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Compd.	ESI-MS (m/z) [M+H]⁺	¹³C NMR (CDCl₃, 150 MHz)	¹H NMR (600 MHz, DMSO-d₆)
B	673.17	185.7, 170.2, 170.2, 169.0, 169.0, 162.2, 160.5, 152.2, 151.4, 147.0, 142.9, 139.2, 131.5, 127.2, 122.7, 119.7, 118.2, 109.8, 109.5, 109.1, 108.5, 98.8, 96.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.3	δ 11.12 (s, 1H), 7.35-6.89 (m, 6H), 6.31 (d, J = 2.3 Hz, 1H), 6.28 (d, J = 2.2 Hz, 1H), 5.75 (t, J = 12.1 Hz, 1H), 5.52 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 12.2 Hz, 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 7.9 Hz, 1H), 3.99 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H)
I₁	799.18	185.5, 170.2, 170.2, 169.1, 169.0, 162.2, 157.1, 152.2, 151.4, 147.0, 142.9, 139.2, 131.5, 127.2, 122.6, 119.7, 118.3, 110.1, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 44.7, 28.6, 28.4, 22.4, 20.7, 20.7, 20.3, 20.3, 14.1	δ 9.11 (m, 1H), 7.32-6.84 (m, 6H), 6.41 (d, J = 2.3 Hz, 1H), 6.09 (d, J = 2.2 Hz, 1H), 5.68 (t, J = 12.1 Hz, 1H), 5.50 (d, J = 12.2 Hz, 1H), 5.12 (t, J = 11.8 Hz, 1H), 4.66-4.59 (m, 1H), 4.20 (s, 1H), 4.14 (d, J = 7.8 Hz, 1H), 3.88 (dd, J = 12.7, 5.1 Hz, 1H), 3.79 (s, 3H), 2.87 (m, 2H), 2.28 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H), 1.52 (m, 2H), 1.29 (m, 2H), 1.28 (m, 2H), 0.87 (t, J = 7.5 Hz, 3H)
I₂	850.19	185.7, 171.1, 169.8, 169.1, 169.0, 162.2, 157.1, 152.2, 151.4, 148.7, 147.0, 142.9, 139.2, 138.6, 131.5, 130.4, 127.2, 125.5, 123.3, 119.7, 118.2, 113.9, 113.1, 109.8, 109.5, 108.8, 108.5, 100.8, 98.8, 84.3, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.2	δ 10.58 (s, 1H), 7.86-7.19 (m, 5H), 7.05-6.89 (m, 6H), 6.36 (d, J = 2.3 Hz, 1H), 6.23 (d, J = 2.2 Hz, 1H), 5.85 (t, J = 12.1 Hz, 1H), 5.52 (d, J = 12.1 Hz, 1H), 5.14 (t, J = 11.6 Hz, 1H), 4.65-4.59 (m, 1H), 4.12 (d, J = 8.6 Hz, 1H), 3.95 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.24 (s, 3H), 2.18 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H)
I₃	823.15	185.7, 170.2, 170.2, 169.0, 169.0, 163.7, 162.6, 157.1, 152.2, 151.4, 147.0, 142.9, 139.3, 139.2, 131.5, 131.1, 127.2, 122.7, 119.7, 118.2, 115.0, 110.5, 109.8, 109.5, 109.1, 108.5, 104.8, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.3	δ 10.67 (s, 1H), 7.86-7.19 (m, 4H), 7.37-6.95 (m, 6H), 6.56 (t, J = 7.5 Hz, 1H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.76 (t, J = 12.3 Hz, 1H), 5.52 (d, J = 12.2 Hz, 1H), 5.11 (t, J = 11.7 Hz, 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 9.6 Hz, 1H), 3.98 (dd, J = 12.6, 5.1 Hz, 1H), 3.79 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H)
I₄	799.82	186.1, 170.2, 170.2, 169.0, 169.0, 162.6, 157.1, 152.2, 151.4, 147.0, 142.9, 139.2, 131.5, 127.2, 122.7, 119.7, 118.2, 109.8, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 41.9, 38.3, 24.9, 20.7, 20.7, 20.3, 20.3	δ 7.35-6.89 (m, 6H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.76 (t, J = 12.1 Hz, 1H), 5.52 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 11.6 Hz, 1H), 4.94-4.69 (m, 1H), 4.20 (s, 1H), 4.14 (d, J = 9.8 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.87 (t, J = 6.8 Hz, 2H), 2.27 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H), 1.59 (m, 2H), 1.53 (m, 2H), 0.91 (d, J = 2.3 Hz, 6H)
I₅	883.15	185.7, 170.2, 170.2, 169.0, 169.0, 162.6, 157.1, 152.2, 151.4, 147.0, 142.9, 139.2, 134.9, 132.4, 131.5, 128.5, 127.2, 126.2, 122.8, 122.7, 119.7, 118.2, 115.7, 109.6, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.3	δ 10.73 (s, 1H), 7.55-7.35 (m, 8H), 6.89-6.88 (m, 2H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.76 (t, J = 12.1 Hz, 1H), 5.52 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 11.6 Hz, 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 10.6 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H)
I₆	805.16	184.9, 170.4, 170.2, 169.0, 169.0, 162.6, 157.1, 152.2, 151.4, 147.0, 142.9, 139.2, 137.7, 131.5, 129.5, 129.5, 127.2, 123.2, 122.4, 119.7, 119.4, 119.4, 118.2, 109.8, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.3	δ 10.53 (s, 1H), 7.35-7.18 (m, 6H), 6.89-6.80 (m, 5H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.76 (t, J = 12.3 Hz, 1H), 5.52 (d, J = 12.3 Hz, 1H), 5.11 (t, J = 11.8 Hz, 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 9.9 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H)
I₇	825.21	185.4, 170.2, 170.1, 169.0, 169.0, 162.6, 157.1, 153.3, 152.2, 151.4, 147.0, 142.9, 139.2, 131.5, 130.0, 127.2, 124.5, 124.5, 122.7, 119.7, 118.2, 115.1, 115.1, 109.8, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.3	δ 10.62 (s, 1H), 7.35-6.89 (m, 6H), 6.85-6.78 (m, 4H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.4 Hz, 1H), 5.76 (t, J = 12.1 Hz, 1H), 5.52 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 11.3 Hz, 1H), 4.68-4.57 (m, 1H), 4.14 (d, J = 8.9 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 2.37 (s, 3H), 2.26 (s, 3H), 2.04 (s, 3H), 1.87 (s, 3H)
I₈	840.22	185.7, 170.3, 170.3, 169.0, 169.0, 162.6, 157.1, 152.2, 151.4, 147.0, 142.9, 139.2, 139.1, 135.1, 131.5, 130.9, 127.2, 122.7, 122.3, 119.7, 119.2, 118.2, 117.5, 109.8, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.8, 20.7, 20.3, 20.3	δ 10.59 (s, 1H), 7.35-6.89 (m, 6H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.66 (t, J = 12.0 Hz, 1H), 5.32 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 11.6 Hz, 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 9.6 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H)
I₉	850.39	185.6, 170.2, 170.2, 169.0, 169.0, 162.6, 157.1, 152.2, 151.4, 147.0, 142.9, 140.2, 139.2, 138.8, 138.1, 131.5, 131.2, 127.2, 122.7, 120.8, 119.7, 118.2, 118.1, 109.8, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 79.2, 73.5, 63.3, 55.8, 20.7, 20.5, 20.3, 20.3	δ 10.89 (s, 1H), 8.43 (d, J = 7.26 Hz, 1H), 8.31 (d, J = 7.30 Hz, 1H), 7.35-6.89 (m, 6H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.76 (t, J = 12.1 Hz, 1H), 5.52 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 11.6 Hz, 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 10.6 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H)
I₁₀	909.21	194.3, 185.7, 170.2, 170.2, 162.6, 157.1, 152.2, 151.4, 147.0, 144.7, 142.9, 139.2, 138.4, 137.4, 133.5, 132.4, 131.5, 131.8, 130.3, 128.4, 128.4, 127.2, 123.1, 122.7, 120.3, 119.7, 118.2, 114.6, 109.8, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.3	δ 10.82 (s, 1H), 7.81-7.61 (m, 5H), 7.60-7.08 (m, 4H), 7.05-6.59 (m, 6H), 6.37 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.76 (t, J = 12.1 Hz, 1H), 5.52 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 11.6 Hz, 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 9.7 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H)
I₁₁	851.33	185.7, 170.2, 169.2, 169.0, 162.6, 157.8, 152.5, 150.4, 146.5, 142.8, 137.3, 135.2, 132.4, 129.2, 128.4, 127.8, 126.2, 123.5, 122.7, 119.7, 118.2, 115.7, 109.6, 109.5, 109.2, 108.5, 102.8, 98.8, 84.1, 79.7, 77.9, 76.1, 63.4, 56.7, 20.7, 20.7, 20.3, 20.3	δ 10.58 (s, 1H), 8.04-7.35 (m, 8H), 6.89-6.57 (m, 2H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.76 (t, J = 11.1 Hz, 1H), 5.38 (d, J = 12.1 Hz, 1H), 5.17 (t, J = 10.9 Hz 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 9.4 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H), 2.19 (s, 3H), 2.04 (s, 3H)
I₁₂	884.66	185.8, 169.0, 169.0, 168.7, 168.3, 162.6, 157.1, 152.2, 151.4, 147.0, 142.9, 139.2, 134.9, 132.4, 130.6, 128.5, 127.2, 126.2, 123.8, 122.1, 118.7, 118.2, 115.7, 109.6, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.3	δ 10.58 (s, 1H), 7.18 (s, 1H), 7.07-6.87 (m, 9H), 6.45 (d, J = 2.3 Hz, 1H), 6.37 (d, J = 2.2 Hz, 1H), 6.10 (t, J = 12.1 Hz, 1H), 5.38 (d, J = 12.1 Hz, 1H), 5.17 (t, J = 11.5 Hz, 1H), 4.57 (m, 1H), 4.14 (d, J = 9.7 Hz, 1H), 3.83 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H), 2.19 (s, 3H), 2.04 (s, 3H)
I₁₃	823.75	185.7, 170.2, 170.2, 168.4, 157.3, 157.1, 152.2, 151.4, 147.0, 142.9, 139.2, 134.9, 132.4, 131.5, 128.5, 126.3, 126.2, 122.8, 122.7, 119.7, 118.2, 115.7, 109.6, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 58.8, 20.7, 20.7, 20.3, 20.3	δ 10.61 (s, 1H), 7.55-7.35 (m, 8H), 6.96-6.88 (m, 2H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.76 (t, J = 12.1 Hz, 1H), 5.52 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 11.9 Hz 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 9.8 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H), 2.19 (s, 3H), 2.04 (s, 3H)
I₁₄	819.79	185.7, 170.2, 170.2, 168.4, 157.3, 157.1, 152.2, 151.4, 147.0, 142.9, 139.2, 134.9, 132.4, 131.5, 128.5, 127.2, 126.2, 122.8, 122.7, 119.7, 118.2, 115.7, 109.6, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.3	δ 10.58 (s, 1H), 7.37-7.05 (m, 8H), 6.97-6.87 (m, 2H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.76 (t, J = 12.1 Hz, 1H), 5.52 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 11.6 Hz 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 9.6 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.87 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H)
I₁₅	840.20	185.7, 169.0, 169.0, 162.6, 157.1, 152.2, 151.4, 147.0, 142.9, 139.2, 136.9, 132.4, 131.5, 129.5, 127.6, 126.2, 122.8, 122.7, 119.7, 118.2, 115.7, 109.6, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.3	δ 10.59 (s, 1H), 7.95-7.35 (m, 8H), 6.94-6.88 (m, 2H), 6.41 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.83 (t, J = 12.1 Hz, 1H), 5.58 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 11.9 Hz, 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 7.6 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H), 2.09 (s, 3H), 2.04 (s, 3H)

Compd.	ESI-MS (m/z) [M+H]⁺	¹³C NMR (CDCl₃, 150 MHz)	¹H NMR (600 MHz, DMSO-d₆)
B	673.17	185.7, 170.2, 170.2, 169.0, 169.0, 162.2, 160.5, 152.2, 151.4, 147.0, 142.9, 139.2, 131.5, 127.2, 122.7, 119.7, 118.2, 109.8, 109.5, 109.1, 108.5, 98.8, 96.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.3	δ 11.12 (s, 1H), 7.35-6.89 (m, 6H), 6.31 (d, J = 2.3 Hz, 1H), 6.28 (d, J = 2.2 Hz, 1H), 5.75 (t, J = 12.1 Hz, 1H), 5.52 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 12.2 Hz, 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 7.9 Hz, 1H), 3.99 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H)
I₁	799.18	185.5, 170.2, 170.2, 169.1, 169.0, 162.2, 157.1, 152.2, 151.4, 147.0, 142.9, 139.2, 131.5, 127.2, 122.6, 119.7, 118.3, 110.1, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 44.7, 28.6, 28.4, 22.4, 20.7, 20.7, 20.3, 20.3, 14.1	δ 9.11 (m, 1H), 7.32-6.84 (m, 6H), 6.41 (d, J = 2.3 Hz, 1H), 6.09 (d, J = 2.2 Hz, 1H), 5.68 (t, J = 12.1 Hz, 1H), 5.50 (d, J = 12.2 Hz, 1H), 5.12 (t, J = 11.8 Hz, 1H), 4.66-4.59 (m, 1H), 4.20 (s, 1H), 4.14 (d, J = 7.8 Hz, 1H), 3.88 (dd, J = 12.7, 5.1 Hz, 1H), 3.79 (s, 3H), 2.87 (m, 2H), 2.28 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H), 1.52 (m, 2H), 1.29 (m, 2H), 1.28 (m, 2H), 0.87 (t, J = 7.5 Hz, 3H)
I₂	850.19	185.7, 171.1, 169.8, 169.1, 169.0, 162.2, 157.1, 152.2, 151.4, 148.7, 147.0, 142.9, 139.2, 138.6, 131.5, 130.4, 127.2, 125.5, 123.3, 119.7, 118.2, 113.9, 113.1, 109.8, 109.5, 108.8, 108.5, 100.8, 98.8, 84.3, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.2	δ 10.58 (s, 1H), 7.86-7.19 (m, 5H), 7.05-6.89 (m, 6H), 6.36 (d, J = 2.3 Hz, 1H), 6.23 (d, J = 2.2 Hz, 1H), 5.85 (t, J = 12.1 Hz, 1H), 5.52 (d, J = 12.1 Hz, 1H), 5.14 (t, J = 11.6 Hz, 1H), 4.65-4.59 (m, 1H), 4.12 (d, J = 8.6 Hz, 1H), 3.95 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.24 (s, 3H), 2.18 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H)
I₃	823.15	185.7, 170.2, 170.2, 169.0, 169.0, 163.7, 162.6, 157.1, 152.2, 151.4, 147.0, 142.9, 139.3, 139.2, 131.5, 131.1, 127.2, 122.7, 119.7, 118.2, 115.0, 110.5, 109.8, 109.5, 109.1, 108.5, 104.8, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.3	δ 10.67 (s, 1H), 7.86-7.19 (m, 4H), 7.37-6.95 (m, 6H), 6.56 (t, J = 7.5 Hz, 1H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.76 (t, J = 12.3 Hz, 1H), 5.52 (d, J = 12.2 Hz, 1H), 5.11 (t, J = 11.7 Hz, 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 9.6 Hz, 1H), 3.98 (dd, J = 12.6, 5.1 Hz, 1H), 3.79 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H)
I₄	799.82	186.1, 170.2, 170.2, 169.0, 169.0, 162.6, 157.1, 152.2, 151.4, 147.0, 142.9, 139.2, 131.5, 127.2, 122.7, 119.7, 118.2, 109.8, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 41.9, 38.3, 24.9, 20.7, 20.7, 20.3, 20.3	δ 7.35-6.89 (m, 6H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.76 (t, J = 12.1 Hz, 1H), 5.52 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 11.6 Hz, 1H), 4.94-4.69 (m, 1H), 4.20 (s, 1H), 4.14 (d, J = 9.8 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.87 (t, J = 6.8 Hz, 2H), 2.27 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H), 1.59 (m, 2H), 1.53 (m, 2H), 0.91 (d, J = 2.3 Hz, 6H)
I₅	883.15	185.7, 170.2, 170.2, 169.0, 169.0, 162.6, 157.1, 152.2, 151.4, 147.0, 142.9, 139.2, 134.9, 132.4, 131.5, 128.5, 127.2, 126.2, 122.8, 122.7, 119.7, 118.2, 115.7, 109.6, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.3	δ 10.73 (s, 1H), 7.55-7.35 (m, 8H), 6.89-6.88 (m, 2H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.76 (t, J = 12.1 Hz, 1H), 5.52 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 11.6 Hz, 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 10.6 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H)
I₆	805.16	184.9, 170.4, 170.2, 169.0, 169.0, 162.6, 157.1, 152.2, 151.4, 147.0, 142.9, 139.2, 137.7, 131.5, 129.5, 129.5, 127.2, 123.2, 122.4, 119.7, 119.4, 119.4, 118.2, 109.8, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.3	δ 10.53 (s, 1H), 7.35-7.18 (m, 6H), 6.89-6.80 (m, 5H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.76 (t, J = 12.3 Hz, 1H), 5.52 (d, J = 12.3 Hz, 1H), 5.11 (t, J = 11.8 Hz, 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 9.9 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H)
I₇	825.21	185.4, 170.2, 170.1, 169.0, 169.0, 162.6, 157.1, 153.3, 152.2, 151.4, 147.0, 142.9, 139.2, 131.5, 130.0, 127.2, 124.5, 124.5, 122.7, 119.7, 118.2, 115.1, 115.1, 109.8, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.3	δ 10.62 (s, 1H), 7.35-6.89 (m, 6H), 6.85-6.78 (m, 4H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.4 Hz, 1H), 5.76 (t, J = 12.1 Hz, 1H), 5.52 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 11.3 Hz, 1H), 4.68-4.57 (m, 1H), 4.14 (d, J = 8.9 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 2.37 (s, 3H), 2.26 (s, 3H), 2.04 (s, 3H), 1.87 (s, 3H)
I₈	840.22	185.7, 170.3, 170.3, 169.0, 169.0, 162.6, 157.1, 152.2, 151.4, 147.0, 142.9, 139.2, 139.1, 135.1, 131.5, 130.9, 127.2, 122.7, 122.3, 119.7, 119.2, 118.2, 117.5, 109.8, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.8, 20.7, 20.3, 20.3	δ 10.59 (s, 1H), 7.35-6.89 (m, 6H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.66 (t, J = 12.0 Hz, 1H), 5.32 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 11.6 Hz, 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 9.6 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H)
I₉	850.39	185.6, 170.2, 170.2, 169.0, 169.0, 162.6, 157.1, 152.2, 151.4, 147.0, 142.9, 140.2, 139.2, 138.8, 138.1, 131.5, 131.2, 127.2, 122.7, 120.8, 119.7, 118.2, 118.1, 109.8, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 79.2, 73.5, 63.3, 55.8, 20.7, 20.5, 20.3, 20.3	δ 10.89 (s, 1H), 8.43 (d, J = 7.26 Hz, 1H), 8.31 (d, J = 7.30 Hz, 1H), 7.35-6.89 (m, 6H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.76 (t, J = 12.1 Hz, 1H), 5.52 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 11.6 Hz, 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 10.6 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H)
I₁₀	909.21	194.3, 185.7, 170.2, 170.2, 162.6, 157.1, 152.2, 151.4, 147.0, 144.7, 142.9, 139.2, 138.4, 137.4, 133.5, 132.4, 131.5, 131.8, 130.3, 128.4, 128.4, 127.2, 123.1, 122.7, 120.3, 119.7, 118.2, 114.6, 109.8, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.3	δ 10.82 (s, 1H), 7.81-7.61 (m, 5H), 7.60-7.08 (m, 4H), 7.05-6.59 (m, 6H), 6.37 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.76 (t, J = 12.1 Hz, 1H), 5.52 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 11.6 Hz, 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 9.7 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H)
I₁₁	851.33	185.7, 170.2, 169.2, 169.0, 162.6, 157.8, 152.5, 150.4, 146.5, 142.8, 137.3, 135.2, 132.4, 129.2, 128.4, 127.8, 126.2, 123.5, 122.7, 119.7, 118.2, 115.7, 109.6, 109.5, 109.2, 108.5, 102.8, 98.8, 84.1, 79.7, 77.9, 76.1, 63.4, 56.7, 20.7, 20.7, 20.3, 20.3	δ 10.58 (s, 1H), 8.04-7.35 (m, 8H), 6.89-6.57 (m, 2H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.76 (t, J = 11.1 Hz, 1H), 5.38 (d, J = 12.1 Hz, 1H), 5.17 (t, J = 10.9 Hz 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 9.4 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H), 2.19 (s, 3H), 2.04 (s, 3H)
I₁₂	884.66	185.8, 169.0, 169.0, 168.7, 168.3, 162.6, 157.1, 152.2, 151.4, 147.0, 142.9, 139.2, 134.9, 132.4, 130.6, 128.5, 127.2, 126.2, 123.8, 122.1, 118.7, 118.2, 115.7, 109.6, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.3	δ 10.58 (s, 1H), 7.18 (s, 1H), 7.07-6.87 (m, 9H), 6.45 (d, J = 2.3 Hz, 1H), 6.37 (d, J = 2.2 Hz, 1H), 6.10 (t, J = 12.1 Hz, 1H), 5.38 (d, J = 12.1 Hz, 1H), 5.17 (t, J = 11.5 Hz, 1H), 4.57 (m, 1H), 4.14 (d, J = 9.7 Hz, 1H), 3.83 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H), 2.19 (s, 3H), 2.04 (s, 3H)
I₁₃	823.75	185.7, 170.2, 170.2, 168.4, 157.3, 157.1, 152.2, 151.4, 147.0, 142.9, 139.2, 134.9, 132.4, 131.5, 128.5, 126.3, 126.2, 122.8, 122.7, 119.7, 118.2, 115.7, 109.6, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 58.8, 20.7, 20.7, 20.3, 20.3	δ 10.61 (s, 1H), 7.55-7.35 (m, 8H), 6.96-6.88 (m, 2H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.76 (t, J = 12.1 Hz, 1H), 5.52 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 11.9 Hz 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 9.8 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H), 2.19 (s, 3H), 2.04 (s, 3H)
I₁₄	819.79	185.7, 170.2, 170.2, 168.4, 157.3, 157.1, 152.2, 151.4, 147.0, 142.9, 139.2, 134.9, 132.4, 131.5, 128.5, 127.2, 126.2, 122.8, 122.7, 119.7, 118.2, 115.7, 109.6, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.3	δ 10.58 (s, 1H), 7.37-7.05 (m, 8H), 6.97-6.87 (m, 2H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.76 (t, J = 12.1 Hz, 1H), 5.52 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 11.6 Hz 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 9.6 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.87 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H)
I₁₅	840.20	185.7, 169.0, 169.0, 162.6, 157.1, 152.2, 151.4, 147.0, 142.9, 139.2, 136.9, 132.4, 131.5, 129.5, 127.6, 126.2, 122.8, 122.7, 119.7, 118.2, 115.7, 109.6, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.3	δ 10.59 (s, 1H), 7.95-7.35 (m, 8H), 6.94-6.88 (m, 2H), 6.41 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.83 (t, J = 12.1 Hz, 1H), 5.58 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 11.9 Hz, 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 7.6 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H), 2.09 (s, 3H), 2.04 (s, 3H)

Compd.	Inhibition rate/%	IC₅₀/μmol·L^-1
Sliybin	26.36	22.01	> 50.00
C	77.99	26.63	48.02
I₁	93.06	59.67	22.46
I₂	45.65	35.98	> 50.00
I₃	84.80	28.53	> 50.00
I₄	87.02	40.61	32.80
I₅	41.58	28.74	> 50.00
I₆	73.35	36.04	32.72
I₇	64.64	37.85	42.63
I₈	29.81	26.55	> 50.00
I₉	59.36	29.41	> 50.00
I₁₀	32.83	22.50	> 50.00
I₁₁	40.70	29.12	37.81
I₁₂	48.24	33.48	47.92
I₁₃	57.12	32.70	48.83
I₁₄	53.76	37.50	> 50.00
I₁₅	51.43	35.89	46.72
Palbociclib	54.94	29.36	45.32

Compd.	Inhibition rate/%	IC₅₀/μmol·L^-1
Sliybin	26.36	22.01	> 50.00
C	77.99	26.63	48.02
I₁	93.06	59.67	22.46
I₂	45.65	35.98	> 50.00
I₃	84.80	28.53	> 50.00
I₄	87.02	40.61	32.80
I₅	41.58	28.74	> 50.00
I₆	73.35	36.04	32.72
I₇	64.64	37.85	42.63
I₈	29.81	26.55	> 50.00
I₉	59.36	29.41	> 50.00
I₁₀	32.83	22.50	> 50.00
I₁₁	40.70	29.12	37.81
I₁₂	48.24	33.48	47.92
I₁₃	57.12	32.70	48.83
I₁₄	53.76	37.50	> 50.00
I₁₅	51.43	35.89	46.72
Palbociclib	54.94	29.36	45.32

靶向CDK4/6抑制剂水飞蓟宾衍生物的合成及抗肿瘤活性研究

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高诗特 ¹^,² , 蒯振彧 ³ , 张志鹏 ¹ , 孟艳秋 ¹^,^*

药学学报 | 研究论文 2023,58(3): 721-728

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药学学报 |研究论文 2023 , 58 (3) : 721 -728

靶向CDK4/6抑制剂水飞蓟宾衍生物的合成及抗肿瘤活性研究

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高诗特¹^,², 蒯振彧³, 张志鹏¹, 孟艳秋¹^,^*

作者信息

1.沈阳化工大学, 辽宁沈阳 110142

2.沈阳科技学院, 辽宁沈阳 110166

3.马鞍山职业技术学院, 安徽马鞍山 243031

通讯作者:

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

Study on the modification and anti-tumor activity of silybin derivatives for CDK4/6 targeted

Shi-te GAO¹^,², Zhen-yu KUAI³, Zhi-peng ZHANG¹, Yan-qiu MENG¹^,^*

Affiliations

1. Shenyang University of Chemical Technology, Shenyang 110142, China

2. Shenyang Institute of Science and Technology, Shenyang 110166, China

3. Ma'anshan Vocational and Technical College, Ma'anshan 243031, China

出版时间: 2023-03-12 doi: 10.16438/j.0513-4870.2022-0972

文章导航

摘要

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本文借助计算机辅助设计, 结合已上市的CDK4/6抑制剂活性片段构建药效团模型, 设计合成了15个水飞蓟宾C-7位结构衍生物。经MS、¹³C NMR和¹H NMR谱图解析确认, 15个化合物均为未见文献报道的新化合物。采用MTT法, 对人肝癌细胞(HepG-2) 进行了初步的体外抗肿瘤活性研究。实验结果表明, 所有化合物均比母体水飞蓟宾的活性有提高, 其中化合物I₁对人HepG-2细胞有一定的抑制作用, 值得进一步研究。

关键词

水飞蓟宾衍生物 / CDK4/6抑制剂 / 结构修饰 / 抗肿瘤活性

Abstract

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By using computer-aided drug design, the activities group model which CDK4/6 inhibitors on the market were introduced to silybin C-7, and a series of silybin derivatives were designed and synthesized, and the structure was confirmed by MS, ¹³C NMR and ¹H NMR. The in vitro antitumor activity evaluation of the target compound was carried out by MTT method, and the in vitro anti-tumor activity was carried out in human hepatocellular carcinoma cells (HepG-2). Experimental results show that all compounds are higher than the activity of the parent silybin, of which compound I₁ has a certain inhibitory effect on human HepG-2 cells, which is worth further study.

Key words

derivative of silybin / CDK4/6 inhibitor / structural modification / anti-tumor activity

引用本文

高诗特, 蒯振彧, 张志鹏, 孟艳秋. 靶向CDK4/6抑制剂水飞蓟宾衍生物的合成及抗肿瘤活性研究. 药学学报, 2023 , 58 (3) : 721 -728 . DOI: 10.16438/j.0513-4870.2022-0972

Shi-te GAO, Zhen-yu KUAI, Zhi-peng ZHANG, Yan-qiu MENG. Study on the modification and anti-tumor activity of silybin derivatives for CDK4/6 targeted[J]. Acta Pharmaceutica Sinica, 2023 , 58 (3) : 721 -728 . DOI: 10.16438/j.0513-4870.2022-0972

正文

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水飞蓟素来源于植物水飞蓟成熟的种子, 水飞蓟宾是水飞蓟素中最主要的活性成分。天然的水飞蓟宾是等量的两种非对映异构体水飞蓟宾A和水飞蓟宾B的混合物(图 1)。

水飞蓟宾具有稳定肝细胞膜、抗肝纤维化、清除氧自由基、抗肿瘤和抗病毒等生物活性^{[1, 2]}, 目前临床上主要用于肝胆系统疾病的治疗。最新研究表明水飞蓟宾对肺癌、前列腺癌、肝癌等具有一定的抑制活性^[3]。对其作用机制的研究发现, 水飞蓟宾可下调ALDH1A1的表达, 从而抑制RARα激活, 起到抑制前列腺癌的生长和侵袭的作用^[4]。水飞蓟宾与二甲双胍联用, 调控cyclin D₁和hTERT基因, 抑制T47D乳腺癌细胞生长^[5]。水飞蓟宾上调p15INK4B基因, 诱导细胞周期G1期阻滞, 抑制人胰腺癌SW1990细胞的活性^[6]。

通过细胞周期控制可防止细胞无限制的增殖。周期蛋白依赖性激酶4/6 (CDK4/6) 是细胞调控分裂周期的基本驱动因子, CDK4/6的过度表达成为多种肿瘤诊断的生物标志物。Song等^[7]报道MLN0128作为Pan-mTOR抑制剂可有效诱导细胞凋亡, 与CDK4/6酶抑制剂palbociclib联用可增强MLN0128 mTOR抑制活性从而发挥协同抑制肝内胆管癌增殖的作用。

目前, 已上市的CDK4/6抑制剂包括palbociclib^{[8, 9]}、ribociclib^[10]和abemaciclib^[11] (图 2)。这些药物的结构中多采用仲胺(-NH-) 为linker链接其他药效团, 且在临床上均有不同程度的耐药性^{[12, 13]}。因此, 寻找和开发新型的抑制CDK4/6酶活性的小分子抑制剂, 对肿瘤药物研究具有极其重要的意义。

本文借助计算机设计及药效团拼合原理, 以水飞蓟宾为先导化合物, 通过在C-7位^[14]拼合磺胺基团, 设计合成了一系列新型水飞蓟宾衍生物, 以palbociclib为阳性对照药, 并开展了体外抗肿瘤活性测试及CDK4/6酶活性测试。

结果与讨论

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1 化学合成

如合成路线1所示, 以水飞蓟宾为原料, 使用乙酸酐为酰化试剂, 在4-二甲氨基吡啶(4-dimethylaminopyridine, DMAP) 的催化下合成中间体A; 中间体A在吡啶中, 与丙胺反应30 s, 得到中间体B; 中间体B在二氯甲烷(DCM) 中与磺酰氯反应得到中间体C; 中间体C与相应的胺反应得到目标化合物I₁~I₁₅。化合物结构经MS、¹³C NMR和¹H NMR确认, 数据见表 1。

2 生物活性评价

以palbociclib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 2。

MTT实验结果显示, 药物浓度在10与100 μmol·L^-1时对HepG-2的抑制率均优于母体水飞蓟宾。与反应中间体C相比, 在C-7位引入磺胺结构可提高化合物的抗肿瘤活性。在C-7位连接脂肪烃取代基的化合物I₁、I₄比芳香烃侧链化合物具有更好的抗肿瘤活性, 且随着取代基碳数的增加, 其抗肿瘤活性也随之增加。其中化合物I₁对HepG-2的抑制率为59.67%, 有明显的抑制作用。

3 CDK4/6酶活性测试

体外CDK4/6激酶抑制活性实验结果显示, 代表化合物I₁的IC₅₀值为0.96 μmol·L^-1, 与阳性对照物palbociclib (IC₅₀ 1.03 μmol·L^-1) 相当, 表明化合物可通过直接抑制CDK4/6的活性发挥抗肿瘤作用。

4 分子对接

使用MVD 6.0 (Molegro Virtual Docker) 软件打开CDK4/6靶蛋白(PDB: 5L2S), 选择Docking Wizard确定CDK4/6靶蛋白活性区域位置^[15]。使用Chem Draw 3D 12.0构建silybin的3D构象^[16], 与活性区域位置进行半柔性对接, 靶蛋白构象不变, palbociclib化学结构进行适当的改变, 选择打分函数MolDock Score [GRID] 与构象搜寻MolDock SE, 得到相应的分子对接分数。将模拟化合物用相同的方法与CDK4/6靶蛋白(PDB Code: 5L2S) 进行对接, 得到分子对接分数。其中化合物I₁对接结果最好。

将对接完毕后得到的一系列化合物优化后的结构文件, 相应的对接文件用Discovery studio 4.0软件解析后得到化合物与CDK4/6靶蛋白的对接立体与平面图像。化合物I₁通过氢键、疏水键和范德华力等作用与氨基酸GLU120、GLN301、ASP270、PRO298、ILE269发生相互作用, 从而与靶蛋白稳定结合(图 3)。阳性对照药物palbociclib与CDK4/6活性空腔中的ALA291、ASP134、ALA285氨基酸产生氢键与疏水键等相互作用(图 4)。对接数据表明化合物I₁优于palbociclib与CDK4/6靶蛋白的结合情况, 且能与靶蛋白稳定结合。

5 结论

以水飞蓟宾为先导化合物, 对其C-7位进行结构改造, 设计合成了15个新型水飞蓟宾磺胺衍生物, 其结构通过NMR和MS表征。分子对接结果表明, 水飞蓟宾C-7位磺胺衍生物与多数氨基酸残基形成氢键, 实现与CDK蛋白稳定结合。体外抗肿瘤活性测试结果显示, 水飞蓟宾拼合磺胺结合的结构衍生物I₁、I₄、I₆、I₇、I₁₁可提高抗肿瘤活性, 明显强于母体, 其中化合物I₁活性最高, 优于阳性对照药物palbociclib。进一步体外酶活性实验结果表明, 化合物I₁对CDK的抑制活性与阳性对照药物palbociclib相当。因此, 水飞蓟宾C-7位拼合磺胺基团, 可增强抗肿瘤活性。对水飞蓟宾衍生物的进一步结构设计、优化和药理活性研究具有一定的指导意义。

实验部分

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电子天平购于上海精密科学仪器有限公司; Büchi旋蒸仪、Büchi Melting Point Apparatus B-540 (瑞士Büchi公司); BrukerARX-600型核磁共振分析仪, CDCl₃为溶剂, TMS为内标, 购于瑞士BRUKER公司; SHZ-D3水循环泵、DF-101S集热式恒温加热磁力搅拌器(巩义市予华仪器有限公司); ZF-1三用紫外分析仪(上海精科实业有限公司)。

细胞株选用人肝癌细胞HepG-2 (沈阳药科大学)。

RPMI-1640培养基、胰蛋白酶(trypsin)、标准胎牛血清(FBS), 购于上海图赫实业有限公司; 氯化钠、乙二胺四乙酸(EDTA)、氯化钾、碳酸氢钠、磷酸氢二钠、磷酸二氢钾、二甲基亚砜(DMSO)、噻唑蓝、青霉素G、HEPES、链霉素(上海麦克林生化科技有限公司); 市售纯净水。

1 化学合成

1.1 3, 5, 7, 20, 23-五乙酸水飞蓟宾酯(A) 的制备

将水飞蓟宾(0.964 0 g, 2 mmol) 溶解在10 mL吡啶溶液中, 在室温下搅拌, 随后加入乙酸酐(2 mL, 3.5 mmol) 与5 mg DMAP, 将反应混合物在室温下继续搅拌5 min, TLC检测反应终点。反应结束后, 将100 mL冰水倒入混合物中, 快速搅拌析出白色固体, 抽滤, 用水洗涤滤饼, 干燥得1.365 0 g白色粉末状固体即化合物A。产率99%, mp 111~117 ℃。

1.2 3, 5, 20, 23-四乙酸水飞蓟宾酯(B) 的制备

将化合物A (1.384 0 g, 2 mmol) 溶于10 mL吡啶溶液中, 在冰浴条件下滴加丙胺溶液(0.33 mL, 4 mmol), 搅拌30 s, 立即加入冰醋酸(0.23 mL, 4 mmol) 淬灭反应。将反应混合物缓慢倒入200 mL冰水中, 快速搅拌析出白色固体, 抽滤, 用水洗涤滤饼, 干燥得1.279 0 g白色粉末状固体即化合物B。产率98%, mp 132~135 ℃。

1.3 3, 5, 20, 23-四乙酸水飞蓟宾磺酸酯(C) 的制备

将化合物B (0.325 0 g, 0.5 mmol) 溶于5 mL二氯甲烷溶液中, 在室温下搅拌, 随后加入磺酰氯(0.052 5 mL, 0.6 mmol) 与NaH (0.024 g, 0.5 mmol) 室温反应1 h。得淡黄色液体, 减压蒸发溶剂(DCM), 粗品在15 mL甲醇中重结晶, 过滤、干燥得0.265 6 g淡黄色片状固体即化合物C。产率: 71%, mp 125~128 ℃。

1.4 化合物(I₁) 的合成

将化合物C (0.748 1 g, 0.5 mmol) 溶于5 mL二氯甲烷溶液中, 加入正戊胺(0.058 0 mL, 0.5 mmol), 随后加入三乙胺(0.277 0 mL, 1.5 mmol) 催化, 室温下搅拌1.5 h, TLC检测反应终点。反应结束后, 过滤除去沉淀物(三乙胺盐酸盐), 减压蒸发溶剂(THF), 粗品在15 mL甲醇中重结晶, 过滤、干燥得0.455 8 g黄色粉末状固体I₁。产率: 58%, mp 110~127 ℃。

1.5 化合物(I₂) 的合成

按照I₁的合成方法, 加入间硝基苯胺(0.052 0 mL, 0.5 mmol)。得0.304 5 g淡黄色粉末状固体I₂。产率: 37%, mp 134~148 ℃。

1.6 化合物(I₃) 的合成

按照I₁的合成方法, 加入间氟苯胺(0.048 0 mL, 0.5 mmol)。得0.334 7 g黄色片状固体I₃。产率: 42%, mp 130~137 ℃。

1.7 化合物(I₄) 的合成

按照I₁的合成方法, 加入异戊胺(0.058 0 mL, 0.5 mmol)。得0.356 1 g黄色片状固体I₄。产率: 46%, mp 120~124 ℃。

1.8 化合物(I₅) 的合成

按照I₁的合成方法, 加入邻溴苯胺(0.054 0 mL, 0.5 mmol)。得0.435 9 g淡黄色粉末状固体I₅。产率: 51%, mp 130~137 ℃。

1.9 化合物(I₆) 的合成

按照I₁的合成方法, 加入苯胺(0.045 0 mL, 0.5 mmol)。得0.350 6 g白色粉末状固体I₆。产率: 45%, mp 104~112 ℃。

1.10 化合物(I₇) 的合成

按照I₁的合成方法, 加入对甲氧基苯胺(0.057 0 mL, 0.5 mmol)。得0.311 5 g黄色粉末状固体I₇。产率: 39%, mp 136~143 ℃。

1.11 化合物(I₈) 的合成

按照I₁的合成方法, 加入间氯苯胺(0.052 0 mL, 0.5 mmol)。得0.201 6 g黄色粉末状固体I₈。产率: 25%, mp 127~131 ℃。

1.12 化合物(I₉) 的合成

按照I₁的合成方法, 加入3, 4-二硝基苯胺(0.066 0 mL, 0.5 mmol)。得0.296 2 g淡黄色粉末状固体I₉。产率: 36%, mp 118~125 ℃。

1.13 化合物(I₁₀) 的合成

按照I₁的合成方法, 加入4-氨基二苯甲酮(0.091 0 mL, 0.5 mmol)。得0.378 5 g黄色粉末状固体I₁₀。产率: 43%, mp 124~129 ℃。

1.14 化合物(I₁₁) 的合成

按照I₁的合成方法, 加入2-碘苯胺(0.107 6 mL, 0.5 mmol)。得0.435 9 g淡黄色粉末状固体I₁₁。产率: 40%, mp 131~147 ℃。

1.15 化合物(I₁₂) 的合成

按照I₁的合成方法, 加入3-溴苯胺(0.086 0 mL, 0.5 mmol)。得1.725 1 g淡黄色粉末状固体I₁₂。产率: 39%, mp 140~148 ℃。

1.16 化合物(I₁₃) 的合成

按照I₁的合成方法, 加入4-氟苯胺(0.055 6 mL, 0.5 mmol)。得1.812 2 g淡黄色粉末状固体I₁₃。产率: 44%, mp 124~128 ℃。

1.17 化合物(I₁₄) 的合成

按照I₁的合成方法, 加入对甲苯胺(0.053 6 mL, 0.5 mmol)。得1.310 5 g淡黄色粉末状固体I₁₄。产率: 52%, mp 129~133℃。

1.18 化合物(I₁₅) 的合成

按照I₁的合成方法, 加入对氯苯胺(0.063 8 mL, 0.5 mmol)。得0.974 4 g淡黄色粉末状固体I₁₅。产率: 47%, mp 129~137 ℃。

2 初步体外活性测试

采用MTT比色法, 以palbociclib为阳性对照药物, 因其为以CDK4/6为靶点抗癌药物, 选用人肝癌细胞(HepG-2) 进行目标化合物的体外细胞毒活性测试。将水飞蓟宾、阳性对照药palbociclib及待测目标化合物以DMSO助溶后, 使用培养液配成100、20、4、0.8和0.16 μmol·L^-1的工作液。取对数生长期的人肝癌细胞(HepG-2), 用0.25%的胰酶消化, 离心, 制成每毫升2×10⁴个的细胞悬液, 备用。将加药并于培养箱中孵育48 h后的96孔板中培养基轻轻甩出, 然后加入配制好的MTT溶液(5 mg·mL^-1), 每孔20 μL, 放入培养箱中继续孵育3 h。取出孵育3 h的96孔板, 将其中的MTT溶液轻轻甩出, 每孔加100 μL的DMSO, 送进酶标仪, 在490 nm下测光密度(OD) 值, 并记录数据。

按公式(1) 计算药物对肿瘤细胞体外增殖的抑制率(inhibition rate, IR):

(1)$ \mathrm{I}\mathrm{R}\mathrm{\%}=\frac{{\overline{\mathrm{O}\mathrm{D}}}_{\mathrm{c}\mathrm{o}\mathrm{n}\mathrm{t}\mathrm{r}\mathrm{o}\mathrm{l}}-{\overline{\mathrm{O}\mathrm{D}}}_{\mathrm{s}\mathrm{a}\mathrm{m}\mathrm{p}\mathrm{l}\mathrm{e}}}{{\overline{\mathrm{O}\mathrm{D}}}_{\mathrm{c}\mathrm{o}\mathrm{n}\mathrm{t}\mathrm{r}\mathrm{o}\mathrm{l}}-{\overline{\mathrm{O}\mathrm{D}}}_{\mathrm{b}\mathrm{l}\mathrm{a}\mathrm{n}\mathrm{k}}}\times 100\mathrm{\%} $

其中, $ \overline{\mathrm{O}\mathrm{D}} $_control: 未加药孔的OD值; $ \overline{\mathrm{O}\mathrm{D}} $_sample: 加药孔的OD值; $ \overline{\mathrm{O}\mathrm{D}} $_blank: 只加DMSO孔的OD值。

用IC₅₀计算软件来计算半数抑制浓度(IC₅₀)。

3 CDK4/6受体抑制实验

CDK4/CycD3和CDK6/CycD3来自Carna公司。Peptide FAM-P8和Peptide FAM-P18均来自GL Biochem公司。ATP和EDTA来自Sigma公司。取2 μL (10 μmol·L^-1) 化合物I₁ (20% DMSO), 18 μL激酶缓冲液(50 mmol·L^-1 HEPES, pH 7.5, 5 mmol·L^-1 MgCl₂, 1 mmol·L^-1 DTT, 0.001 5% Brij-35), 10 μL FAM标记肽和ATP的混合物进行激酶反应。反应混合物在30 ℃下孵育40 min, 然后加入25 μL停止缓冲液停止反应, palbociclib作为阳性对照药物。最后从Caliper中读取转换值, 采用Hill方程与OriginPro 8软件对所测化合物对靶蛋白的IC₅₀值进行计算。

作者贡献: 孟艳秋对本文提供指导性支持, 设计论文总纲, 终审论文; 高诗特负责文章撰写, 调研整理文献, 设计研究方案, 实施研究过程, 采集整理数据; 蒯振彧工作支持, 计算机辅助药物设计, 修订论文, 论文校正; 张志鹏参与研究, 统计分析, 提供技术支持。

利益冲突: 本文不存在任何利益相关问题。

基金

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辽宁省重点研发计划项目(2019JH2/10300034)
辽宁省教育厅重点项目(LJKZ0427)
沈阳市重大科技成果转化项目(20-203-5-45)
沈阳化工大学重点攻关项目(LDB2019001)
安徽省高校自然科学研究项目(KJ2021A1340)

参考文献

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排序方式：

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Jangra A, Kasbe P, Pandey SN, et al. Hesperidin and silibinin ameliorate aluminum-induced neurotoxicity: modulation of antioxidants and inflammatory cytokines level in mice hippocampus[J]. Biol Trace Elem Res, 2015, 168: 462-471.

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Vladimír K, Petr M, Kateřina P, et al. Biotransformation of silybin and its congeners[J]. Curr Drug Metab, 2013, 14: 1009-1021.

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Raub TJ, Wishart GN, Kulanthaivel P, et al. Brain exposure of two selective dual CDK4 and CDK6 inhibitors and the antitumor activity of CDK4 and CDK6 inhibition in combination with temozolomide in an intracranial glioblastoma xenograft[J]. Drug Metab Dispos, 2015, 43: 1360-1371.

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2023年第58卷第3期

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doi: 10.16438/j.0513-4870.2022-0972

接收时间：2022-08-08
首发时间：2025-11-21
出版时间：2023-03-12

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收稿日期：2022-08-08
修回日期：2022-09-15

基金

辽宁省重点研发计划项目(2019JH2/10300034)

辽宁省教育厅重点项目(LJKZ0427)

沈阳市重大科技成果转化项目(20-203-5-45)

沈阳化工大学重点攻关项目(LDB2019001)

安徽省高校自然科学研究项目(KJ2021A1340)

作者信息

1.沈阳化工大学, 辽宁沈阳 110142

2.沈阳科技学院, 辽宁沈阳 110166

3.马鞍山职业技术学院, 安徽马鞍山 243031

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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]⁺	¹³C NMR (CDCl₃, 150 MHz)	¹H NMR (600 MHz, DMSO-d₆)
B	673.17	185.7, 170.2, 170.2, 169.0, 169.0, 162.2, 160.5, 152.2, 151.4, 147.0, 142.9, 139.2, 131.5, 127.2, 122.7, 119.7, 118.2, 109.8, 109.5, 109.1, 108.5, 98.8, 96.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.3	δ 11.12 (s, 1H), 7.35-6.89 (m, 6H), 6.31 (d, J = 2.3 Hz, 1H), 6.28 (d, J = 2.2 Hz, 1H), 5.75 (t, J = 12.1 Hz, 1H), 5.52 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 12.2 Hz, 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 7.9 Hz, 1H), 3.99 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H)
I₁	799.18	185.5, 170.2, 170.2, 169.1, 169.0, 162.2, 157.1, 152.2, 151.4, 147.0, 142.9, 139.2, 131.5, 127.2, 122.6, 119.7, 118.3, 110.1, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 44.7, 28.6, 28.4, 22.4, 20.7, 20.7, 20.3, 20.3, 14.1	δ 9.11 (m, 1H), 7.32-6.84 (m, 6H), 6.41 (d, J = 2.3 Hz, 1H), 6.09 (d, J = 2.2 Hz, 1H), 5.68 (t, J = 12.1 Hz, 1H), 5.50 (d, J = 12.2 Hz, 1H), 5.12 (t, J = 11.8 Hz, 1H), 4.66-4.59 (m, 1H), 4.20 (s, 1H), 4.14 (d, J = 7.8 Hz, 1H), 3.88 (dd, J = 12.7, 5.1 Hz, 1H), 3.79 (s, 3H), 2.87 (m, 2H), 2.28 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H), 1.52 (m, 2H), 1.29 (m, 2H), 1.28 (m, 2H), 0.87 (t, J = 7.5 Hz, 3H)
I₂	850.19	185.7, 171.1, 169.8, 169.1, 169.0, 162.2, 157.1, 152.2, 151.4, 148.7, 147.0, 142.9, 139.2, 138.6, 131.5, 130.4, 127.2, 125.5, 123.3, 119.7, 118.2, 113.9, 113.1, 109.8, 109.5, 108.8, 108.5, 100.8, 98.8, 84.3, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.2	δ 10.58 (s, 1H), 7.86-7.19 (m, 5H), 7.05-6.89 (m, 6H), 6.36 (d, J = 2.3 Hz, 1H), 6.23 (d, J = 2.2 Hz, 1H), 5.85 (t, J = 12.1 Hz, 1H), 5.52 (d, J = 12.1 Hz, 1H), 5.14 (t, J = 11.6 Hz, 1H), 4.65-4.59 (m, 1H), 4.12 (d, J = 8.6 Hz, 1H), 3.95 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.24 (s, 3H), 2.18 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H)
I₃	823.15	185.7, 170.2, 170.2, 169.0, 169.0, 163.7, 162.6, 157.1, 152.2, 151.4, 147.0, 142.9, 139.3, 139.2, 131.5, 131.1, 127.2, 122.7, 119.7, 118.2, 115.0, 110.5, 109.8, 109.5, 109.1, 108.5, 104.8, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.3	δ 10.67 (s, 1H), 7.86-7.19 (m, 4H), 7.37-6.95 (m, 6H), 6.56 (t, J = 7.5 Hz, 1H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.76 (t, J = 12.3 Hz, 1H), 5.52 (d, J = 12.2 Hz, 1H), 5.11 (t, J = 11.7 Hz, 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 9.6 Hz, 1H), 3.98 (dd, J = 12.6, 5.1 Hz, 1H), 3.79 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H)
I₄	799.82	186.1, 170.2, 170.2, 169.0, 169.0, 162.6, 157.1, 152.2, 151.4, 147.0, 142.9, 139.2, 131.5, 127.2, 122.7, 119.7, 118.2, 109.8, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 41.9, 38.3, 24.9, 20.7, 20.7, 20.3, 20.3	δ 7.35-6.89 (m, 6H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.76 (t, J = 12.1 Hz, 1H), 5.52 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 11.6 Hz, 1H), 4.94-4.69 (m, 1H), 4.20 (s, 1H), 4.14 (d, J = 9.8 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.87 (t, J = 6.8 Hz, 2H), 2.27 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H), 1.59 (m, 2H), 1.53 (m, 2H), 0.91 (d, J = 2.3 Hz, 6H)
I₅	883.15	185.7, 170.2, 170.2, 169.0, 169.0, 162.6, 157.1, 152.2, 151.4, 147.0, 142.9, 139.2, 134.9, 132.4, 131.5, 128.5, 127.2, 126.2, 122.8, 122.7, 119.7, 118.2, 115.7, 109.6, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.3	δ 10.73 (s, 1H), 7.55-7.35 (m, 8H), 6.89-6.88 (m, 2H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.76 (t, J = 12.1 Hz, 1H), 5.52 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 11.6 Hz, 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 10.6 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H)
I₆	805.16	184.9, 170.4, 170.2, 169.0, 169.0, 162.6, 157.1, 152.2, 151.4, 147.0, 142.9, 139.2, 137.7, 131.5, 129.5, 129.5, 127.2, 123.2, 122.4, 119.7, 119.4, 119.4, 118.2, 109.8, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.3	δ 10.53 (s, 1H), 7.35-7.18 (m, 6H), 6.89-6.80 (m, 5H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.76 (t, J = 12.3 Hz, 1H), 5.52 (d, J = 12.3 Hz, 1H), 5.11 (t, J = 11.8 Hz, 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 9.9 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H)
I₇	825.21	185.4, 170.2, 170.1, 169.0, 169.0, 162.6, 157.1, 153.3, 152.2, 151.4, 147.0, 142.9, 139.2, 131.5, 130.0, 127.2, 124.5, 124.5, 122.7, 119.7, 118.2, 115.1, 115.1, 109.8, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.3	δ 10.62 (s, 1H), 7.35-6.89 (m, 6H), 6.85-6.78 (m, 4H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.4 Hz, 1H), 5.76 (t, J = 12.1 Hz, 1H), 5.52 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 11.3 Hz, 1H), 4.68-4.57 (m, 1H), 4.14 (d, J = 8.9 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 2.37 (s, 3H), 2.26 (s, 3H), 2.04 (s, 3H), 1.87 (s, 3H)
I₈	840.22	185.7, 170.3, 170.3, 169.0, 169.0, 162.6, 157.1, 152.2, 151.4, 147.0, 142.9, 139.2, 139.1, 135.1, 131.5, 130.9, 127.2, 122.7, 122.3, 119.7, 119.2, 118.2, 117.5, 109.8, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.8, 20.7, 20.3, 20.3	δ 10.59 (s, 1H), 7.35-6.89 (m, 6H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.66 (t, J = 12.0 Hz, 1H), 5.32 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 11.6 Hz, 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 9.6 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H)
I₉	850.39	185.6, 170.2, 170.2, 169.0, 169.0, 162.6, 157.1, 152.2, 151.4, 147.0, 142.9, 140.2, 139.2, 138.8, 138.1, 131.5, 131.2, 127.2, 122.7, 120.8, 119.7, 118.2, 118.1, 109.8, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 79.2, 73.5, 63.3, 55.8, 20.7, 20.5, 20.3, 20.3	δ 10.89 (s, 1H), 8.43 (d, J = 7.26 Hz, 1H), 8.31 (d, J = 7.30 Hz, 1H), 7.35-6.89 (m, 6H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.76 (t, J = 12.1 Hz, 1H), 5.52 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 11.6 Hz, 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 10.6 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H)
I₁₀	909.21	194.3, 185.7, 170.2, 170.2, 162.6, 157.1, 152.2, 151.4, 147.0, 144.7, 142.9, 139.2, 138.4, 137.4, 133.5, 132.4, 131.5, 131.8, 130.3, 128.4, 128.4, 127.2, 123.1, 122.7, 120.3, 119.7, 118.2, 114.6, 109.8, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.3	δ 10.82 (s, 1H), 7.81-7.61 (m, 5H), 7.60-7.08 (m, 4H), 7.05-6.59 (m, 6H), 6.37 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.76 (t, J = 12.1 Hz, 1H), 5.52 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 11.6 Hz, 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 9.7 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H)
I₁₁	851.33	185.7, 170.2, 169.2, 169.0, 162.6, 157.8, 152.5, 150.4, 146.5, 142.8, 137.3, 135.2, 132.4, 129.2, 128.4, 127.8, 126.2, 123.5, 122.7, 119.7, 118.2, 115.7, 109.6, 109.5, 109.2, 108.5, 102.8, 98.8, 84.1, 79.7, 77.9, 76.1, 63.4, 56.7, 20.7, 20.7, 20.3, 20.3	δ 10.58 (s, 1H), 8.04-7.35 (m, 8H), 6.89-6.57 (m, 2H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.76 (t, J = 11.1 Hz, 1H), 5.38 (d, J = 12.1 Hz, 1H), 5.17 (t, J = 10.9 Hz 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 9.4 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H), 2.19 (s, 3H), 2.04 (s, 3H)
I₁₂	884.66	185.8, 169.0, 169.0, 168.7, 168.3, 162.6, 157.1, 152.2, 151.4, 147.0, 142.9, 139.2, 134.9, 132.4, 130.6, 128.5, 127.2, 126.2, 123.8, 122.1, 118.7, 118.2, 115.7, 109.6, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.3	δ 10.58 (s, 1H), 7.18 (s, 1H), 7.07-6.87 (m, 9H), 6.45 (d, J = 2.3 Hz, 1H), 6.37 (d, J = 2.2 Hz, 1H), 6.10 (t, J = 12.1 Hz, 1H), 5.38 (d, J = 12.1 Hz, 1H), 5.17 (t, J = 11.5 Hz, 1H), 4.57 (m, 1H), 4.14 (d, J = 9.7 Hz, 1H), 3.83 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H), 2.19 (s, 3H), 2.04 (s, 3H)
I₁₃	823.75	185.7, 170.2, 170.2, 168.4, 157.3, 157.1, 152.2, 151.4, 147.0, 142.9, 139.2, 134.9, 132.4, 131.5, 128.5, 126.3, 126.2, 122.8, 122.7, 119.7, 118.2, 115.7, 109.6, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 58.8, 20.7, 20.7, 20.3, 20.3	δ 10.61 (s, 1H), 7.55-7.35 (m, 8H), 6.96-6.88 (m, 2H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.76 (t, J = 12.1 Hz, 1H), 5.52 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 11.9 Hz 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 9.8 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H), 2.19 (s, 3H), 2.04 (s, 3H)
I₁₄	819.79	185.7, 170.2, 170.2, 168.4, 157.3, 157.1, 152.2, 151.4, 147.0, 142.9, 139.2, 134.9, 132.4, 131.5, 128.5, 127.2, 126.2, 122.8, 122.7, 119.7, 118.2, 115.7, 109.6, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.3	δ 10.58 (s, 1H), 7.37-7.05 (m, 8H), 6.97-6.87 (m, 2H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.76 (t, J = 12.1 Hz, 1H), 5.52 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 11.6 Hz 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 9.6 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.87 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H)
I₁₅	840.20	185.7, 169.0, 169.0, 162.6, 157.1, 152.2, 151.4, 147.0, 142.9, 139.2, 136.9, 132.4, 131.5, 129.5, 127.6, 126.2, 122.8, 122.7, 119.7, 118.2, 115.7, 109.6, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.3	δ 10.59 (s, 1H), 7.95-7.35 (m, 8H), 6.94-6.88 (m, 2H), 6.41 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.83 (t, J = 12.1 Hz, 1H), 5.58 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 11.9 Hz, 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 7.6 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H), 2.09 (s, 3H), 2.04 (s, 3H)

Compd.

ESI-MS (m/z)
[M+H]⁺

¹³C NMR (CDCl₃, 150 MHz)

¹H NMR (600 MHz, DMSO-d₆)

673.17

185.7, 170.2, 170.2, 169.0, 169.0, 162.2, 160.5, 152.2, 151.4, 147.0, 142.9, 139.2, 131.5, 127.2, 122.7, 119.7, 118.2, 109.8, 109.5, 109.1, 108.5, 98.8, 96.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.3

δ 11.12 (s, 1H), 7.35-6.89 (m, 6H), 6.31 (d, J = 2.3 Hz, 1H), 6.28 (d, J = 2.2 Hz, 1H), 5.75 (t, J = 12.1 Hz, 1H), 5.52 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 12.2 Hz, 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 7.9 Hz, 1H), 3.99 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H)

I₁

799.18

185.5, 170.2, 170.2, 169.1, 169.0, 162.2, 157.1, 152.2, 151.4, 147.0, 142.9, 139.2, 131.5, 127.2, 122.6, 119.7, 118.3, 110.1, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 44.7, 28.6, 28.4, 22.4, 20.7, 20.7, 20.3, 20.3, 14.1

δ 9.11 (m, 1H), 7.32-6.84 (m, 6H), 6.41 (d, J = 2.3 Hz, 1H), 6.09 (d, J = 2.2 Hz, 1H), 5.68 (t, J = 12.1 Hz, 1H), 5.50 (d, J = 12.2 Hz, 1H), 5.12 (t, J = 11.8 Hz, 1H), 4.66-4.59 (m, 1H), 4.20 (s, 1H), 4.14 (d, J = 7.8 Hz, 1H), 3.88 (dd, J = 12.7, 5.1 Hz, 1H), 3.79 (s, 3H), 2.87 (m, 2H), 2.28 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H), 1.52 (m, 2H), 1.29 (m, 2H), 1.28 (m, 2H), 0.87 (t, J = 7.5 Hz, 3H)

I₂

850.19

185.7, 171.1, 169.8, 169.1, 169.0, 162.2, 157.1, 152.2, 151.4, 148.7, 147.0, 142.9, 139.2, 138.6, 131.5, 130.4, 127.2, 125.5, 123.3, 119.7, 118.2, 113.9, 113.1, 109.8, 109.5, 108.8, 108.5, 100.8, 98.8, 84.3, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.2

δ 10.58 (s, 1H), 7.86-7.19 (m, 5H), 7.05-6.89 (m, 6H), 6.36 (d, J = 2.3 Hz, 1H), 6.23 (d, J = 2.2 Hz, 1H), 5.85 (t, J = 12.1 Hz, 1H), 5.52 (d, J = 12.1 Hz, 1H), 5.14 (t, J = 11.6 Hz, 1H), 4.65-4.59 (m, 1H), 4.12 (d, J = 8.6 Hz, 1H), 3.95 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.24 (s, 3H), 2.18 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H)

I₃

823.15

185.7, 170.2, 170.2, 169.0, 169.0, 163.7, 162.6, 157.1, 152.2, 151.4, 147.0, 142.9, 139.3, 139.2, 131.5, 131.1, 127.2, 122.7, 119.7, 118.2, 115.0, 110.5, 109.8, 109.5, 109.1, 108.5, 104.8, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.3

δ 10.67 (s, 1H), 7.86-7.19 (m, 4H), 7.37-6.95 (m, 6H), 6.56 (t, J = 7.5 Hz, 1H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.76 (t, J = 12.3 Hz, 1H), 5.52 (d, J = 12.2 Hz, 1H), 5.11 (t, J = 11.7 Hz, 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 9.6 Hz, 1H), 3.98 (dd, J = 12.6, 5.1 Hz, 1H), 3.79 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H)

I₄

799.82

186.1, 170.2, 170.2, 169.0, 169.0, 162.6, 157.1, 152.2, 151.4, 147.0, 142.9, 139.2, 131.5, 127.2, 122.7, 119.7, 118.2, 109.8, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 41.9, 38.3, 24.9, 20.7, 20.7, 20.3, 20.3

δ 7.35-6.89 (m, 6H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.76 (t, J = 12.1 Hz, 1H), 5.52 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 11.6 Hz, 1H), 4.94-4.69 (m, 1H), 4.20 (s, 1H), 4.14 (d, J = 9.8 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.87 (t, J = 6.8 Hz, 2H), 2.27 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H), 1.59 (m, 2H), 1.53 (m, 2H), 0.91 (d, J = 2.3 Hz, 6H)

I₅

883.15

185.7, 170.2, 170.2, 169.0, 169.0, 162.6, 157.1, 152.2, 151.4, 147.0, 142.9, 139.2, 134.9, 132.4, 131.5, 128.5, 127.2, 126.2, 122.8, 122.7, 119.7, 118.2, 115.7, 109.6, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.3

δ 10.73 (s, 1H), 7.55-7.35 (m, 8H), 6.89-6.88 (m, 2H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.76 (t, J = 12.1 Hz, 1H), 5.52 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 11.6 Hz, 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 10.6 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H)

I₆

805.16

184.9, 170.4, 170.2, 169.0, 169.0, 162.6, 157.1, 152.2, 151.4, 147.0, 142.9, 139.2, 137.7, 131.5, 129.5, 129.5, 127.2, 123.2, 122.4, 119.7, 119.4, 119.4, 118.2, 109.8, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.3

δ 10.53 (s, 1H), 7.35-7.18 (m, 6H), 6.89-6.80 (m, 5H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.76 (t, J = 12.3 Hz, 1H), 5.52 (d, J = 12.3 Hz, 1H), 5.11 (t, J = 11.8 Hz, 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 9.9 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H)

I₇

825.21

185.4, 170.2, 170.1, 169.0, 169.0, 162.6, 157.1, 153.3, 152.2, 151.4, 147.0, 142.9, 139.2, 131.5, 130.0, 127.2, 124.5, 124.5, 122.7, 119.7, 118.2, 115.1, 115.1, 109.8, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.3

δ 10.62 (s, 1H), 7.35-6.89 (m, 6H), 6.85-6.78 (m, 4H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.4 Hz, 1H), 5.76 (t, J = 12.1 Hz, 1H), 5.52 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 11.3 Hz, 1H), 4.68-4.57 (m, 1H), 4.14 (d, J = 8.9 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 2.37 (s, 3H), 2.26 (s, 3H), 2.04 (s, 3H), 1.87 (s, 3H)

I₈

840.22

185.7, 170.3, 170.3, 169.0, 169.0, 162.6, 157.1, 152.2, 151.4, 147.0, 142.9, 139.2, 139.1, 135.1, 131.5, 130.9, 127.2, 122.7, 122.3, 119.7, 119.2, 118.2, 117.5, 109.8, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.8, 20.7, 20.3, 20.3

δ 10.59 (s, 1H), 7.35-6.89 (m, 6H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.66 (t, J = 12.0 Hz, 1H), 5.32 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 11.6 Hz, 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 9.6 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H)

I₉

850.39

185.6, 170.2, 170.2, 169.0, 169.0, 162.6, 157.1, 152.2, 151.4, 147.0, 142.9, 140.2, 139.2, 138.8, 138.1, 131.5, 131.2, 127.2, 122.7, 120.8, 119.7, 118.2, 118.1, 109.8, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 79.2, 73.5, 63.3, 55.8, 20.7, 20.5, 20.3, 20.3

δ 10.89 (s, 1H), 8.43 (d, J = 7.26 Hz, 1H), 8.31 (d, J = 7.30 Hz, 1H), 7.35-6.89 (m, 6H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.76 (t, J = 12.1 Hz, 1H), 5.52 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 11.6 Hz, 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 10.6 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H)

I₁₀

909.21

194.3, 185.7, 170.2, 170.2, 162.6, 157.1, 152.2, 151.4, 147.0, 144.7, 142.9, 139.2, 138.4, 137.4, 133.5, 132.4, 131.5, 131.8, 130.3, 128.4, 128.4, 127.2, 123.1, 122.7, 120.3, 119.7, 118.2, 114.6, 109.8, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.3

δ 10.82 (s, 1H), 7.81-7.61 (m, 5H), 7.60-7.08 (m, 4H), 7.05-6.59 (m, 6H), 6.37 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.76 (t, J = 12.1 Hz, 1H), 5.52 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 11.6 Hz, 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 9.7 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H)

I₁₁

851.33

185.7, 170.2, 169.2, 169.0, 162.6, 157.8, 152.5, 150.4, 146.5, 142.8, 137.3, 135.2, 132.4, 129.2, 128.4, 127.8, 126.2, 123.5, 122.7, 119.7, 118.2, 115.7, 109.6, 109.5, 109.2, 108.5, 102.8, 98.8, 84.1, 79.7, 77.9, 76.1, 63.4, 56.7, 20.7, 20.7, 20.3, 20.3

δ 10.58 (s, 1H), 8.04-7.35 (m, 8H), 6.89-6.57 (m, 2H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.76 (t, J = 11.1 Hz, 1H), 5.38 (d, J = 12.1 Hz, 1H), 5.17 (t, J = 10.9 Hz 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 9.4 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H), 2.19 (s, 3H), 2.04 (s, 3H)

I₁₂

884.66

185.8, 169.0, 169.0, 168.7, 168.3, 162.6, 157.1, 152.2, 151.4, 147.0, 142.9, 139.2, 134.9, 132.4, 130.6, 128.5, 127.2, 126.2, 123.8, 122.1, 118.7, 118.2, 115.7, 109.6, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.3

δ 10.58 (s, 1H), 7.18 (s, 1H), 7.07-6.87 (m, 9H), 6.45 (d, J = 2.3 Hz, 1H), 6.37 (d, J = 2.2 Hz, 1H), 6.10 (t, J = 12.1 Hz, 1H), 5.38 (d, J = 12.1 Hz, 1H), 5.17 (t, J = 11.5 Hz, 1H), 4.57 (m, 1H), 4.14 (d, J = 9.7 Hz, 1H), 3.83 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H), 2.19 (s, 3H), 2.04 (s, 3H)

I₁₃

823.75

185.7, 170.2, 170.2, 168.4, 157.3, 157.1, 152.2, 151.4, 147.0, 142.9, 139.2, 134.9, 132.4, 131.5, 128.5, 126.3, 126.2, 122.8, 122.7, 119.7, 118.2, 115.7, 109.6, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 58.8, 20.7, 20.7, 20.3, 20.3

δ 10.61 (s, 1H), 7.55-7.35 (m, 8H), 6.96-6.88 (m, 2H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.76 (t, J = 12.1 Hz, 1H), 5.52 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 11.9 Hz 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 9.8 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H), 2.19 (s, 3H), 2.04 (s, 3H)

I₁₄

819.79

185.7, 170.2, 170.2, 168.4, 157.3, 157.1, 152.2, 151.4, 147.0, 142.9, 139.2, 134.9, 132.4, 131.5, 128.5, 127.2, 126.2, 122.8, 122.7, 119.7, 118.2, 115.7, 109.6, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.3

δ 10.58 (s, 1H), 7.37-7.05 (m, 8H), 6.97-6.87 (m, 2H), 6.31 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.76 (t, J = 12.1 Hz, 1H), 5.52 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 11.6 Hz 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 9.6 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.87 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H)

I₁₅

840.20

185.7, 169.0, 169.0, 162.6, 157.1, 152.2, 151.4, 147.0, 142.9, 139.2, 136.9, 132.4, 131.5, 129.5, 127.6, 126.2, 122.8, 122.7, 119.7, 118.2, 115.7, 109.6, 109.5, 109.1, 108.5, 100.8, 98.8, 84.1, 79.7, 78.6, 73.5, 63.3, 55.8, 20.7, 20.7, 20.3, 20.3

δ 10.59 (s, 1H), 7.95-7.35 (m, 8H), 6.94-6.88 (m, 2H), 6.41 (d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.83 (t, J = 12.1 Hz, 1H), 5.58 (d, J = 12.1 Hz, 1H), 5.11 (t, J = 11.9 Hz, 1H), 4.66-4.59 (m, 1H), 4.14 (d, J = 7.6 Hz, 1H), 3.98 (dd, J = 12.4, 5.1 Hz, 1H), 3.79 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H), 2.09 (s, 3H), 2.04 (s, 3H)

Compd.	Inhibition rate/%	IC₅₀/μmol·L^-1
Sliybin	26.36	22.01	> 50.00
C	77.99	26.63	48.02
I₁	93.06	59.67	22.46
I₂	45.65	35.98	> 50.00
I₃	84.80	28.53	> 50.00
I₄	87.02	40.61	32.80
I₅	41.58	28.74	> 50.00
I₆	73.35	36.04	32.72
I₇	64.64	37.85	42.63
I₈	29.81	26.55	> 50.00
I₉	59.36	29.41	> 50.00
I₁₀	32.83	22.50	> 50.00
I₁₁	40.70	29.12	37.81
I₁₂	48.24	33.48	47.92
I₁₃	57.12	32.70	48.83
I₁₄	53.76	37.50	> 50.00
I₁₅	51.43	35.89	46.72
Palbociclib	54.94	29.36	45.32

Compd.

Inhibition rate/%

IC₅₀/μmol·L^-1

100 μmol·L^-1

10 μmol·L^-1

Sliybin

26.36

22.01

> 50.00

77.99

26.63

48.02

I₁

93.06

59.67

22.46

I₂

45.65

35.98

> 50.00

I₃

84.80

28.53

> 50.00

I₄

87.02

40.61

32.80

I₅

41.58

28.74

> 50.00

I₆

73.35

36.04

32.72

I₇

64.64

37.85

42.63

I₈

29.81

26.55

> 50.00

I₉

59.36

29.41

> 50.00

I₁₀

32.83

22.50

> 50.00

I₁₁

40.70

29.12

37.81

I₁₂

48.24

33.48

47.92

I₁₃

57.12

32.70

48.83

I₁₄

53.76

37.50

> 50.00

I₁₅

51.43

35.89

46.72

Palbociclib

54.94

29.36

45.32