁺

Elemental analysis/found (Calcd.)

618.2

75.62 (75.74)

8.43 (8.46)

2.27 (2.26)

618.4

75.73 (75.76)

8.49 (8.48)

2.26 (2.27)

632.4

75.86 (75.98)

8.64 (8.61)

2.23 (2.22)

632.3

75.89 (75.95)

9.06 (9.02)

2.17 (2.16)

646.5

76.28 (76.19)

8.72 (8.73)

2.18 (2.17)

660.4

76.45 (76.39)

8.83 (8.85)

2.13 (2.12)

619.4

73.57 (73.70)

8.33 (8.30)

4.54 (4.52)

633.4

73.99 (73.96)

8.47 (8.44)

4.43 (4.42)

633.1

73.83 (73.97)

8.38 (8.40)

4.41 (4.40)

681.4

75.92 (75.80)

7.83 (7.84)

4.10 (4.11)

Compd.	ESI-MS (m/z) [M+H]⁺	Elemental analysis/found (Calcd.)
3	618.2	75.62 (75.74)	8.43 (8.46)	2.27 (2.26)
4	618.4	75.73 (75.76)	8.49 (8.48)	2.26 (2.27)
5	632.4	75.86 (75.98)	8.64 (8.61)	2.23 (2.22)
6	632.3	75.89 (75.95)	9.06 (9.02)	2.17 (2.16)
7	646.5	76.28 (76.19)	8.72 (8.73)	2.18 (2.17)
8	660.4	76.45 (76.39)	8.83 (8.85)	2.13 (2.12)
11	619.4	73.57 (73.70)	8.33 (8.30)	4.54 (4.52)
12	633.4	73.99 (73.96)	8.47 (8.44)	4.43 (4.42)
13	633.1	73.83 (73.97)	8.38 (8.40)	4.41 (4.40)
14	681.4	75.92 (75.80)	7.83 (7.84)	4.10 (4.11)

Compd.

ESI-MS (m/z) [M+H]⁺

Elemental analysis/found (Calcd.)

618.2

75.62 (75.74)

8.43 (8.46)

2.27 (2.26)

618.4

75.73 (75.76)

8.49 (8.48)

2.26 (2.27)

632.4

75.86 (75.98)

8.64 (8.61)

2.23 (2.22)

632.3

75.89 (75.95)

9.06 (9.02)

2.17 (2.16)

646.5

76.28 (76.19)

8.72 (8.73)

2.18 (2.17)

660.4

76.45 (76.39)

8.83 (8.85)

2.13 (2.12)

619.4

73.57 (73.70)

8.33 (8.30)

4.54 (4.52)

633.4

73.99 (73.96)

8.47 (8.44)

4.43 (4.42)

633.1

73.83 (73.97)

8.38 (8.40)

4.41 (4.40)

681.4

75.92 (75.80)

7.83 (7.84)

4.10 (4.11)

Compd.	¹H NMR (CDCl₃)
3	7.76 (s, 1H, NH), 7.45 (d, 1H, J = 8.2 Hz, Ar-H), 7.29 (s, 1H, Ar-H), 7.16 (s, 1H, Ar-H), 5.51 (s, 1H, H-12), 3.96 (s, 2H, -COOCH₂CH₂CH₃), 2.28 (d, 1H, J = 10.8 Hz, H-18), 1.63-1.49 (m, 3H, -COOCH₂CH₂CH₃), 1.58 (s, 2H, -COOCH₂CH₂CH₃), 1.24 (s, 1H, H-9), 1.16, 1.14, 1.07, 1.02, 0.92, 0.99, 0.87 (s, each 3H)
4	7.74 (s, 1H, NH), 7.45 (d, 1H, J = 9.2 Hz, Ar-H), 7.19 (s, 1H, Ar-H), 7.15 (s, 1H, Ar-H), 5.64 (s, 1H, H-12), 4.27 (s, 1H, -COOCH(CH₃)CH₃), 2.28 (d, 1H, J = 9.6 Hz, H-18), 1.44 (d, 3H, J = 9.5 Hz, -COOCH(CH₃)CH₃), 1.43 (d, 3H, J = 9.5 Hz, -COOCH(CH₃)CH₃), 1.29 (s, 1H, H-9), 1.23, 1.19, 1.08, 1.02, 1.01, 0.97, 0.87 (s, each 3H)
5	7.74 (s, 1H, NH), 7.45 (d, 1H, J = 9.7 Hz, Ar-H), 7.19 (s, 1H, Ar-H), 7.06 (s, 1H, Ar-H), 5.71 (s, 1H, H-12), 4.01 (s, 2H, -COOCH₂CH₂CH₂CH₃), 2.37 (d, 1H, J = 8.7 Hz, H-18), 1.53 (s, 2H, -COOCH₂CH₂CH₂CH₃), 1.47 (s, 2H, -COOCH₂CH₂CH₂CH₃), 1.29 (s, 1H, H-9), 1.24 (s, 2H, -COOCH₂CH₂CH₂CH₃), 1.14, 1.11, 1.02, 0.95, 0.92, 0.91, 0.88 (s, each 3H)
6	7.72 (s, 1H, NH), 7.45 (d, 1H, J = 9.2 Hz, Ar-H), 7.17 (s, 1H, Ar-H), 7.05 (s, 1H, Ar-H), 5.72 (s, 1H, H-12), 3.75 (d, 2H, J = 10.2 Hz, -COOCH₂CH(CH₃)CH₃), 2.35 (d, 1H, J = 8.9 Hz, H-18), 1.41 (s, 1H, -COOCH₂CH(CH₃)CH₃), 1.36-1.22 (m, 3H, -COOCH₂CH(CH₃)CH₃), 1.24 (s, 1H, H-9), 1.15-1.08 (m, 3H, -COOCH₂CH(CH₃)CH₃), 1.12, 1.01, 1.02, 0.98, 0.92, 0.88, 0.86 (s, each 3H)
7	7.78 (s, 1H, NH), 7.43 (d, 1H, J = 8.9 Hz, Ar-H), 7.14 (s, 1H, Ar-H), 7.07 (s, 1H, Ar-H), 5.64 (s, 1H, H-12), 3.98 (t, 2H, J = 8.4 Hz, -COOCH₂CH₂CH₂CH₂CH₃), 2.42 (d, 1H, J = 8.9 Hz, H-18), 1.75 (s, 2H, -COOCH₂CH₂CH₂CH₂CH₃), 1.42 (s, 2H, -COOCH₂CH₂CH₂CH₂CH₃), 1.29 (s, 2H, -COOCH₂CH₂CH₂CH₂CH₃), 1.25 (s, 1H, H-9), 1.15 (s, 3H, -COOCH₂CH₂CH₂CH₂CH₃), 1.13, 1.11, 1.06, 1.01, 0.99, 0.89, 0.88 (s, each 3H)
8	7.72 (s, 1H, NH), 7.45 (d, 1H, J = 9.3 Hz, Ar-H), 7.05 (s, 1H, Ar-H), 7.04 (s, 1H, Ar-H), 5.64 (s, 1H, H-12), 4.04 (s, 2H, -COOCH₂CH₂CH₂CH₂CH₂CH₃), 2.98 (s, 2H, -COOCH₂CH₂CH₂CH₂CH₂CH₃), 2.44 (d, 1H, J = 9.1 Hz, H-18), 1.49 (s, 2H, -COOCH₂CH₂CH₂CH₂CH₂CH₃), 1.38 (s, 2H, -COOCH₂CH₂CH₂CH₂CH₂CH₃), 1.32 (s, 1H, H-9), 1.26 (s, 2H, -COOCH₂CH₂CH₂CH₂CH₂CH₃), 1.25 (s, 3H, -COOCH₂CH₂CH₂CH₂CH₂CH₃), 1.15, 1.12, 1.09, 1.01, 0.99, 0.99, 0.89 (s, each 3H)
11	7.72 (s, 1H, NH), 7.40 (d, 1H, J = 9.3 Hz, Ar-H), 7.34 (s, 1H, Ar-H), 7.17 (s, 1H, Ar-H), 6.61 (br, 1H, NH), 5.56 (s, 1H, H-12), 3.63 (s, 2H, -CH₂OH), 3.49 (s, 2H, -CH₂), 1.31 (s, 1H, H-9), 1.23, 1.13, 1.06, 1.05, 0.98, 0.94, 0.93 (s, each 3H)
12	7.81 (s, 1H, NH), 7.33 (d, 1H, J = 9.2 Hz, Ar-H), 7.17 (s, 1H, Ar-H), 7.05 (s, 1H, Ar-H), 6.58 (br, 1H, NH), 5.73 (s, 1H, H-12), 4.15-3.98 (m, 1H, -NHCH(CH₃)CH₂OH), 3.88 (d, 2H, J = 8.6 Hz, -NHCH(CH₃)CH₂OH), 1.32-1.21 (m, 3H, -NHCH(CH₃)CH₂OH), 1.22 (s, 1H, H-9), 1.15, 1.14, 1.12, 1.11, 1.04, 0.98, 0.94 (s, each 3H)
13	7.88 (s, 1H, NH), 7.45 (d, 1H, J = 9.4 Hz, Ar-H), 7.23 (s, 1H, Ar-H), 7.14 (s, 1H, Ar-H), 6.60 (br, 1H, NH), 5.67 (s, 1H, H-12), 3.58 (s, 2H, -NHCH₂CH₂CH₂OH), 3.58 (s, 1H, -NHCH_aCH₂CH₂OH), 3.13 (s, 1H, NHCH_bOH), 1.34 (s, 2H, -NHCH₂CH₂CH₂OH), 1.24 (s, 1H, H-9), 1.11, 1.03, 0.98, 0.91, 0.89, 0.88, 0.83 (s, each 3H)
14	8.38 (s, 1H, NH), 7.46 (d, 1H, J = 9.5 Hz, Ar-H), 7.44 (s, 1H, Ar-H), 7.34-7.15 (m, 4H, Ar-H), 7.14 (s, 1H, Ar-H), 6.61 (br, 1H, NH), 5.67 (s, 1H, H-12), 5.11 (s, 2H, CH₂OH), 1.31 (s, 1H, H-9), 1.23, 1.11, 1.09, 1.05, 0.98, 0.97, 0.88 (s, each 3H)

Compd.

¹H NMR (CDCl₃)

7.76 (s, 1H, NH), 7.45 (d, 1H, J = 8.2 Hz, Ar-H), 7.29 (s, 1H, Ar-H), 7.16 (s, 1H, Ar-H), 5.51 (s, 1H, H-12), 3.96 (s, 2H, -COOCH₂CH₂CH₃), 2.28 (d, 1H, J = 10.8 Hz, H-18), 1.63-1.49 (m, 3H, -COOCH₂CH₂CH₃), 1.58 (s, 2H, -COOCH₂CH₂CH₃), 1.24 (s, 1H, H-9), 1.16, 1.14, 1.07, 1.02, 0.92, 0.99, 0.87 (s, each 3H)

7.74 (s, 1H, NH), 7.45 (d, 1H, J = 9.2 Hz, Ar-H), 7.19 (s, 1H, Ar-H), 7.15 (s, 1H, Ar-H), 5.64 (s, 1H, H-12), 4.27 (s, 1H, -COOCH(CH₃)CH₃), 2.28 (d, 1H, J = 9.6 Hz, H-18), 1.44 (d, 3H, J = 9.5 Hz, -COOCH(CH₃)CH₃), 1.43 (d, 3H, J = 9.5 Hz, -COOCH(CH₃)CH₃), 1.29 (s, 1H, H-9), 1.23, 1.19, 1.08, 1.02, 1.01, 0.97, 0.87 (s, each 3H)

7.74 (s, 1H, NH), 7.45 (d, 1H, J = 9.7 Hz, Ar-H), 7.19 (s, 1H, Ar-H), 7.06 (s, 1H, Ar-H), 5.71 (s, 1H, H-12), 4.01 (s, 2H, -COOCH₂CH₂CH₂CH₃), 2.37 (d, 1H, J = 8.7 Hz, H-18), 1.53 (s, 2H, -COOCH₂CH₂CH₂CH₃), 1.47 (s, 2H, -COOCH₂CH₂CH₂CH₃), 1.29 (s, 1H, H-9), 1.24 (s, 2H, -COOCH₂CH₂CH₂CH₃), 1.14, 1.11, 1.02, 0.95, 0.92, 0.91, 0.88 (s, each 3H)

7.72 (s, 1H, NH), 7.45 (d, 1H, J = 9.2 Hz, Ar-H), 7.17 (s, 1H, Ar-H), 7.05 (s, 1H, Ar-H), 5.72 (s, 1H, H-12), 3.75 (d, 2H, J = 10.2 Hz, -COOCH₂CH(CH₃)CH₃), 2.35 (d, 1H, J = 8.9 Hz, H-18), 1.41 (s, 1H, -COOCH₂CH(CH₃)CH₃), 1.36-1.22 (m, 3H, -COOCH₂CH(CH₃)CH₃), 1.24 (s, 1H, H-9), 1.15-1.08 (m, 3H, -COOCH₂CH(CH₃)CH₃), 1.12, 1.01, 1.02, 0.98, 0.92, 0.88, 0.86 (s, each 3H)

7.78 (s, 1H, NH), 7.43 (d, 1H, J = 8.9 Hz, Ar-H), 7.14 (s, 1H, Ar-H), 7.07 (s, 1H, Ar-H), 5.64 (s, 1H, H-12), 3.98 (t, 2H, J = 8.4 Hz, -COOCH₂CH₂CH₂CH₂CH₃), 2.42 (d, 1H, J = 8.9 Hz, H-18), 1.75 (s, 2H, -COOCH₂CH₂CH₂CH₂CH₃), 1.42 (s, 2H, -COOCH₂CH₂CH₂CH₂CH₃), 1.29 (s, 2H, -COOCH₂CH₂CH₂CH₂CH₃), 1.25 (s, 1H, H-9), 1.15 (s, 3H, -COOCH₂CH₂CH₂CH₂CH₃), 1.13, 1.11, 1.06, 1.01, 0.99, 0.89, 0.88 (s, each 3H)

7.72 (s, 1H, NH), 7.45 (d, 1H, J = 9.3 Hz, Ar-H), 7.05 (s, 1H, Ar-H), 7.04 (s, 1H, Ar-H), 5.64 (s, 1H, H-12), 4.04 (s, 2H, -COOCH₂CH₂CH₂CH₂CH₂CH₃), 2.98 (s, 2H, -COOCH₂CH₂CH₂CH₂CH₂CH₃), 2.44 (d, 1H, J = 9.1 Hz, H-18), 1.49 (s, 2H, -COOCH₂CH₂CH₂CH₂CH₂CH₃), 1.38 (s, 2H, -COOCH₂CH₂CH₂CH₂CH₂CH₃), 1.32 (s, 1H, H-9), 1.26 (s, 2H, -COOCH₂CH₂CH₂CH₂CH₂CH₃), 1.25 (s, 3H, -COOCH₂CH₂CH₂CH₂CH₂CH₃), 1.15, 1.12, 1.09, 1.01, 0.99, 0.99, 0.89 (s, each 3H)

7.72 (s, 1H, NH), 7.40 (d, 1H, J = 9.3 Hz, Ar-H), 7.34 (s, 1H, Ar-H), 7.17 (s, 1H, Ar-H), 6.61 (br, 1H, NH), 5.56 (s, 1H, H-12), 3.63 (s, 2H, -CH₂OH), 3.49 (s, 2H, -CH₂), 1.31 (s, 1H, H-9), 1.23, 1.13, 1.06, 1.05, 0.98, 0.94, 0.93 (s, each 3H)

7.81 (s, 1H, NH), 7.33 (d, 1H, J = 9.2 Hz, Ar-H), 7.17 (s, 1H, Ar-H), 7.05 (s, 1H, Ar-H), 6.58 (br, 1H, NH), 5.73 (s, 1H, H-12), 4.15-3.98 (m, 1H, -NHCH(CH₃)CH₂OH), 3.88 (d, 2H, J = 8.6 Hz, -NHCH(CH₃)CH₂OH), 1.32-1.21 (m, 3H, -NHCH(CH₃)CH₂OH), 1.22 (s, 1H, H-9), 1.15, 1.14, 1.12, 1.11, 1.04, 0.98, 0.94 (s, each 3H)

7.88 (s, 1H, NH), 7.45 (d, 1H, J = 9.4 Hz, Ar-H), 7.23 (s, 1H, Ar-H), 7.14 (s, 1H, Ar-H), 6.60 (br, 1H, NH), 5.67 (s, 1H, H-12), 3.58 (s, 2H, -NHCH₂CH₂CH₂OH), 3.58 (s, 1H, -NHCH_aCH₂CH₂OH), 3.13 (s, 1H, NHCH_bOH), 1.34 (s, 2H, -NHCH₂CH₂CH₂OH), 1.24 (s, 1H, H-9), 1.11, 1.03, 0.98, 0.91, 0.89, 0.88, 0.83 (s, each 3H)

8.38 (s, 1H, NH), 7.46 (d, 1H, J = 9.5 Hz, Ar-H), 7.44 (s, 1H, Ar-H), 7.34-7.15 (m, 4H, Ar-H), 7.14 (s, 1H, Ar-H), 6.61 (br, 1H, NH), 5.67 (s, 1H, H-12), 5.11 (s, 2H, CH₂OH), 1.31 (s, 1H, H-9), 1.23, 1.11, 1.09, 1.05, 0.98, 0.97, 0.88 (s, each 3H)

Compd.	¹H NMR (CDCl₃)
3	7.76 (s, 1H, NH), 7.45 (d, 1H, J = 8.2 Hz, Ar-H), 7.29 (s, 1H, Ar-H), 7.16 (s, 1H, Ar-H), 5.51 (s, 1H, H-12), 3.96 (s, 2H, -COOCH₂CH₂CH₃), 2.28 (d, 1H, J = 10.8 Hz, H-18), 1.63-1.49 (m, 3H, -COOCH₂CH₂CH₃), 1.58 (s, 2H, -COOCH₂CH₂CH₃), 1.24 (s, 1H, H-9), 1.16, 1.14, 1.07, 1.02, 0.92, 0.99, 0.87 (s, each 3H)
4	7.74 (s, 1H, NH), 7.45 (d, 1H, J = 9.2 Hz, Ar-H), 7.19 (s, 1H, Ar-H), 7.15 (s, 1H, Ar-H), 5.64 (s, 1H, H-12), 4.27 (s, 1H, -COOCH(CH₃)CH₃), 2.28 (d, 1H, J = 9.6 Hz, H-18), 1.44 (d, 3H, J = 9.5 Hz, -COOCH(CH₃)CH₃), 1.43 (d, 3H, J = 9.5 Hz, -COOCH(CH₃)CH₃), 1.29 (s, 1H, H-9), 1.23, 1.19, 1.08, 1.02, 1.01, 0.97, 0.87 (s, each 3H)
5	7.74 (s, 1H, NH), 7.45 (d, 1H, J = 9.7 Hz, Ar-H), 7.19 (s, 1H, Ar-H), 7.06 (s, 1H, Ar-H), 5.71 (s, 1H, H-12), 4.01 (s, 2H, -COOCH₂CH₂CH₂CH₃), 2.37 (d, 1H, J = 8.7 Hz, H-18), 1.53 (s, 2H, -COOCH₂CH₂CH₂CH₃), 1.47 (s, 2H, -COOCH₂CH₂CH₂CH₃), 1.29 (s, 1H, H-9), 1.24 (s, 2H, -COOCH₂CH₂CH₂CH₃), 1.14, 1.11, 1.02, 0.95, 0.92, 0.91, 0.88 (s, each 3H)
6	7.72 (s, 1H, NH), 7.45 (d, 1H, J = 9.2 Hz, Ar-H), 7.17 (s, 1H, Ar-H), 7.05 (s, 1H, Ar-H), 5.72 (s, 1H, H-12), 3.75 (d, 2H, J = 10.2 Hz, -COOCH₂CH(CH₃)CH₃), 2.35 (d, 1H, J = 8.9 Hz, H-18), 1.41 (s, 1H, -COOCH₂CH(CH₃)CH₃), 1.36-1.22 (m, 3H, -COOCH₂CH(CH₃)CH₃), 1.24 (s, 1H, H-9), 1.15-1.08 (m, 3H, -COOCH₂CH(CH₃)CH₃), 1.12, 1.01, 1.02, 0.98, 0.92, 0.88, 0.86 (s, each 3H)
7	7.78 (s, 1H, NH), 7.43 (d, 1H, J = 8.9 Hz, Ar-H), 7.14 (s, 1H, Ar-H), 7.07 (s, 1H, Ar-H), 5.64 (s, 1H, H-12), 3.98 (t, 2H, J = 8.4 Hz, -COOCH₂CH₂CH₂CH₂CH₃), 2.42 (d, 1H, J = 8.9 Hz, H-18), 1.75 (s, 2H, -COOCH₂CH₂CH₂CH₂CH₃), 1.42 (s, 2H, -COOCH₂CH₂CH₂CH₂CH₃), 1.29 (s, 2H, -COOCH₂CH₂CH₂CH₂CH₃), 1.25 (s, 1H, H-9), 1.15 (s, 3H, -COOCH₂CH₂CH₂CH₂CH₃), 1.13, 1.11, 1.06, 1.01, 0.99, 0.89, 0.88 (s, each 3H)
8	7.72 (s, 1H, NH), 7.45 (d, 1H, J = 9.3 Hz, Ar-H), 7.05 (s, 1H, Ar-H), 7.04 (s, 1H, Ar-H), 5.64 (s, 1H, H-12), 4.04 (s, 2H, -COOCH₂CH₂CH₂CH₂CH₂CH₃), 2.98 (s, 2H, -COOCH₂CH₂CH₂CH₂CH₂CH₃), 2.44 (d, 1H, J = 9.1 Hz, H-18), 1.49 (s, 2H, -COOCH₂CH₂CH₂CH₂CH₂CH₃), 1.38 (s, 2H, -COOCH₂CH₂CH₂CH₂CH₂CH₃), 1.32 (s, 1H, H-9), 1.26 (s, 2H, -COOCH₂CH₂CH₂CH₂CH₂CH₃), 1.25 (s, 3H, -COOCH₂CH₂CH₂CH₂CH₂CH₃), 1.15, 1.12, 1.09, 1.01, 0.99, 0.99, 0.89 (s, each 3H)
11	7.72 (s, 1H, NH), 7.40 (d, 1H, J = 9.3 Hz, Ar-H), 7.34 (s, 1H, Ar-H), 7.17 (s, 1H, Ar-H), 6.61 (br, 1H, NH), 5.56 (s, 1H, H-12), 3.63 (s, 2H, -CH₂OH), 3.49 (s, 2H, -CH₂), 1.31 (s, 1H, H-9), 1.23, 1.13, 1.06, 1.05, 0.98, 0.94, 0.93 (s, each 3H)
12	7.81 (s, 1H, NH), 7.33 (d, 1H, J = 9.2 Hz, Ar-H), 7.17 (s, 1H, Ar-H), 7.05 (s, 1H, Ar-H), 6.58 (br, 1H, NH), 5.73 (s, 1H, H-12), 4.15-3.98 (m, 1H, -NHCH(CH₃)CH₂OH), 3.88 (d, 2H, J = 8.6 Hz, -NHCH(CH₃)CH₂OH), 1.32-1.21 (m, 3H, -NHCH(CH₃)CH₂OH), 1.22 (s, 1H, H-9), 1.15, 1.14, 1.12, 1.11, 1.04, 0.98, 0.94 (s, each 3H)
13	7.88 (s, 1H, NH), 7.45 (d, 1H, J = 9.4 Hz, Ar-H), 7.23 (s, 1H, Ar-H), 7.14 (s, 1H, Ar-H), 6.60 (br, 1H, NH), 5.67 (s, 1H, H-12), 3.58 (s, 2H, -NHCH₂CH₂CH₂OH), 3.58 (s, 1H, -NHCH_aCH₂CH₂OH), 3.13 (s, 1H, NHCH_bOH), 1.34 (s, 2H, -NHCH₂CH₂CH₂OH), 1.24 (s, 1H, H-9), 1.11, 1.03, 0.98, 0.91, 0.89, 0.88, 0.83 (s, each 3H)
14	8.38 (s, 1H, NH), 7.46 (d, 1H, J = 9.5 Hz, Ar-H), 7.44 (s, 1H, Ar-H), 7.34-7.15 (m, 4H, Ar-H), 7.14 (s, 1H, Ar-H), 6.61 (br, 1H, NH), 5.67 (s, 1H, H-12), 5.11 (s, 2H, CH₂OH), 1.31 (s, 1H, H-9), 1.23, 1.11, 1.09, 1.05, 0.98, 0.97, 0.88 (s, each 3H)

Compd.

¹H NMR (CDCl₃)

Compd.	Inhibition rate/% (10 μmol·L^-1)
UA	12.62	13.34	> 20	> 20
3	18.25	21.19	> 20	> 20
4	36.57	35.35	12.38	9.95
5	25.49	19.35	> 20	7.50
6	48.96	54.60	10.22	3.12
7	30.93	38.52	> 20	> 20
8	41.28	38.81	> 20	10.74
11	39.58	42.16	> 20	> 20
12	52.83	49.56	8.96	12.45
13	29.36	27.53	> 20	> 20
14	33.69	24.31	> 20	> 20
Paclitaxel	52.75	50.82	14.35	7.87
Adriamycin	64.37	59.38	3.48	2.07

Compd.

Inhibition rate/% (10 μmol·L^-1)

IC₅₀/μmol·L^-1

HepG2

SGC7901

HepG2

SGC7901

12.62

13.34

> 20

18.25

21.19

> 20

36.57

35.35

12.38

9.95

25.49

19.35

> 20

7.50

48.96

54.60

10.22

3.12

30.93

38.52

> 20

41.28

38.81

> 20

10.74

39.58

42.16

> 20

52.83

49.56

8.96

12.45

29.36

27.53

> 20

33.69

24.31

> 20

Paclitaxel

52.75

50.82

14.35

7.87

Adriamycin

64.37

59.38

3.48

2.07

Compd.	Inhibition rate/% (10 μmol·L^-1)
UA	12.62	13.34	> 20	> 20
3	18.25	21.19	> 20	> 20
4	36.57	35.35	12.38	9.95
5	25.49	19.35	> 20	7.50
6	48.96	54.60	10.22	3.12
7	30.93	38.52	> 20	> 20
8	41.28	38.81	> 20	10.74
11	39.58	42.16	> 20	> 20
12	52.83	49.56	8.96	12.45
13	29.36	27.53	> 20	> 20
14	33.69	24.31	> 20	> 20
Paclitaxel	52.75	50.82	14.35	7.87
Adriamycin	64.37	59.38	3.48	2.07

Compd.

Inhibition rate/% (10 μmol·L^-1)

IC₅₀/μmol·L^-1

HepG2

SGC7901

HepG2

SGC7901

12.62

13.34

> 20

18.25

21.19

> 20

36.57

35.35

12.38

9.95

25.49

19.35

> 20

7.50

48.96

54.60

10.22

3.12

30.93

38.52

> 20

41.28

38.81

> 20

10.74

39.58

42.16

> 20

52.83

49.56

8.96

12.45

29.36

27.53

> 20

33.69

24.31

> 20

Paclitaxel

52.75

50.82

14.35

7.87

Adriamycin

64.37

59.38

3.48

2.07

熊果酸衍生物的合成及初步体外抗肿瘤活性研究

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潘洪双 , 李磊 , 崔华博 , 杨丽娜 , 于婷婷 , 孟艳秋 ^*

药学学报 | 研究论文 2017,52(12): 1890-1894

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药学学报 | 研究论文 2017, 52(12): 1890-1894

熊果酸衍生物的合成及初步体外抗肿瘤活性研究

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潘洪双, 李磊, 崔华博, 杨丽娜, 于婷婷, 孟艳秋^*

作者信息

沈阳化工大学制药工程教研室, 辽宁沈阳 110142

通讯作者:

* 孟艳秋, Tel:86-24-89383903, Fax:86-24-89383760, E-mail:myq6581@163.com

Synthesis and anti-tumor activity of derivatives of ursolic acid in vitro

Hong-shuang PAN, Lei LI, Hua-bo CUI, Li-na YANG, Ting-ting YU, Yan-qiu MENG^*

Affiliations

Department of Pharmaceutical Engineering, Shenyang University of Chemical Technology, Shenyang 110142, China

出版时间: 2017-12-12 doi: 10.16438/j.0513-4870.2017-0692

文章导航

摘要

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以熊果酸为先导化合物，在其A环骈合4-氯吲哚环，同时对C-28位进行成酯、酰胺化等结构修饰，设计合成了两类共10个新型熊果酸A环衍生物，其结构经¹H NMR、MS等确认。采用MTT法，选用人肝癌细胞（HepG2）和人胃癌细胞（SGC7901）对所得化合物进行初步的体外抗肿瘤活性测试。结果表明，所测化合物对HepG2、SGC7901肿瘤细胞的抑制作用均强于母体熊果酸，尤其是化合物6、12表现出较为显著的抗肿瘤活性，与已上市药物紫杉醇活性相当，值得进一步研究。

关键词

熊果酸A环 / 结构修饰 / 抗肿瘤活性

Abstract

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A series of ursolic acid derivatives were synthesized by the introduction of 4-chloroindole compounds at A ring and esterification and amidation at C-28 position, which structures were characterized by ¹H NMR, MS and etc. The cytotoxic activity of derivatives was evaluated against HepG2 and SGC7901 cells in vitro by MTT assay, in which paclitaxel and adriamycin were used as a positive control. The results indicated that all of derivatives can inhibit cell proliferation in HepG2 and SGC7901 cells with a better activity than ursolic acid. Especially, the compounds 6 and 12 showed significant antitumor activity comparable to the paclitaxel. The compounds are worthy to be studied further.

Key words

ursolic acid A ring / structural modification / antitumor activity

引用本文

潘洪双, 李磊, 崔华博, 杨丽娜, 于婷婷, 孟艳秋. 熊果酸衍生物的合成及初步体外抗肿瘤活性研究. 药学学报, 2017 , 52 (12) : 1890 -1894 . DOI: 10.16438/j.0513-4870.2017-0692

Hong-shuang PAN, Lei LI, Hua-bo CUI, Li-na YANG, Ting-ting YU, Yan-qiu MENG. Synthesis and anti-tumor activity of derivatives of ursolic acid in vitro[J]. Acta Pharmaceutica Sinica, 2017 , 52 (12) : 1890 -1894 . DOI: 10.16438/j.0513-4870.2017-0692

正文

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熊果酸(ursolic acid, UA)又名乌索酸(乌苏酸), 存在于多种天然药用植物中, 近来有学者发现可以从苹果渣中提取熊果酸^[1], 其市场发展潜力巨大。熊果酸具有五环三萜类化合物的典型结构, 具有抗炎^[2]、护心脑血管^[3]、抗癌保肝^[4]、抗菌, 抗HIV病毒^[5]等多种药理作用。目前, 对熊果酸的结构修饰多集中在A环、C-3位和C-28位^{[6, 7]}。研究证明, 在熊果酸C-3位保持极性基团对其保持活性十分重要^[8], 在C-28位连接氨基醇类化合物、成酯等结构改造均能使熊果酸抗肿瘤活性有不同程度的提高^{[9, 10]}, 而在其A环引入杂环时, 对其抗肿瘤活性也会产生较大影响^[11-13]。本文以熊果酸为先导化合物, 参考前人对五环三萜类化合物进行结构改造的经验^[14-16], 对熊果酸A环、C-11位、C-28位进行结构改造, 设计合成了两类共10个熊果酸A环衍生物。

以熊果酸为起始原料, 用三氧化铬将C-3位和C-11位同时氧化, 得到3, 11-氧代-乌苏烷型-12-烯-28-酸(1), 将中间体1与卤代烷类化合物反应后再与4-氯苯肼盐酸盐反应, 生成一系列5'-氯-[2, 3-b]-吲哚-乌苏烷型-11-羰基-12-烯-28-羧酸酯类衍生物(3~8)。将中间体1与氨基醇类化合物反应后再与4-氯苯肼盐酸盐反应得到一系列5'-氯-[2, 3-b]-吲哚-乌苏烷型-11-羰基-12-烯-28-酰-氨基醇类衍生物(11~14), 见合成路线图 1。

结果与讨论

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1 化学合成

以熊果酸为先导化合物, 对其A环、C-11和C-28进行结构改造, 设计并合成了两类共10个熊果酸衍生物, 其结构¹H NMR、MS等确证。数据见表 1和表 2。

2 生物活性评价

以紫杉醇(paclitaxel)和多柔比星(adriamycin)为阳性对照物, 采用四甲基偶氮唑盐法(MTT比色法)对合成的化合物进行初步的体外抗肿瘤活性测试, 实验结果见表 3。

从表中可以看出, 在化合物浓度为1×10^-5 mol·L^-1时所测试的目标化合物对HepG2和SGC7901细胞的生长均具有一定的抑制作用, 且优于母体熊果酸。C-28位羧基连接卤代烷类化合物成酯时, 化合物抗肿瘤活性化合物6 > 4 > 8 > 7 > 5 > 3, 结果表明连接具有支链的卤代烷较直链卤代烷有更好的活性; 同时, 随着卤代烷碳链的增长, 其抗肿瘤活性也有所增加。C-28位羧基连接氨基醇类化合物成醇胺时, 化合物12表现出较好的抗肿瘤活性, 对两种肿瘤细胞的抑制率分别为52.83%和49.56%, 与阳性对照药紫杉醇活性相当。综上所述, 认为化合物6、12值得进一步研究。

3 小结

本文以熊果酸为先导化合物, 对其A环、C-11和C-28进行结构改造, 设计合成了两类共10个熊果酸衍生物, 经体外初步药理活性测试显示, 熊果酸A环骈合4-氯吲哚环, 同时C-28位羧基与卤代烷反应成酯可以提高熊果酸抗肿瘤活性, 卤代烷的长短及结构对其活性有较大影响; 而当C-28位羧基与氨基醇反应成醇胺时也可提高熊果酸的抗肿瘤活性, 连接氨基醇的结构是影响活性的主要因素。本研究结果对熊果酸的进一步结构修饰有一定的参考意义。

实验部分

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X-4数字显示显微熔点测定仪; ARX-300 MHz核磁共振仪, CDCl₃为溶剂, TMS为内标; 热电-菲尼根LCQ型质谱仪。熊果酸购于陕西慧科植物开发有限公司; 薄层色谱硅胶GF254、硅胶H为青岛海洋化工有限公司生产, 显色剂为10%硫酸乙醇溶液; 活性测试所用的RPMI-1640培养基(含10%胎牛血清、100 u·mL^-1青霉素、100 μg·mL^-1链霉素); 溴化四氮唑盐(MTT)、蛋白酶K (proteinase K)和小牛血清蛋白(BSA)购于上海图赫实业有限公司; 阳性对照物紫杉醇(paclitaxel)、阿霉素(adriamycin)购于阿斯利康制药有限公司; 人癌细胞HepG2、SGC7901细胞为沈阳药科大学提供。所用试剂均为分析纯或化学纯。

1 化学合成

1.1 3, 11-氧代-乌苏烷型-12-烯-28-羧酸的制备(1)

将熊果酸(228 mg, 0.5 mmol)溶解于5%乙酸酐的乙酸溶液中(0.75 mL乙酸酐, 14.25 mL乙酸), 加入CrO3 (99.6 mg, 0.99 mmol), 室温反应, TLC检测反应终点。4 h反应完毕, 加入水(20 mL)和二氯甲烷(20 mL), 分层后, 水层以二氯甲烷(20 mL)萃取两次, 合并有机相, 用饱和碳酸氢钠溶液洗涤至微碱性, 再水洗至中性, 无水硫酸钠干燥, 减压抽滤, 滤液减压脱溶得到绿色胶状物。粗品经硅胶柱色谱分离纯化, 洗脱剂为石油醚-乙酸乙酯=5：1, 得白色固体, 中间体1。

1.2 5'-氯-[2, 3-b]-吲哚-乌苏烷型-11-羰基-12-烯-28-羧酸正丙酯(3)

将中间体UA₁ (126 mg, 0.22 mmol)溶于N, N-二甲基甲酰胺(DMF, 4 mL), 加入无水碳酸钾(0.06 g, 0.44 mmol), 缓慢滴加4倍当量1-溴丙烷(0.88 mmol), 室温反应, TLC检测反应终点(展开剂:石油醚-乙酸乙酯=5：1), 5 h反应结束。减压蒸出剩余的卤代烷后, 加入饱和食盐水(20 mL)和乙酸乙酯(20 mL), 分离有机相, 有机相用饱和食盐水(20 mL×3)萃取3次, 有机相用无水硫酸镁干燥, 过滤, 滤液减压脱溶得淡黄色固体。粗品经硅胶柱色谱纯化, 洗脱剂为石油醚-乙酸乙酯=13：1, 得白色固体2。

将4-氯苯肼盐酸盐(180 mg, 0.1 mmol)溶解于冰乙酸(10 mL), 118 ℃冷凝回流。将化合物2a (50 mg, 0.1 mmol)溶解在冰乙酸(5 mL)中, 缓慢滴加到4-氯苯肼盐酸盐溶液中, 继续回流, 以TLC监测反应终点。4 h反应结束, 向反应体系中缓慢滴加水(10 mL), 降至室温, 析出黄褐色固体, 减压抽滤, 水洗滤饼至中性。室温干燥, 得黄褐色固体。粗品经硅胶柱色谱纯化, 洗脱剂为石油醚-乙酸乙酯=3：1, 得白色粉末状固体3。产率为58.3%, mp 157~159 ℃。

1.3 5'-氯-[2, 3-b]-吲哚-乌苏烷型-11-羰基-12-烯-28-羧酸异丙酯(4)

按照化合物3的合成方法, 由中间体1与1-溴异丙烷反应后再与4-氯苯肼盐酸盐反应。最终粗品经硅胶柱色谱纯化, 洗脱剂为石油醚-乙酸乙酯=13：1, 得白色粉末状固体4, 产率为54.6%。mp 140~144 ℃。

1.4 5'-氯-[2, 3-b]-吲哚-乌苏烷型-11-羰基-12-烯-28-羧酸正丁酯(5)

按照化合物3的合成方法, 由中间体1与1-溴正丁烷反应后再与4-氯苯肼盐酸盐反应。最终粗品经硅胶柱色谱纯化, 洗脱剂为石油醚-乙酸乙酯=15：1, 得白色粉末状固体5, 产率为46.6%。mp 229~233 ℃。

1.5 5'-氯-[2, 3-b]-吲哚-乌苏烷型-11-羰基-12-烯-28-羧酸异丁酯(6)

按照化合物3的合成方法, 由中间体2与1-溴异丁烷反应再与4-氯苯肼盐酸盐反应。最终粗品经硅胶柱色谱纯化, 洗脱剂为石油醚-乙酸乙酯=15：1, 得白色粉末状固体6, 产率为44.8%, mp 225~227 ℃。

1.6 5'-氯-[2, 3-b]-吲哚-乌苏烷型-11-羰基-12-烯-28-羧酸正戊酯(7)

按照化合物3的合成方法, 由中间体2与溴代正戊烷反应再与4-氯苯肼盐酸盐反应。最终粗品经硅胶柱色谱纯化, 洗脱剂为石油醚-乙酸乙酯=13：1, 得白色粉末状固体7, 产率为53.2%。mp 241~245 ℃。

1.7 5'-氯-[2, 3-b]-吲哚-乌苏烷型-11-羰基-12-烯-28-羧酸正己酯(8)

按照化合物3的合成方法, 由中间体2与溴己烷反应后再与4-氯苯肼盐酸盐反应。最终粗品经硅胶柱色谱纯化, 洗脱剂为石油醚-乙酸乙酯=7：1, 得白色粉末状固体8, 产率为45.5%。mp 249~254 ℃。

1.8 5'-氯-[2, 3-b]-吲哚-乌苏烷型-11-羰基-12-烯-28-酰-氨基乙醇(11)

将中间体1 (120 mg, 0.2 mmol)溶解于5 mL二氯甲烷, 加入草酰氯(0.8 mmol), 并加入2滴DMF作为催化剂, 在室温下搅拌4 h, 生成5'-Cl-[2, 3-b]-吲哚-乌苏烷型-11-羰基-12-烯-28-酰氯(9)。蒸除溶剂二氯甲烷和草酰氯, 残余物加入2 mL环己烷, 减压蒸除环己烷, 反复操作两次。向产物中加入二氯甲烷, 用三乙胺调pH至8~9, 待pH稳定后再加入氨基乙醇(0.8 mmol), 室温搅拌24 h, TLC监测反应终点, 反应完成后, 加入30 mL水, 使其分层, 用盐酸调pH至3, 减压蒸除反应溶剂, 析出黄色固体。最终粗品经硅胶柱色谱纯化, 洗脱剂为石油醚-乙酸乙酯=7：1, 得白色粉末状固体10。

将4-氯苯肼盐酸盐(180 mg, 0.1 mmol)溶解于冰乙酸(10 mL), 118 ℃冷凝回流。将化合物10 (50 mg, 0.1 mmol)溶解在冰乙酸(5 mL)中, 缓慢滴加到4-氯苯肼盐酸盐溶液中, 继续回流, 以TLC监测反应终点。4 h反应结束, 向反应体系中缓慢滴加水(10 mL), 降至室温, 析出黄褐色固体, 减压抽滤, 水洗滤饼至中性。室温干燥, 得黄褐色固体。粗品经硅胶柱色谱纯化, 洗脱剂为石油醚-乙酸乙酯=3：1, 得白色粉末状固体11。产率为48.7%。mp 186~189 ℃。

1.9 5'-氯-[2, 3-b]-吲哚-乌苏烷型-11-羰基-12-烯-28-酰-2-氨基-1-丙醇(12)

按照化合物11的合成方法, 由中间体1与2-氨基-1-丙醇反应后再与4-氯苯肼盐酸盐反应。最终粗品经硅胶柱色谱纯化, 洗脱剂为石油醚-乙酸乙酯=7：1, 得白色粉末状固体12, 产率为44.8%。mp 184~186 ℃。

1.10 5'-氯-[2, 3-b]-吲哚-乌苏烷型-11-羰基-12-烯-28-酰-3-氨基-1-丙醇(13)

按照化合物11的合成方法, 由中间体1与3-氨基-1-丙醇反应后再与4-氯苯肼盐酸盐反应。最终粗品经硅胶柱色谱纯化, 洗脱剂为石油醚-乙酸乙酯=7：1, 得白色粉末状固体13, 产率为44.6%。mp 142~144 ℃。

1.11 5'-氯-[2, 3-b]-吲哚-乌苏烷型-11-羰基-12-烯-28-酰-2-氨基苄醇(14)

按照化合物11的合成方法, 由中间体1与邻氨基苄醇反应后再与4-氯苯肼盐酸盐反应。最终粗品经硅胶柱色谱纯化, 洗脱剂为石油醚-乙酸乙酯=7：1, 得白色粉末状固体14, 产率为61.2%。mp 244~248 ℃。

2 初步体外活性测试

选择人肺癌细胞(HepG2)和人胃癌细胞(SGC7901)靶细胞, 以紫杉醇(paclitaxel)和阿霉素(adriamycin)为阳性对照物。用MTT比色法测定化合物细胞毒活性。

取0.25%胰蛋白酶消化单层培养的SGC7901 (HepG2)细胞, 用含10%胎牛血清RPMI 1640培养液调整细胞数为每毫升2×10⁴~4×10⁴个的单细胞悬液, 以每孔200 μL接种于96孔培养板中。将培养板放入CO₂培养箱, 在37 ℃、5% CO₂及饱和湿度条件下培养, 待培养细胞贴壁后, 分别加入浓度为1×10^-5、1×10^-6、1×10^-7、1×10^-8 mol·L^-1的待测药物, 每浓度6个孔, 实验设空白对照组, 继续放入CO₂培养箱, 在37 ℃、5% CO₂及饱和湿度条件下培养72 h。培养72 h后, 每孔加入MTT溶液(5 mg·mL^-1 20 μL, 37 ℃继续培养4 h, 中止培养, 离心弃去孔内上清液, 每孔加入DMSO 150 μL溶解甲臜沉淀, 超声振荡10 min混均。在MR700型酶联免疫检测仪上测定570 nm处各孔吸收度(A)值, 按公式:抑制率/% = [1-(A_实验组-A_空白组) / (A_对照组-A_空白组)] × 100%。计算化合物对细胞的抑制率, 重复测试3次, 取平均值为最终结果。

基金

收起

国家自然科学基金资助项目(21372156)
辽宁省自然科学基金资助项目(201605288)
沈阳市科学技术计划资助项目(F-16-230-6-00)

参考文献

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文献

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参考文献引证文献

排序方式：

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Meng YQ, Zhang LF, Liu DY, et al. Synthesis and antitumor activity evaluation of novel ursolic acid derivatives[J]. J Asian Nat Prod Res, 2016, 18:280-288.

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Liu MC, Yang SJ, Jin LH, et al. Synthesis and evaluation as potential antitumor agents of novel ursolic acid derivatives[J]. Med Chem Res, 2016, 25:1-13.

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Liu D, Meng YQ, Zhao J, et al. Synthesis and anti-tumor activity of novel amide derivatives of ursolic acid[J]. Chem Res Chin Univ, 2008, 24:42-46.

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Meng YQ, Zhao YW, Kuai ZY, et al. Synthesis and antitumor activity evaluation of novel oleanolic acid derivatives[J]. J Asian Nat Prod Res, 2017, 19:1000-1010.

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Chen Y, Hou X, Zhi D, et al. Synthesis, characterization and anticancer activity of oleanolic acid and ursolic acid derivatives[J]. Chin J Org Chem (有机化学), 2016, 36:795-802.

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Meng YQ, Liu D, Bai ZW, et al. Synthesis and anti-tumor activity of ursolic acid derivatives[J]. Acta Pharm Sin (药学学报), 2011, 46:556-560.

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2017年第52卷第12期

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doi: 10.16438/j.0513-4870.2017-0692

接收时间：2017-07-17
首发时间：2026-01-14
出版时间：2017-12-12

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收稿日期：2017-07-17
修回日期：2017-09-04

基金

国家自然科学基金资助项目(21372156)

辽宁省自然科学基金资助项目(201605288)

沈阳市科学技术计划资助项目(F-16-230-6-00)

作者信息

沈阳化工大学制药工程教研室, 辽宁沈阳 110142

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* 孟艳秋, Tel:86-24-89383903, Fax:86-24-89383760, E-mail:myq6581@163.com

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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.	ESI-MS (m/z) [M+H]⁺	Elemental analysis/found (Calcd.)
3	618.2	75.62 (75.74)	8.43 (8.46)	2.27 (2.26)
4	618.4	75.73 (75.76)	8.49 (8.48)	2.26 (2.27)
5	632.4	75.86 (75.98)	8.64 (8.61)	2.23 (2.22)
6	632.3	75.89 (75.95)	9.06 (9.02)	2.17 (2.16)
7	646.5	76.28 (76.19)	8.72 (8.73)	2.18 (2.17)
8	660.4	76.45 (76.39)	8.83 (8.85)	2.13 (2.12)
11	619.4	73.57 (73.70)	8.33 (8.30)	4.54 (4.52)
12	633.4	73.99 (73.96)	8.47 (8.44)	4.43 (4.42)
13	633.1	73.83 (73.97)	8.38 (8.40)	4.41 (4.40)
14	681.4	75.92 (75.80)	7.83 (7.84)	4.10 (4.11)

Compd.

ESI-MS (m/z) [M+H]⁺

Elemental analysis/found (Calcd.)

618.2

75.62 (75.74)

8.43 (8.46)

2.27 (2.26)

618.4

75.73 (75.76)

8.49 (8.48)

2.26 (2.27)

632.4

75.86 (75.98)

8.64 (8.61)

2.23 (2.22)

632.3

75.89 (75.95)

9.06 (9.02)

2.17 (2.16)

646.5

76.28 (76.19)

8.72 (8.73)

2.18 (2.17)

660.4

76.45 (76.39)

8.83 (8.85)

2.13 (2.12)

619.4

73.57 (73.70)

8.33 (8.30)

4.54 (4.52)

633.4

73.99 (73.96)

8.47 (8.44)

4.43 (4.42)

633.1

73.83 (73.97)

8.38 (8.40)

4.41 (4.40)

681.4

75.92 (75.80)

7.83 (7.84)

4.10 (4.11)

Compd.	¹H NMR (CDCl₃)
3	7.76 (s, 1H, NH), 7.45 (d, 1H, J = 8.2 Hz, Ar-H), 7.29 (s, 1H, Ar-H), 7.16 (s, 1H, Ar-H), 5.51 (s, 1H, H-12), 3.96 (s, 2H, -COOCH₂CH₂CH₃), 2.28 (d, 1H, J = 10.8 Hz, H-18), 1.63-1.49 (m, 3H, -COOCH₂CH₂CH₃), 1.58 (s, 2H, -COOCH₂CH₂CH₃), 1.24 (s, 1H, H-9), 1.16, 1.14, 1.07, 1.02, 0.92, 0.99, 0.87 (s, each 3H)
4	7.74 (s, 1H, NH), 7.45 (d, 1H, J = 9.2 Hz, Ar-H), 7.19 (s, 1H, Ar-H), 7.15 (s, 1H, Ar-H), 5.64 (s, 1H, H-12), 4.27 (s, 1H, -COOCH(CH₃)CH₃), 2.28 (d, 1H, J = 9.6 Hz, H-18), 1.44 (d, 3H, J = 9.5 Hz, -COOCH(CH₃)CH₃), 1.43 (d, 3H, J = 9.5 Hz, -COOCH(CH₃)CH₃), 1.29 (s, 1H, H-9), 1.23, 1.19, 1.08, 1.02, 1.01, 0.97, 0.87 (s, each 3H)
5	7.74 (s, 1H, NH), 7.45 (d, 1H, J = 9.7 Hz, Ar-H), 7.19 (s, 1H, Ar-H), 7.06 (s, 1H, Ar-H), 5.71 (s, 1H, H-12), 4.01 (s, 2H, -COOCH₂CH₂CH₂CH₃), 2.37 (d, 1H, J = 8.7 Hz, H-18), 1.53 (s, 2H, -COOCH₂CH₂CH₂CH₃), 1.47 (s, 2H, -COOCH₂CH₂CH₂CH₃), 1.29 (s, 1H, H-9), 1.24 (s, 2H, -COOCH₂CH₂CH₂CH₃), 1.14, 1.11, 1.02, 0.95, 0.92, 0.91, 0.88 (s, each 3H)
6	7.72 (s, 1H, NH), 7.45 (d, 1H, J = 9.2 Hz, Ar-H), 7.17 (s, 1H, Ar-H), 7.05 (s, 1H, Ar-H), 5.72 (s, 1H, H-12), 3.75 (d, 2H, J = 10.2 Hz, -COOCH₂CH(CH₃)CH₃), 2.35 (d, 1H, J = 8.9 Hz, H-18), 1.41 (s, 1H, -COOCH₂CH(CH₃)CH₃), 1.36-1.22 (m, 3H, -COOCH₂CH(CH₃)CH₃), 1.24 (s, 1H, H-9), 1.15-1.08 (m, 3H, -COOCH₂CH(CH₃)CH₃), 1.12, 1.01, 1.02, 0.98, 0.92, 0.88, 0.86 (s, each 3H)
7	7.78 (s, 1H, NH), 7.43 (d, 1H, J = 8.9 Hz, Ar-H), 7.14 (s, 1H, Ar-H), 7.07 (s, 1H, Ar-H), 5.64 (s, 1H, H-12), 3.98 (t, 2H, J = 8.4 Hz, -COOCH₂CH₂CH₂CH₂CH₃), 2.42 (d, 1H, J = 8.9 Hz, H-18), 1.75 (s, 2H, -COOCH₂CH₂CH₂CH₂CH₃), 1.42 (s, 2H, -COOCH₂CH₂CH₂CH₂CH₃), 1.29 (s, 2H, -COOCH₂CH₂CH₂CH₂CH₃), 1.25 (s, 1H, H-9), 1.15 (s, 3H, -COOCH₂CH₂CH₂CH₂CH₃), 1.13, 1.11, 1.06, 1.01, 0.99, 0.89, 0.88 (s, each 3H)
8	7.72 (s, 1H, NH), 7.45 (d, 1H, J = 9.3 Hz, Ar-H), 7.05 (s, 1H, Ar-H), 7.04 (s, 1H, Ar-H), 5.64 (s, 1H, H-12), 4.04 (s, 2H, -COOCH₂CH₂CH₂CH₂CH₂CH₃), 2.98 (s, 2H, -COOCH₂CH₂CH₂CH₂CH₂CH₃), 2.44 (d, 1H, J = 9.1 Hz, H-18), 1.49 (s, 2H, -COOCH₂CH₂CH₂CH₂CH₂CH₃), 1.38 (s, 2H, -COOCH₂CH₂CH₂CH₂CH₂CH₃), 1.32 (s, 1H, H-9), 1.26 (s, 2H, -COOCH₂CH₂CH₂CH₂CH₂CH₃), 1.25 (s, 3H, -COOCH₂CH₂CH₂CH₂CH₂CH₃), 1.15, 1.12, 1.09, 1.01, 0.99, 0.99, 0.89 (s, each 3H)
11	7.72 (s, 1H, NH), 7.40 (d, 1H, J = 9.3 Hz, Ar-H), 7.34 (s, 1H, Ar-H), 7.17 (s, 1H, Ar-H), 6.61 (br, 1H, NH), 5.56 (s, 1H, H-12), 3.63 (s, 2H, -CH₂OH), 3.49 (s, 2H, -CH₂), 1.31 (s, 1H, H-9), 1.23, 1.13, 1.06, 1.05, 0.98, 0.94, 0.93 (s, each 3H)
12	7.81 (s, 1H, NH), 7.33 (d, 1H, J = 9.2 Hz, Ar-H), 7.17 (s, 1H, Ar-H), 7.05 (s, 1H, Ar-H), 6.58 (br, 1H, NH), 5.73 (s, 1H, H-12), 4.15-3.98 (m, 1H, -NHCH(CH₃)CH₂OH), 3.88 (d, 2H, J = 8.6 Hz, -NHCH(CH₃)CH₂OH), 1.32-1.21 (m, 3H, -NHCH(CH₃)CH₂OH), 1.22 (s, 1H, H-9), 1.15, 1.14, 1.12, 1.11, 1.04, 0.98, 0.94 (s, each 3H)
13	7.88 (s, 1H, NH), 7.45 (d, 1H, J = 9.4 Hz, Ar-H), 7.23 (s, 1H, Ar-H), 7.14 (s, 1H, Ar-H), 6.60 (br, 1H, NH), 5.67 (s, 1H, H-12), 3.58 (s, 2H, -NHCH₂CH₂CH₂OH), 3.58 (s, 1H, -NHCH_aCH₂CH₂OH), 3.13 (s, 1H, NHCH_bOH), 1.34 (s, 2H, -NHCH₂CH₂CH₂OH), 1.24 (s, 1H, H-9), 1.11, 1.03, 0.98, 0.91, 0.89, 0.88, 0.83 (s, each 3H)
14	8.38 (s, 1H, NH), 7.46 (d, 1H, J = 9.5 Hz, Ar-H), 7.44 (s, 1H, Ar-H), 7.34-7.15 (m, 4H, Ar-H), 7.14 (s, 1H, Ar-H), 6.61 (br, 1H, NH), 5.67 (s, 1H, H-12), 5.11 (s, 2H, CH₂OH), 1.31 (s, 1H, H-9), 1.23, 1.11, 1.09, 1.05, 0.98, 0.97, 0.88 (s, each 3H)

Compd.

¹H NMR (CDCl₃)

Compd.	Inhibition rate/% (10 μmol·L^-1)
UA	12.62	13.34	> 20	> 20
3	18.25	21.19	> 20	> 20
4	36.57	35.35	12.38	9.95
5	25.49	19.35	> 20	7.50
6	48.96	54.60	10.22	3.12
7	30.93	38.52	> 20	> 20
8	41.28	38.81	> 20	10.74
11	39.58	42.16	> 20	> 20
12	52.83	49.56	8.96	12.45
13	29.36	27.53	> 20	> 20
14	33.69	24.31	> 20	> 20
Paclitaxel	52.75	50.82	14.35	7.87
Adriamycin	64.37	59.38	3.48	2.07

Compd.

Inhibition rate/% (10 μmol·L^-1)

IC₅₀/μmol·L^-1

HepG2

SGC7901

HepG2

SGC7901

12.62

13.34

> 20

18.25

21.19

> 20

36.57

35.35

12.38

9.95

25.49

19.35

> 20

7.50

48.96

54.60

10.22

3.12

30.93

38.52

> 20

41.28

38.81

> 20

10.74

39.58

42.16

> 20

52.83

49.56

8.96

12.45

29.36

27.53

> 20

33.69

24.31

> 20

Paclitaxel

52.75

50.82

14.35

7.87

Adriamycin

64.37

59.38

3.48

2.07