CN103304436B - 天然产物s6-2衍生物及其制备方法和制备抗肿瘤药物的用途 - Google Patents
天然产物s6-2衍生物及其制备方法和制备抗肿瘤药物的用途 Download PDFInfo
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Abstract
本发明属于药物与化工领域，涉及天然产物S6-2的九种新的衍生物，以及其制备方法和抗肿瘤活性。衍生物结构的特殊性在于S6-2或其降解后支链羧基与相应底物(NH2R)所形成的酰胺化结构。合成路线以L-Gly-OMe.HCl,L-Ala-OMe.HCl,L-Val-OMe.HCl,L-Leu-OMe.HCl,L-Met-OMe.HCl,2-Aminoethanol,1-amino-3-propanol为原料，经酰胺化，缩合而成，这些衍生物对所测定的5株肿瘤细胞，具有抗肿瘤作用，有着良好的应用前景。
Description
本申请是2010.12.31申请的发明名称为“天然产物S6-2衍生物及其制备方法和作为抗肿瘤药物的用途”的中国专利申请（申请号201010618518.3）的分案申请。
技术领域
本发明属于药物与化工领域，涉及天然产物S6-2的九种新的衍生物、及相关制备方法和抗肿瘤应用。
背景技术
癌症是威胁人类健康和生命安全的主要疾病，据统计，全世界每年新增癌症患者达400 万人左右。抗肿瘤药物的研究与开发一直是化学家和药物学家关注的热点。寻找高效、高选择性、毒副作用小的抗肿瘤药物是药物研究开发的重要方向之一。
红树林是热带和亚热带沿海地区特有的植物群落，由于其独特的生存环境，能够产生出许多结构新颖独特的代谢产物。目前科学家已从其里面的各种内生真菌代谢产物中分离出很多结构新颖、有显著活性的化合物，许多已进入临床试验阶段。多年来，本课题组主要对中国南海红树林内生真菌代谢产物进行研究，最近我们南海红树林内生真菌BL321 （Genbank accession No, HM569607）中分离得到一个艾里莫芬烷类的倍半萜化合物S6-2（07H239-A），曾有报道其对24株肿瘤细胞的平均IC50为3.2 μg/mL [L. A. McDonald, L. R. Barbieri, V. S. Bernan, J. Janso, P. Lassota, G. T. Garter, J. Nat. Prod. 2004, 67, 1565.]。我们对其进行衍生化，得到9个新的衍生物，所有9个衍生物有强的抗肿瘤活性，在所测试的5株肿瘤细胞中，其中多个衍生物活性比天然产物S6-2更强。
发明内容
本发明的目的在于针对现有技术的不足，提供毒性小、抗肿瘤效果好的天然产物S6-2衍生物。
本发明的另一个目的在于提供该天然产物S6-2衍生物的制备方法。
本发明还有一个目的在于提供该天然产物S6-2衍生物的应用。
本发明通过以下技术方案实现上述目的：
本发明提供了一种天然产物S6-2的衍生物，其特征在于其结构式（I）为：
式中R为L-Gly-OMe、L-Ala-OMe、L-Val-OMe、L-Leu-OMe或L-Met-OMe。
本发明提供了另一种天然产物S6-2的衍生物，其特征在于其结构式（II）为：
式中R为L-Gly-OMe、2-Aminoethanol、1-amino-3-propanol或H。
一种天然产物S6-2衍生物的制备方法，其特征在于包括以下步骤：在DMF中，在1.5当量的偶联试剂DEPC和2.4 当量的催化剂TEA作用下，1当量的天然产物S6-2与1.2 当量的底物NH2R反应，得到如结构式（I）的产物，R为L-Gly-OMe、L-Ala-OMe、L-Val-OMe、L-Leu-OMe或L-Met-OMe。
一种天然产物S6-2衍生物的制备方法，其特征在于：
（1）当R为L-Gly-OMe时，制备方法包括以下步骤：在DMF中，在3.0当量的偶联试剂DEPC和2.4 N当量的催化剂TEA作用下，1当量的天然产物S6-2与2.4当量的底物NH2R反应，得到如结构式（II）的相应产物；
（2）当R为2-Aminoethanol或1-amino-3-propanol时，制备方法包括以下步骤：在THF中，在1.5当量的偶联试剂DEPC和2.4 N当量的催化剂TEA作用下，1当量的天然产物S6-2与1.2 当量的底物NH2R反应，得到如结构式（II）的相应产物；
（3）R为H时，为制备如权利要求1或2所述化合物所得副产物。
上述的制备方法，其特征在于室温下反应2-4小时，用饱和NH4Cl溶液终止反应，用乙酸乙酯等体积液萃取产物2-5次，浓缩，经柱层析和HPLC分离，得到如结构式（I）和结构式（II）的天然产物S6-2的衍生物。
本发明同时公开和保护了该天然产物S6-2衍生物在制备抗肿瘤药物上的用途；以及含有该天然产物S6-2衍生物的抗肿瘤药物。
本发明所述的衍生物其结构特性为天然产物S6-2或其支链降解后与相应底物NH2R所形成的酰胺化结构。
与现有技术相比，本发明具有以下有益效果：
（1）实验证明，本发明所公开的新型天然产物S6-2衍生物有强的抗肿瘤活性，表现出显著的抗肿瘤作用，可用于制备具有选择性抗肿瘤药物；
（2）进一步实验证明，本发明涉及的新型天然产物S6-2衍生物对多种肿瘤细胞株具有显著的抑制作用，而对正常细胞毒性小，在制备抗肿瘤药物上有着广阔的应用空间。
具体实施方式
以下通过具体的实施例进一步说明本发明的技术方案。
实施例1
结构式（I）衍生物的制备
（1）当R基团为L-Gly-OMe时：
将1个当量的 S6-2加入含有1.2 当量的底物NH2R，1.5 当量偶联试剂DEPC和2.4 当量的催化剂TEA的DMF溶液中，室温下反应4h，用饱和NH4Cl溶液终止反应，用乙酸乙酯等体积液萃取产物3次，浓缩，经柱层析和HPLC分离，得到化合物1。
化合物1
化合物 1为白色固体。EI-MS (m/z): 527 (M+); HR-EI-MS calcd for C30H41O7N1 527.2878, found 527.2879; 1H NMR (400 MHz, CDCl3) δ 9.51 (s, 1H), 7.22 (dd, J =15.2, 10.8 Hz, 1H), 6.33 (s, 1H), 6.20 (s, 1H), 6.12 (dd, J = 15.2, 10.8 Hz, 1H), 6.05 (s, 1H), 5.98 (dd, J = 15.2, 8.4 Hz, 1H), 5.75 (d, J = 15.2 Hz, 1H), 5.49 (t, J = 2.6 Hz, 1H), 4.01 (qd, J = 18.3, 5.4 Hz, 2H), 3.73 (s, 3H), 3.66 (dd, J = 14.4, 4.5 Hz, 1H), 2.42 (m, 1H), 2.38 (m, 1H), 2.33 (m, 1H), 2.28 (m, 1H), 2.14 (m, 1H), 2.06 (m, 1H), 1.74 (m, 1H), 1.69 (m, 1H), 1.53 (s, 3H), 1.34 (m, 1H), 1.30 (m, 1H), 1.28 (m, 1H), 1.12 (m, 1H), 1.07 (m, 1H), 1.00 (d, J = 6.7 Hz, 3H), 0.86 (m, 3H), 0.82 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 197.0 (C), 193.3 (CH), 172.1 (C), 170.5 (C), 165.9 (C), 160.0 (C), 151.7 (CH), 148.1 (C), 146.5 (CH), 136.7 (CH2), 129.4 (CH), 126.7 (CH), 118.9 (CH); 72.7 (CH), 55.6 (CH3), 52.6 (CH), 44.1 (CH2), 43.5 (CH2), 41.4 (CH), 38.9 (C), 35.3 (CH), 32..2 (CH), 30.5 (CH2), 30.1 (CH2), 29.9 (CH2), 21.1 (CH3), 20.9 (CH2), 19.8 (CH3), 19.2 (CH3), 11.4 (CH3).
（2）当R基团为L-Ala-OMe时：
将1当量的S6-2加入含有1.2 当量的底物NH2R，1.5 当量偶联试剂DEPC和2.4 当量的催化剂TEA的DMF溶液中，室温下反应4h，用饱和NH4Cl溶液终止反应，用乙酸乙酯等体积液萃取产物3次，浓缩，经柱层析和HPLC分离，得到化合物2。
化合物2
化合物 2为白色固体。EI-MS (m/z): 541 (M+); HR-EI-MS calcd for C31H43O7N 541.3033, found 541.3034; 1H NMR (400 MHz, CDCl3) δ 9.50 (s, 1H), 7.97 (s, 1H), 7.20 (dd, J = 15.2 Hz, 10.8, 1H), 6.33 (s, 1H), 6.19 (s, 1H), 6.10 (dd, J = 15.2, 10.8 Hz, 1H), 6.02 (s, 1H), 5.95 (dd, J =15.2, 8.4 Hz, 1H), 5.73 (d, J = 15.2 Hz, 1H), 5.47 (t, J = 2.6 Hz, 1H), 4.54 (p, J = 7.2 Hz, 1H), 3.67 (s, 3H), 3.64 (dd, J = 14.4, 4.5 Hz, 1H), 2.42 (dd, J = 12.0, 9.0 Hz, 1H), 2.32 (m, 1H), 2.23 (d, J = 13.8, 1H), 2.14 (m, 1H), 2.11 (m, 1H), 2.07 (m, 1H), 1.722 (m, 1H), 1.66 (m, 1H), 1.48 (s, 3H), 1.35 (d, J = 6.7 Hz, 3H), 1.31 (m, 1H), 1.27 (m, 1H), 1.23 (m, 1H), 1.12 (m, 1H), 1.06 (m, 1H), 0.98 (d, J = 6.7 Hz, 3H), 0.83 (m, 3H), 0.80 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 197.1 (C), 193.4 (CH), 173.5 (C), 171.5 (C), 165.9 (C), 160.0 (C), 151.6 (CH), 148.0 (C), 146.4 (CH), 136.6 (CH2), 129.3 (CH), 126.7 (CH), 118.8 (CH); 72.7 (CH), 55.4 (CH3), 52.6 (CH), 48.1 (CH), 44.1 (CH2), 44.0 (CH2), 43.2 (CH), 38.9 (C), 35.2 (CH), 32..2 (CH), 30.4 (CH2), 30.1 (CH2), 21.1 (CH3), 20.8 (CH2), 19.7 (CH3), 19.1 (CH3), 18.3 (CH3), 11.4 (CH3).
（3）当R基团为L-Val-OMe时：
将1当量 S6-2加入含有1.2 当量的底物NH2R，1.5 当量偶联试剂DEPC和2.4 当量的催化剂TEA的DMF溶液中，室温下反应4h，用饱和NH4Cl溶液终止反应，用乙酸乙酯等体积液萃取产物3次，浓缩，经柱层析和HPLC分离，得到化合物3。
化合物3
化合物 3为白色固体。EI-MS (m/z): 569 (M+); HR-EI-MS calcd for C33H47O7N 569.3347, found 569.3342; 1H NMR (CDCl3, 400 MHz)δ9.53 (s, 1H), 7.22 (dd, J =15.2, 10.8 Hz, 1H), 6.34 (s, 1H), 6.20 (s, 1H), 6.12 (dd, J=15.2 Hz, 10.8, 1H), 6.04 (s, 1H), 5.96 (dd, J=15.2 Hz, 8.4, 1H), 5.75 (d, J =15.2 Hz, 1H), 5.49 (t, J = 2.6 Hz, 1H), 4.52 (dd, J = 8.5, 4.7 Hz, 1H), 3.69 (s,3H), 3.64 (dd, J =14.4, 4.5 Hz, 1H), 2.41 (m, 1H), 2.34 (m, 1H), 2.28 (m, 1H), 2.21 (m, 1H), 2.16 (m, 1H), 2.12 (m, 1H), 2.06 (m, 1H), 1.76 (m, 1H), 1.71 (m, H), 1.69 (m, 1H), 1.51 (s, 3H), 1.34 (m, 1H), 1.29 (m, 1H), 1.26 (m, 1H), 1.13 (m, 1H), 1.07 (m, 1H), 1.00 (d, J =6.7 Hz, 3H), 0.92 (d, J =6.7 Hz, 3H), 0.88 (d, J =6.7 Hz, 3H), 0.84 (m, 3H), 0.82 (m, 3H); 13C NMR (CDCl3, 100 MHz) δ 197.1 (C), 193.3 (CH), 172.6 (C), 171.9 (C), 165.9 (C), 159.9 (C), 151.7 (CH), 148.0 (C), 146.5 (CH), 136.3 (CH2), 129.3 (CH), 126.7 (CH), 118.8 (CH); 72.7 (CH), 57.2 (CH3), 55.8 (CH), 52.4 (CH), 44.1 (CH2), 43.8 (CH2), 43.3 (CH), 39.0 (C), 35.3 (CH), 32..2 (CH), 31.2 (CH2), 30.5 (CH), 30.1 (CH2), 21.2 (CH3), 21.1 (CH2), 19.7 (CH3), 19.2 (CH3), 19.1 (CH3), 18.0 (CH3), 11.4 (CH3).
（4）当R基团L-Leu-OMe时：
将1当量 S6-2加入含有1.2 当量的底物NH2R，1.5 当量偶联试剂DEPC和2.4 当量的催化剂TEA的DMF溶液中，室温下反应4h，用饱和NH4Cl溶液终止反应，用乙酸乙酯等体积液萃取产物3次，浓缩，经柱层析和HPLC分离，得到化合物4。
化合物4
化合物 4为白色固体。EI-MS (m/z): 583 (M+); HR-EI-MS calcd for C34H49O7N 583.3504, found 583.3501; 1H NMR (CDCl3, 400 MHz)δ9.53 (s, 1H), 7.22 (dd, J = 15.2, 10.8 Hz, 1H), 6.35 (s, 1H), 6.21 (s, 1H), 6.12 (dd, J = 15.2 Hz, 10.8, 1H), 6.04 (s, 1H), 5.97 (dd, J = 15.2 Hz, 8.4, 1H), 5.82 (d, J = 8.1 Hz, 1H), 5.74 (d, J = 15.2 Hz, 1H), 5.49 (t, J = 2.6 Hz, 1H), 4.59 (td, J = 8.1, 4.8 Hz, 1H), 3.68 (s, 3H), 3.64 (dd, J = 14.4, 4.5 Hz, 1H), 2.39 (m, 1H), 2.31 (m, 1H), 2.24 (m, 1H), 2.15 (m, 1H), 2.13 (m, 1H), 2.09 (m, 1H), 1.74 (m, 1H), 1.69 (m, 2H), 1.62 (m, 1H), 1.50 (s, 3H), 1.33 (m, 1H), 1.28 (m, 1H), 1.23 (m, 1H), 1.14 (m, 1H), 1.08 (m, 1H), 1.00 (d, J = 6.7 Hz, 3H), 0.92 (d, J = 6.2 Hz, 6H), 0.84 (m, 3H), 0.81 (m, 3H); 13C NMR (CDCl3, 100 MHz) δ 197.1 (C), 193.4 (CH), 173.6 (C), 171.8 (C), 165.9 (C), 160.0 (C), 151.7 (CH), 148.0 (C), 146.5 (CH), 136.6 (CH2), 129.3 (CH), 126.7 (CH), 118.8 (CH); 72.7 (CH), 55.6 (CH3), 52.5 (CH), 50.9 (CH), 44.1 (CH2), 44.1 (CH2), 43.3 (CH2), 41.6 (CH), 38.9 (C), 35.3 (CH), 32..2 (CH), 30.4 (CH2), 30.1 (CH2), 29.9 (CH2), 25.2 (CH), 23.0 (CH3), 22.5 (CH3), 21.2 (CH3), 20.9 (CH2), 19.8 (CH3), 19.1 (CH3), 11.4 (CH3).
（5）当R基团为L-Met-OMe时：
将1当量 S6-2加入含有1.2 当量的底物NH2R，1.5 当量偶联试剂DEPC和2.4 当量的催化剂TEA的DMF溶液中，室温下反应4h，用饱和NH4Cl溶液终止反应，用乙酸乙酯等体积液萃取产物3次，浓缩，经柱层析和HPLC分离，得到化合物5。
化合物5
化合物 5为白色固体。ESI-MS (m/z): 600 (M-1); HR-ESI-MS [M + Na]+ calcd for C33H47O7NS 624.2971, found 624.2947; 1H NMR (CDCl3, 400 MHz) δ 9.53 (s, 1H), 7.22 (dd, J = 15.2, 10.8 Hz, 1H), 6.34 (s, 1H), 6.21 (s, 1H), 6.12 (dd, J = 15.2 Hz, 10.8, 1H), 6.05 (s, 1H), 5.97 (dd, J = 15.2 Hz, 8.4, 1H), 5.74 (d, J = 15.2 Hz, 1H), 5.49 (t, J = 2.6 Hz, 1H), 4.68 (td, J = 7.4, 5.0 Hz, 1H), 3.71 (s, 3H), 3.67 (dd, J = 14.4, 4.5 Hz, 1H), 2.49 (m, 2H), 2.39 (m, 1H), 2.32 (m, 1H), 2.25 (m, 1H), 2.17 (m, 1H), 2.14 (m, 1H), 2.11 (m, 1H), 2.08 (m, 3H), 1.98 (m, 2H), 1.74 (m, 1H), 1.68 (m, 1H), 1.50 (s, 3H), 1.34 (m, 1H), 1.31 (m, 1H), 1.26 (m, 1H), 1.15 (m, 1H), 1.08 (m, 1H), 0.99 (d, J = 6.7 Hz, 3H), 0.84 (m, 3H), 0.81 (m, 3H); 13C NMR (CDCl3, 100 MHz) δ 197.1 (C), 193.3 (CH), 172.5 (C), 171.8 (C), 165.9 (C), 159.9 (C), 151.7 (CH), 148.0 (C), 146.5 (CH), 136.5 (CH2), 129.3 (CH), 126.7 (CH), 118.8 (CH); 72.7 (CH), 55.6 (CH3), 52.7 (CH), 51.9 (CH), 44.1 (CH2), 43.9 (CH2), 43.4 (CH2), 39.0 (C), 35.3 (CH), 32..2 (CH), 31.2 (CH2), 30.5 (CH2), 30.4 (CH2), 30.1 (CH2), 21.2 (CH3), 20.9 (CH2), 19.8 (CH3), 19.1 (CH3), 15.8 (CH3), 11.4 (CH3).
结构式（II）衍生物的制备
（6）当R基团为L-Gly-OMe时：
在DMF中，在3.0当量的偶联试剂DEPC和2.4当量的催化剂TEA作用下，1当量S6-2与2.4当量的底物NH2R反应，室温下反应3.5h，用饱和NH4Cl溶液终止反应，用乙酸乙酯等体积液萃取产物5次，浓缩，经柱层析和HPLC分离得到化合物6。
化合物6
化合物 6为白色固体。EI-MS (m/z): 267 (M+); HR-EI-MS calcd for C15H25O3N 267.1829, found 267.1830; 1H NMR (400 MHz, CDCl3) δ 7.19 (dd, J = 15.2, 10.8 Hz, 1H), 6.09 (dd, J = 15.2, 10.8 Hz, 1H), 5.91 (dd, J = 15.1, 8.2 Hz, 2H), 5.80 (d, J = 15.0 Hz, 1H), 4.11 (d, J = 5.2 Hz, 2H), 3.75 (s, 3H), 3.47 (s, 1H), 2.32 (m, 1H), 1.33 (m, 1H), 1.29 (m, 2H), 1.11 (m, 2H), 0.98 (t, J = 6.7 Hz, 3H), 0.85 (m, 3H), 0.81 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 170.8 (C), 166.6 (C), 150.0 (CH), 142.7 (CH), 126.7 (CH), 121.0 (CH), 52.6 (CH3), 44.2 (CH2), 41.6 (CH2), 35.2 (CH), 32.3 (CH), 30.1 (CH2), 21.2 (CH3), 19.2 (CH3), 11.4 (CH3).
（7）当R基团为2-Aminoethanol时：
在THF中，在1.5当量的偶联试剂DEPC和2.4 当量的催化剂TEA作用下，1当量的S6-2与1.2 当量的底物NH2R反应，室温下反应3h，用饱和NH4Cl溶液终止反应，用乙酸乙酯等体积液萃取产物5次，浓缩，经柱层析和HPLC分离，得到化合物7。
化合物7
化合物 7为暗白色固体。EI-MS (m/z): 239 (M+); HR-EI-MS calcd for C14H25O2N 239.1880, found 239.1881; 1H NMR (400 MHz, CDCl3) δ 7.18 (dd, J = 15.2, 10.8 Hz, 1H), 6.08 (dd, J = 15.2, 10.8 Hz, 1H), 5.90 (dd, J = 15.2, 8.3 Hz, 1H), 5.76 (d, J = 15.2 Hz, 1H), 3.73 (t, J = 5.2, 2H), 3.48 (dd, J = 10.1, 5.2 Hz, 2H), 2.31 (m, 1H), 1.32 (m, 1H), 1.26 (m, H), 1.10 (m, 2H), 0.99 (d, J = 6.7 Hz, 3H), 0.85 (m, 3H), 0.81 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 167.9 (C), 150.0 (CH), 142.4 (CH), 126.6 (CH), 121.4 (CH), 62.9 (CH2), 44.2 (CH2), 42.9 (CH2), 35.2 (CH), 32.3 (CH), 30.1 (CH2), 21.2 (CH3), 19.2 (CH3), 11.4 (CH3).
（8）当R基团为1-amino-3-propanol时：
在THF中，在1.5当量的偶联试剂DEPC和2.4 当量的催化剂TEA作用下，1当量的天然产物S6-2与1.2 当量的底物NH2R反应，室温下反应3h，用饱和NH4Cl溶液终止反应，用乙酸乙酯等体积液萃取产物5次，浓缩，经柱层析和HPLC分离，得到化合物8。
化合物8
化合物 8为白色固体。EI-MS (m/z): 254 (M + H); HR-EI-MS calcd for C14H25O2N 253.2036, found 253.2034; 1H NMR (400 MHz, CDCl3) δ 7.18 (dd, J = 15.2, 10.8 Hz, 1H), 6.08 (dd, J = 15.2, 10.8 Hz, 1H), 5.91 (dd, J = 15.2, 8.3 Hz, 1H), 5.73 (d, J = 15.2 Hz, 1H), 3.62 (t, J = 5.6 Hz, 2H), 3.48 (dd, J = 12.2, 5.6 Hz, 2H), 3.18 (brs, 1H), 2.31 (m, 1H), 1.69 (m, 2H), 1.34 (m, 1H), 1.27 (m, 2H), 1.09 (m, 2H), 0.98 (d, J = 6.7 Hz, 3H), 0.84 (m, 3H), 0.81 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 167.8 (C), 150.0 (CH), 142.4 (CH), 126.6 (CH), 121.3 (CH), 59.4 (CH2), 44.2 (CH2), 36.8 (CH2), 35.2 (CH), 32.9 (CH2), 32.3 (CH), 30.1 (CH2), 21.2 (CH3), 19.2 (CH3), 11.4 (CH3).
（9）当R基团为H时：
通过制备如权利1，2所述其它化合物所得副产物。
化合物9
化合物 9为无色油状液体。EI-MS (m/z): 196 (M+); HR-EI-MS calcd for C12H20O2 196.1458, found 196.1460; 1H NMR (400 MHz, CDCl3) δ 7.27 (dd, J = 15.2, 10.8 Hz, 1H), 6.10 (dd, J = 15.2, 10.8 Hz, 1H), 5.95 (dd, J = 15.2, 8.2 Hz, 1H), 5.72 (d, J = 15.2 Hz, 1H), 2.30 (m, 1H), 1.28 (m, 1H), 1.22 (m, 2H), 1.07 (m, 2H), 0.94 (dd, J = 9.0 Hz, 3H), 0.80 (m, 4H), 0.77 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 172.7 (C), 151.9 (CH), 147.7 (CH), 126.5 (CH), 118.4 (CH), 43.8 (CH2), 35.0 (CH), 32.0 (CH), 29.9 (CH2), 20.8 (CH3), 19.0 (CH3), 11.2 (CH3).
实施例2
MTT还原法测化合物1-9的抗肿瘤活性
材料: 四脞盐（MTT）： 用0.01mol/L 的磷酸盐缓冲液（PBS） 溶解MTT〔3- 4,5-dimethythiazol-z-yl）2,5-diphenytetrazolium bromide,SIGMA〕，最终浓度5mg/ml，过滤除菌，分装后4℃避光保存。
MTT裂解液的配制：80g的十二烷基磺酸钠溶解在200ml的N-N－二甲基甲酰胺中，水浴加热助溶，加入200ml蒸馏水，用80％乙酸与1N盐酸（1：1）混合调pH至4.7。
细胞株选用：MDA-MB-435，MCF-7，Hela，PC-3，A549肿瘤细胞株。于37 °C下5%的CO2含量的空气中保藏。
操作步骤：
单细胞悬液接种于96孔板，用培养基将细胞稀释至1×104/ml，每孔加入200ml稀释好的细胞，每组五个平行样在5%CO2中，37 oC室温和饱和湿度下培养24小时。去除培养基，取新配制培养基按系列浓度制备抗癌药物溶液，每孔200ml，培养48小时，每孔加入2mg/ml的MTT 20ml，孵育4小时。尽量完全的吸出孔内培养液，加入DMSO液（150ml/孔），振荡10分钟，使结晶物充分溶解。酶标仪检测各孔OD值，（l=570nm）；以吸收液对药物浓度对数作图，求出IC50值。
抗肿瘤活性结果如表1所示，九个新化合物均表现处对五株肿瘤细胞的抑制性。与天然物S6-2相比，化合物1-5对不同肿瘤细胞的抑制效果明显增强，如对肿瘤细胞MDA-MB-435的抑制效果，化合物1比S6-2提高了近25倍
。
Claims (3)
1.一种天然产物S6-2的衍生物，其特征在于其结构式(II)为：
。
2.一种如权利要求1所述的天然产物S6-2衍生物的制备方法，其特征在于：包括以下步骤：在THF中，在1.5当量的偶联试剂DEPC和2.4 当量的催化剂TEA作用下，1当量的天然产物S6-2与1.2 当量的底物NH2R反应，室温下反应3h，用饱和NH4Cl溶液终止反应，用乙酸乙酯等体积液萃取产物5次，浓缩，经柱层析和HPLC分离，得到权利要求1所示化合物；
所述S6-2为从南海红树林内生真菌BL321中分离得到一个艾里莫芬烷类的倍半萜化合物07H239-A，所述NH2R为2-氨基乙醇。
3.如权利要求1所述的天然产物S6-2衍生物在制备抗肿瘤药物中的用途。
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| 07H239-A, a New Cytotoxic Eremophilane Sesquiterpene from the Marine-Derived Xylariaceous Fungus LL-07H239;Leonard A. McDonald, et al.;《J. Nat. Prod.》;20040714;第67卷(第9期);1565-1567 * |
| cations of Integric Acid and HIV-1 Integrase Inhibitory Activity.《Bioorg. Med. Chem. Lett.》.2000,第10卷(第3期),235-238. * |
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