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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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参考文献引证文献

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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

通讯作者:

*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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TxT

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