• 中国中文核心期刊
  • 中国科学引文数据库核心期刊
  • 中国科技核心期刊
  • 中国高校百佳科技期刊
高级检索

含1,2-苯并噻嗪结构的杂原子取代薁类衍生物的合成及其抗肿瘤活性

赵小美, 王新, 汲霞, 张璟, 张华, 胡国强

赵小美,王新,汲霞,等. 含1,2-苯并噻嗪结构的杂原子取代薁类衍生物的合成及其抗肿瘤活性[J]. 中国药科大学学报,2024,55(5):634 − 638. DOI: 10.11665/j.issn.1000-5048.2023120503
引用本文: 赵小美,王新,汲霞,等. 含1,2-苯并噻嗪结构的杂原子取代薁类衍生物的合成及其抗肿瘤活性[J]. 中国药科大学学报,2024,55(5):634 − 638. DOI: 10.11665/j.issn.1000-5048.2023120503
ZHAO Xiaomei, WANG Xin, JI Xia, et al. Synthesis and antitumor activity of heteroatom-substituted azulenes derivatives of 1,2-benzothiazine[J]. J China Pharm Univ, 2024, 55(5): 634 − 638. DOI: 10.11665/j.issn.1000-5048.2023120503
Citation: ZHAO Xiaomei, WANG Xin, JI Xia, et al. Synthesis and antitumor activity of heteroatom-substituted azulenes derivatives of 1,2-benzothiazine[J]. J China Pharm Univ, 2024, 55(5): 634 − 638. DOI: 10.11665/j.issn.1000-5048.2023120503

含1,2-苯并噻嗪结构的杂原子取代薁类衍生物的合成及其抗肿瘤活性

基金项目: 齐鲁医药学院科研团队支持计划;山东省卫生健康委员会医疗卫生科技项目(No.202202020715);山东省高校科研计划项目(J17KB091)
详细信息
    通讯作者:

    王新: Tel:0533-2829415 E-mail:gggusr-841012@163.com

  • 中图分类号: R914;R965

Synthesis and antitumor activity of heteroatom-substituted azulenes derivatives of 1,2-benzothiazine

Funds: This study was supported by the Program for Scientific Research Team of Qilu Medical University; the Medical Health Science and Technology Project of Health Commission of Shandong Province (No.202202020715); and the Scientific Research Projects of Universities in Shandong Province (J17KB091)
  • 摘要:

    以吡罗昔康甲基物为原料,利用生物电子等排和活性拼接等药物设计原理,设计并合成10个结构新颖的目标化合物,其结构经1H NMR、MS等表征。通过测定对胰腺癌细胞Capan-1、白血病细胞L1210和人肝癌细胞SMMC-7721的抑制活性,评价目标化合物的体外抗肿瘤活性。结果表明,化合物6f(IC50=4.8±0.5 μmol/L)对胰腺癌细胞Capan-1表现出较好的抑制活性;化合物6b(IC50=2.6±0.3 μmol/L)对白血病细胞L1210表现出较好的抑制活性;化合物6c(IC50=2.1±0.2 μmol/L)对人肝癌细胞SMMC-7721表现出较好的抑制活性。初步的抗肿瘤活性实验结果表明,薁类衍生物的引入,对提高该类化合物的抗肿瘤活性有一定的作用。

    Abstract:

    Using methylated pyrroloxicam as a starting material and following the principles of drug design such as bioisosterism and active site binding, we designed and synthesized ten structurally novel target compounds, whose structures were characterized by 1H NMR and MS analysis. The in vitro antitumor activity of these title compounds was evaluated by measuring their inhibitory activity against pancreatic cancer cells Capan-1, leukemia cells L1210, and human liver cancer cells SMMC-7721. The results showed that compound 6f (IC50=4.8±0.5 μmol/L) exhibited good inhibitory activity against Capan-1 pancreatic cancer cells, that compound 6b (IC50=2.6±0.3 μmol/L) showed good inhibitory activity against L1210 leukemia cells, and that compound 6c (IC50=2.1±0.2 μmol/L) displayed good inhibitory activity against SMMC-7721 human liver cancer cells. These preliminary results from the antitumor activity experiments suggest that the introduction of benzothiazine derivatives plays a certain role in enhancing the antitumor activity of this class of compounds.

  • 草珊瑚(Sarcandra glabra)为金粟兰科(Chloranthaceae)草珊瑚属植物,在我国主要分布于南部地区,具有清热凉血,活血消斑,祛风通络的功效,是用于治疗炎症性疾病、风湿关节痛的传统中药[1]。现代药理学研究表明,草珊瑚具有免疫调节[2]、抗炎[3]以及抗肿瘤[4]活性。近些年来,草珊瑚及其提取物在食品以及化妆品等行业的需求也在不断地增长[5]。本课题组围绕草珊瑚中的特征性成分进行了诸多探索[67]。乌药烷倍半萜及其聚合物以其独特的3/5/6环结构、多样的聚合方式以及良好的生物活性也被认为是草珊瑚中最有代表性的化合物[89]。目前对于草珊瑚的化学成分的研究主要集中于极性较小的萜类成分,对于草珊瑚提取物中的大极性成分,特别是苷类成分研究较少[10]

    为了阐明草珊瑚作为常用中药的物质基础,进一步深入研究其中的有效成分。本研究对新鲜草珊瑚叶醇提物乙酸乙酯萃取后水部位进行了系统的研究。从中分离鉴定了8个极性较大的萜苷类化合物和2个迷迭香酸衍生物,分别为sarcaglaboside C (1)、sarcaglaboside D (2)、byzantionoside B (3)、lauroside E (4)、(4Z)-4-[(3S)-3-(β-D-glucopyranosyloxy)butylidene]-3,5,5-trimethyl-2-cyclohexen-1-one (5)、dihydrovomifoliol-O-β-D-glucopyranoside (6)、(+)-abscisyl-β-D-glucopyranoside (7)、9ξ-O-β-D-glucopyranosyloxy-5-megastigmen-4-one (8)、rosmarinic acid methyl ester (9)、methyl isorinate (10)。其中,化合物3~58~9均首次从草珊瑚中分离得到。

    草珊瑚地上部分(约51.5 kg)采自福建省三明市,由中国药科大学生药学教研室张勉教授鉴定为金粟兰科草珊瑚属草珊瑚[Sarcandra glabra (Thunb.) Nakai],凭证标本(202106)存放于中国药科大学中药学院天然药物化学教研室。

    1260/1100分析型高效液相色谱仪、G6520B Q-TOF质谱仪(美国安捷伦公司);制备型高效液相色谱仪、紫外光谱仪(日本岛津公司);AV-600型核磁共振仪(美国布鲁克公司);200~300目硅胶,GF254硅胶(青岛海洋化工有限公司);MCI树脂(三菱化学公司);RP-C18反相柱色谱填料(上海月旭科技公司);Sephadex LH-20(英国GE healthcare Bio-Sciences AB公司);氘代试剂(美国剑桥同位素实验室);所用试剂均为分析纯或色谱纯。

    新鲜的草珊瑚地上部分(51.5 kg),粉碎,用3倍量的85%乙醇回流提取3次,每次3 h。提取液减压浓缩后得到粗浸膏(1553 g)。取适量水使之混悬,依次用2倍量的乙酸乙酯进行萃取,分别得到水部位(731.2 g)和乙酸乙酯部位(545.3 g)。水部位分别经大孔树脂柱色谱粗分段,用乙醇-水(0︰1→1︰0)梯度洗脱,得到5个馏分(Fr. A-E)。对馏分Fr. B以及Fr. C采用硅胶柱色谱、MCI柱色谱、凝胶柱色谱、制备液相色谱等分离方法,共得到10个化合物。其中,在馏分Fr. B中分离得到化合物15~10,在馏分Fr. B中分离得到化合物2~4。化合物1~10 的结构式见图1

    Figure  1.  Chemical structures of compounds 1-10

    化合物1  白色无定形粉末,(+)-HR-ESI-MS m/z 433.1851 [M+Na]+。分子式为C21H30O8。其1H NMR谱图显示了1组葡萄糖基信号,2个甲基单峰信号;5个烯氢信号;1个连氧取代氢信号。13C NMR谱图显示1个酯羰基碳信号,3组碳碳双键信号,1个缩醛碳信号。结合以上信息分析该化合物为榄香烷倍半萜糖苷类化合物。具体的核磁数据如下:1H NMR (600 MHz, MeOD) δ: 5.83 (1H, m, H-1), 4.99 (1H, m, H-2α), 5.01 (1H, m, H-2β), 5.06 (1H, m, H-3α), 5.40 (1H, m, H-3β), 2.34 (1H, dd, J=12.2 Hz, 3.2 Hz, H-5), 2.81 (1H, dd, J=14.4 Hz, 4.2Hz, H-6α), 2.72 (1H, t, J=13.9 Hz, H-6β), 4.92 (1H, m, H-8), 1.36 (1H, t, J=12 Hz, H-9α), 2.14 (1H, dd, J =12.1 Hz, 6.1Hz, H-9β), 1.80 (1H, s, H3-13), 1.21 (1H, s, H3-14), 4.08 (1H, d, J=13 Hz, H-15α), 4.29 (1H, d, J=13 Hz, H-15β), 4.25 (1H, d, J=7.8 Hz, H-1′), 3.34 (1H, t, J=8.9 Hz, H-2′), 3.27 (1H, d, J=8.7 Hz, H-3′), 3.24 (1H, ddd, J=9.6Hz, 5.7Hz, 2.2Hz, H-4′), 3.20 (1H, dd, J=9.2 Hz, 7.9 Hz, H-5′), 3.66 (1H, dd, J=11.9 Hz, 5.5 Hz, H-6′α), 3.86 (1H, dd, J=11.8 Hz, 2.3 Hz, H-6′β); 13C NMR (150 MHz, MeOD) δ: 146.7 (C-1), 111.2 (C-2), 119.0 (C-3), 145.9 (C-4), 55.8 (C-5), 27.9 (C-6), 163.8 (C-7), 78.4 (C-8), 45.6 (C-9), 40.6 (C-10), 119.2 (C-11), 176.0 (C-12), 6.7 (C-13), 15.3 (C-14), 73.3 (C-15), 102.9 (C-1′), 73.8 (C-2′), 76.8 (C-3′), 70.3 (C-4′), 76.6 (C-5′), 61.4 (C-6′)。该化合物的波谱数据与文献[11]报道的基本一致,故鉴定化合物1为sarcaglaboside C。

    化合物2  白色无定形粉末,(+)-HR-ESI-MS m/z 565.2284 [M+Na]+。分子式为C26H38O121H NMR (600 MHz, MeOD) δ: 5.84 (1H, m, H-1), 5.02 (1H, m, H-2α), 5.02 (1H, m, H-2β), 5.02 (1H, m, H-3α), 5.42 (1H, m, H-3β), 2.73 (1H, t, J=13.9 Hz, H-5), 2.86 (1H, dd, J=14.4 Hz, 4.1 Hz, H-6α), 2.34 (1H, dd, J=13.4 Hz, 4 Hz, H-6β), 4.92 (1H, m, H-8), 1.38 (1H, t, J=12 Hz, H-9α), 2.16 (1H, dt, J=13.5 Hz, 6.7 Hz, H-9β), 1.82 (1H, s, H3-13), 1.23 (1H, s, H3-14), 4.10 (1H, d, J=12.9 Hz, H-15α), 4.26 (1H, m, H-15β), 4.27 (1H, m, H-1′), 3.21 (1H, m, H-2′), 3.37 (1H, m, H-3′), 3.27 (1H, t, J=9.3 Hz, H-4′), 3.37 (1H, m, H-5′), 3.40 (1H, m, H-6′α), 3,96 (1H, m, H-6′β), 4.93 (1H, m, H-1′′), 3.78 (1H, d, J=9.5 Hz, H-2′′), 3.61 (1H, dd, J=11.3 Hz, 6.5 Hz, H-4′′α), 3.91 (1H, d, J=2.5 Hz, H-4′′β), 3.59 (1H, br.s, H-5′′α), 3.59 (1H, br.s, H-5′′β); 13C NMR (150 MHz, MeOD) δ: 147.3 (C-1), 111.8 (C-2), 114.7 (C-3), 146.3 (C-4), 54.4 (C-5), 28.4 (C-6), 164.5 (C-7), 79.7 (C-8), 46.2 (C-9), 41.2 (C-10), 119.7 (C-11), 176.5 (C-12), 7.3 (C-13), 15.9 (C-14), 74.3 (C-15), 103.5 (C-1′), 74.1 (C-2′), 77.2 (C-3′), 70.9 (C-4′), 76.2 (C-5′), 67.9 (C-6′), 110.1 (C-1′′), 77.2 (C-2′′), 79.0 (C-3′′), 74.1 (C-4′′), 64.6 (C-5′′)。该化合物的波谱数据与文献[11]报道的基本一致,故鉴定化合物2为sarcaglaboside D。

    化合物3  黄色油状物,(+)-HR-ESI-MS m/z 395.2214 [M+Na]+。分子式为C19H32O7。其1H NMR谱图显示了1组葡萄糖基信号,3个甲基单峰信号;1个甲基双峰信号,1个烯氢信号,1个连氧取代氢信号。13C NMR谱图显示1个酮羰基碳信号,1组碳碳双键信号,1个缩醛碳信号。结合以上信息分析该化合物为紫罗兰酮型倍半萜糖苷类化合物。具体的核磁数据如下:1H NMR (600 MHz, MeOD) δ: 1.98 (1H, m, H-2α), 2.46 (1H, d, J=17.4 Hz, H-2β), 5.81 (1H, s, H-4), 1.98 (1H, m, H-6), 1.50 (1H, ddd, J=19.2 Hz, 9.6 Hz, 4.8 Hz, H-7α), 1.98 (1H, m, H-7β), 1.65 (1H, m, H-8α), 1.65 (1H, m, H-8β), 3.91 (1H, m, H-9), 1.19 (1H, d, J=6.2 Hz, H-10), 1.00 (1H, s, H3-11), 1.09 (1H, s, H3-12), 2.05 (1H, s, H3-13), 4.32 (1H, t, J=9.5 Hz, H-1′), 3.14 (1H, t, J=8.5 Hz, H-2′), 3.64 (1H, dt, J=15.1 Hz, 7 Hz, H-3′), 3.35 (1H, t, J=8.4 Hz, H-4′), 3.27 (1H, m, H-5′), 3.89 (1H, m, H-6′α), 3.83 (1H, m, H-6′β); 13C NMR (150 MHz, MeOD) δ: 46.7 (C-1), 36.6 (C-2), 201.0 (C-3), 124.0 (C-4), 168.7 (C-5), 51.0 (C-6), 36.4 (C-7), 35.9 (C-8), 70.5 (C-9), 23.6 (C-10), 25.4 (C-11), 26.1 (C-12), 18.5 (C-13), 100.7 (C-1′), 76.8 (C-2′), 73.8 (C-3′), 76.5 (C-4′), 74.2 (C-5′), 61.6 (C-6′)。该化合物的波谱数据与文献[12]报道的基本一致,故鉴定化合物3为byzantionoside B。

    化合物4  黄色油状物,(+)-HR-ESI-MS m/z 411.2116 [M+Na]+。分子式为C19H32O81H NMR (600 MHz, MeOD) δ: 2.05 (1H, m, H-2α), 2.46 (1H, d, J=17.4 Hz, H-2β), 5.81 (1H, s, H-4), 1.98 (1H, m, H-6), 1.50 (1H, m, H-7), 1.65 (1H, m, H-8α), 1.65 (1H, m, H-8β), 3.87 (1H, m, H-9), 1.19 (1H, d, J=6.2 Hz, H-10), 1.00 (1H, s, H3-11), 1.09 (1H, s, H3-12), 4.19 (1H, dd, J=15.6 Hz, 2 Hz, H-13), 4.36 (1H, dd, J=15.6 Hz, 2 Hz, H-13), 4.32 (1H, t, J=9.5 Hz, H-1′), 3.14 (1H, t, J=5.8 Hz, H-2′), 3.27 (1H, m, H-3′), 3.27 (1H, m, H-4′), 3.35 (1H, m, H-5′), 3.64 (1H, dp, J=15.1 Hz, 7 Hz, 6.4 Hz, H-6′α), 3.87 (1H, m, H-6′β); 13C NMR (150 MHz, MeOD) δ: 36.4 (C-1), 51.0 (C-2), 201.0 (C-3), 124.0 (C-4), 168.7 (C-5), 46.7 (C-6), 23.6 (C-7), 36.6 (C-8), 74.2 (C-9), 18.5 (C-10), 25.4 (C-11), 26.1 (C-12), 74.2 (C-13), 100.7 (C-1′), 73.8 (C-2′), 76.8 (C-3′), 70.5 (C-4′), 76.5 (C-5′), 61.5 (C-6′)。 该化合物的波谱数据与文献[13]报道的基本一致,故鉴定化合物4为lauroside E。

    化合物5  黄色油状物,(+)-HR-ESI-MS m/z 393.2136 [M+Na]+。分子式为C19H32O71H NMR (600 MHz, MeOD) δ: 2.66 (1H, dd, J=17.3 Hz, 11.6 Hz, 6.7 Hz, H-2α), 2.66 (1H, dd, J=17.3 Hz, 11.6 Hz, 6.7 Hz, H-2β), 5.86 (1H, s, H-4), 6.34 (1H, d, J=6.4 Hz, H-7), 2.31 (1H, d, J=8.6 Hz, H-8α), 2.31 (1H, d, J=8.6 Hz, H-8β), 4.35 (1H, d, J=7.8 Hz, H-9), 1.28 (1H, d, J=2.2 Hz, H-10), 1.25 (1H, s, H3-11), 1.25 (1H, s, H3-12), 2.11 (1H, s, H3-13), 4.36 (1H, m, H-1′), 4.03 (1H, m, H-2′), 3.26 (1H, dt, J=11.7 Hz, 6.5 Hz, H-3′), 3.15 (1H, m, H-4′), 3.35 (1H, m, H-5′), 3.84 (1H, m, H-6′α), 3.98 (1H, m, H-6′β); 13C NMR (150 MHz, MeOD) δ: 53.2 (C-1), 37.8 (C-2), 200.8 (C-3), 124.0 (C-4), 157.9 (C-5), 141.7 (C-6), 134.2 (C-7), 37.2 (C-8), 76.7 (C-9), 21.3 (C-10), 27.7 (C-11), 27.7 (C-12), 18.7 (C-13), 101.1 (C-1′), 73.7 (C-2′), 76.6 (C-3′), 70.5 (C-4′), 74.3 (C-5′), 61.7 (C-6′)。该化合物的波谱数据与文献[14]报道的基本一致,故鉴定化合物5为(4Z)-4-[(3S)-3-(β-D-glucopyranosyloxy)butylidene]-3,5,5-trimethyl-2-cyclohexen-1-one。

    化合物6  黄色油状物,(+)-HR-ESI-MS m/z 411.2116 [M+Na]+。分子式为C19H32O81H NMR (600 MHz, MeOD) δ: 2.61 (1H, d, J=12 Hz, H-2α), 2.15 (1H, d, J=12 Hz, H-2β), 5.83 (1H, s, H-4), 2.15 (1H, d, J=12 Hz, H-7α), 1.82 (1H, m, H-7β), 1.79 (1H, m, H-8α), 1.49 (1H, tt, J=12.9 Hz, 4.5 Hz, H-8β), 4.07 (1H, m, H-9), 1.17 (1H, d, J=6.2 Hz, H-10), 1.02 (1H, s, H3-11), 1.10 (1H, s, H3-12), 2.04 (1H, s, H3-13), 4.36 (1H, m, H-1′), 3.13 (1H, dd, J=9.2 Hz, 7.8 Hz, H-2′), 3.81 (1H, q, J=6 Hz, H-3′), 3.26 (1H, m, H-4′), 3.26 (1H, m, H-5′), 3.85 (1H, dd, J=11.6 Hz, 5.3 Hz, H-6′α), 3.34 (1H, m, H-6′β); 13C NMR (150 MHz, MeOD) δ: 42.0 (C-1), 50.2 (C-2), 200.2 (C-3), 125.8 (C-4), 170.9 (C-5), 78.4 (C-6), 34.0 (C-7), 32.7 (C-8), 75.3 (C-9), 20.9 (C-10), 23.8 (C-11), 23.3 (C-12), 19.2 (C-13), 101.4 (C-1′), 74.3 (C-2′), 77.0 (C-3′), 70.9 (C-4′), 77.3 (C-5′), 62.0 (C-6′)。该化合物的波谱数据与文献[15]报道的基本一致,故鉴定化合物6为dihydrovomifoliol-O-β-D-glucopyranoside。

    化合物7  黄色油状物,(+)-HR-ESI-MS m/z 459.1917 [M+Na]+。分子式为C21H30O91H NMR (600 MHz, MeOD) δ: 2.21 (1H, d, J=16.9 Hz, H-2α), 2.56 (1H, d, J=16.9 Hz, H-2β), 5.96 (1H, s, H-4), 6.35 (1H, d, J=16.1 Hz, H-7), 7.83 (1H, d, J=16.1 Hz, H-8), 5.84 (1H, s, H-10), 1.09 (1H, s, H3-12), 2.04 (1H, s, H3-13), 2.04 (1H, br.s, H3-14), 1.95 (1H, br.s, H3-15), 5.52 (1H, d, J=8.2 Hz, H-1′), 3.78 (1H, q, J=6.1 Hz, H-2′), 3.27 (1H, m, H-3′), 3.43 (1H, m, H-4′), 3.43 (1H, m, H-5′), 3.86 (1H, dd, J=12.1 Hz, 2.1 Hz, H-6′α), 3.71 (1H, m, H-6′β); 13C NMR (150 MHz, MeOD) δ: 41.5 (C-1), 49.2 (C-2), 199.5 (C-3), 126.3 (C-4), 152.2 (C-5), 77.4 (C-6), 137.9 (C-7), 127.8 (C-8), 128.5 (C-9), 116.7 (C-10), 164.4 (C-11), 18.1 (C-12), 18.1 (C-13), 22.2 (C-14), 19.9 (C-15), 94.0 (C-1′), 69.7 (C-2′), 76.7 (C-3′), 72.6 (C-4′), 67.8 (C-5′), 61.0 (C-6′)。该化合物的波谱数据与文献[16]报道的基本一致,故鉴定化合物7为 (+)-abscisyl-β-D-glucopyranoside。

    化合物8  黄色油状物,(+)-HR-ESI-MS m/z 395.2214 [M+Na]+。分子式为C19H32O71H NMR (600 MHz, MeOD) δ: 1.81 (1H, m, H-2α), 1.81 (1H, m, H-2β), 2.44 (1H, dd, J=7.5 Hz, 4.2 Hz, H-3α), 2.44 (1H, dd, J=7.5 Hz, 4.2 Hz, H-3β), 2.54 (1H, m, H-7α), 2.31 (1H, m, H-7β), 1.68 (1H, m, H-8α), 1.68 (1H, m, H-8β), 3.96 (1H, tt, J=7 Hz, 3.4 Hz, H-9), 1.76 (1H, s, H-10), 1.20 (1H, s, H3-11), 1.20 (1H, s, H3-12), 1.23 (1H, d, J=6.2 Hz, H-13), 4.35 (1H, d, J=7 Hz, H-1′), 3.16 (1H, m, H-2′), 3.28 (1H, m, H-3′), 3.31 (1H, m, H-4′), 3.28 (1H, m, H-5′), 3.88 (1H, ddd, J=11.4 Hz, 7 Hz, 1.4 Hz, H-6′α), 3.67 (1H, m, H-6′β); 13C NMR (150 MHz, MeOD) δ: 36.7 (C-1), 37.6 (C-2), 36.4 (C-3), 200.7 (C-4), 132.7 (C-5), 167.9 (C-6), 27.1 (C-7), 34.2 (C-8), 71.0 (C-9), 10.9 (C-10), 26.3 (C-11), 26.3 (C-12), 18.9 (C-13), 101.4 (C-1′), 74.9 (C-2′), 77.0 (C-3′), 74.3 (C-4′), 77.4 (C-5′), 62.1 (C-6′)。该化合物的波谱数据与文献[17]报道的基本一致,故鉴定化合物8为9ξ-O-β-D-glucopyranosyloxy-5-megastigmen-4-one。

    化合物9  白色方晶,(+)-HR-ESI-MS m/z 397.3121 [M+Na]+。分子式为C19H18O81H NMR (600 MHz, MeOD) δ: 7.05 (1H, d, J=2.1 Hz, H-2), 6.96 (1H, dd, J=8.2 Hz, 2 Hz, H-5), 6.78 (1H, d, J=8.1 Hz, H-6), 7.55 (1H, d, J=15.9 Hz, H-7), 6.26 (1H, d, J=15.9 Hz, H-8), 6.73 (2H, m, H-2′, H-6′), 6.57 (1H, dd, J=8.1 Hz, 2 Hz, H-5′), 3.04 (1H, qd, J=14.3 Hz, 6.4 Hz, H2-7′), 5.19 (1H, dd, J=7.7 Hz, 5.1 Hz, H-8′), 3.70 (1H, s, H3-OCH3); 13C NMR (150 MHz, MeOD) δ: 126.1 (C-1), 114.9 (C-2), 148.6 (C-3), 146.6 (C-4), 121.8 (C-5), 116.1 (C-6), 144.8 (C-7), 112.7 (C-8), 166.9 (C-9), 127.3 (C-1′), 115.1 (C-2′), 145.5 (C-3′), 144.8 (C-4′), 113.8 (C-5′), 120.4 (C-6′), 36.5 (C-7′), 73.3 (C-8′), 170.8 (C-9′), 51.3 (C-OCH3)。该化合物的波谱数据与文献[18]报道的基本一致,故鉴定化合物9为rosmarinic acid methyl ester。

    化合物10  白色方晶,(+)-HR-ESI-MS m/z 381.1117 [M+Na]+。分子式为C19H18O71H NMR (600 MHz, MeOD) δ: 7.06 (1H, d, J=2.1 Hz, H-2), 6.96 (1H, dd, J=8.2 Hz, 2 Hz, H-5), 6.81 (1H, d, J=8.1 Hz, H-6), 7.56 (1H, d, J=15.9 Hz, H-7), 6.27 (1H, d, J=15.9 Hz, H-8), 7.10 (2H, m, H-2′, H-6′), 6.75 (2H, dd, J=8.1 Hz, 2 Hz, H-3′, H-5′), 3.11 (1H, m, H2-7′), 5.22 (1H, dd, J=7.7 Hz, 5.1 Hz, H-8′), 3.71 (1H, s, H3-OCH3); 13C NMR (150 MHz, MeOD) δ: 126.2 (C-1), 113.9 (C-2), 148.6 (C-3), 146.6 (C-4), 121.8 (C-5), 112.7 (C-6), 156.0 (C-7), 122.3 (C-8), 166.9 (C-9), 130.1 (C-1′), 115.1 (C-2′, C-6′), 114.9 (C-3′, C-5′), 145.4 (C-4′), 36.3 (C-7′), 73.3 (C-8′), 170.8 (C-9′), 51.3 (C-OCH3)。该化合物的波谱数据与文献[19]报道的基本一致,故鉴定化合物10为methyl isorinate。

    草珊瑚中含有结构丰富的化合物,包括酚酸类,以乌药烷倍半萜及其多聚体组成的萜类,黄酮类以及香豆素类。本研究以草珊瑚地上部分的水萃取层为研究对象,系统地研究了其中的化学成分。从中发现了2个榄香烷糖苷类化合物,6个紫罗兰酮糖苷类化合物以及2个酚酸类化合物。上述化合物都具有较大的极性。其中,化合物3~58~9首次从草珊瑚中分离得到。这些化合物的发现有助于丰富草珊瑚植物中化合物的类型,有利于对草珊瑚作为常用中药含有的有效成分的理解,并为后续药理活性研究提供了重要的物质基础。基于草珊瑚用于治疗炎症性疾病的经验,后续可以对分离得到的上述化合物进行抗炎活性研究。

  • 1.   Synthetic route of the target compounds

    Table  1   Physical properties of compounds 5a 5j and 6a6j

    Compd. Formula Yield/% mp/℃ Elemental analysis(%,Calcd.)
    C H N
    5a C20H19N5O4S2 45 192–193 55.52(55.50) 4.21(4.19) 15.27(15.31)
    5b C20H18FN5O4S2 47 196–198 50.48(50.52) 3.78(3.82) 14.81(14.73)
    5c C20H17BrFN5O4S2 45 203–205 43.35(43.33) 3.05(3.09) 12.65(12.63)
    5d C20H19N5O5S2 42 202–204 50.75(50.73) 4.02(4.04) 14.75(14.79)
    5e C21H21N5O4S2 48 198–200 53.53(53.49) 4.55(4.49) 14.81(14.85)
    5f C20H17Cl2N5O4S2 49 210–212 45.65(45.63) 3.32(3.26) 13.34(13.30)
    5g C18H17N5O4S3 52 221–223 46.58(46.64) 3.68(3.70) 15.13(15.11)
    5h C18H22N6O4S2 50 233–235 47.91(47.99) 4.88(4.92) 18.69(18.65)
    5i C23H23N5O4S2 42 228–230 55.48(55.52) 4.68(4.66) 14.03(14.07)
    5j C23H24N6O4S2 41 225–227 53.93(53.89) 4.74(4.72) 16.36(16.40)
    6a C20H17N5O3S2 64 229–231 54.60(54.66) 3.94(3.90) 15.97(15.93)
    6b C20H16FN5O3S2 65 222–224 52.57(52.51) 3.51(3.53) 15.35(15.31)
    6c C20H15BrFN5O3S2 60 224–226 44.86(44.78) 2.86(2.82) 13.12(13.06)
    6d C20H17N5O4S2 61 223–226 52.68(52.74) 3.72(3.76) 15.36(15.38)
    6e C21H19N5O3S2 67 225–227 55.63(55.61) 4.26(4.22) 15.38(15.44)
    6f C20H15Cl2N5O3S2 66 240–242 47.19(47.25) 2.99(2.97) 13.80(13.78)
    6g C18H15N5O3S3 73 249–251 48.57(48.53) 3.35(3.39) 15.70(15.72)
    6h C18H20N6O3S2 71 261–263 49.95(49.99) 4.72(4.66) 19.45(19.43)
    6i C23H21N5O3S2 59 258–260 57.64(57.60) 4.39(4.41) 14.62(14.60)
    6j C23H22N6O3S2 59 252–254 55.82(55.86) 4.54(4.48) 16.95(16.99)
    下载: 导出CSV

    Table  2   Spectral data of compounds 36i

    Compd.1H NMR (400 MHz, DMSO-d6) δ13C NMR (100 MHz , DMSO-d6) δMS m/z [M+H]+
    312.96(1H,s,-OH),7.73-7.95(4H,m,Ph-H),3.00(3H,s,-NCH3)160,156,134,132,129,127,124,110,37312
    412.84(1H,s,-OH),7.69-7.91(4H,m,Ph-H),5.27(2H,s,-NH2),3.11(3H,s,-NCH3)167,156,144,134,132,129,127,124,111,38326
    5a12.88(1H,s,-OH),7.65-7.89(9H,m,Ph-H),5.43(2H,s,-NH2),3.31(2H,t,-SCH2),3.13(3H,s,-NCH3),3.05(2H,t,-CH2-C=O)200,159,156,144,137,134,133,132,129,127,124,111,42,38,27458
    5b12.82(1H,s,-OH),7.45-7.86(8H,m,Ph-H),5.46(2H,s,-NH2),3.35(2H,t,-SCH2),3.12(3H,s,-NCH3),3.02(2H,t,-CH2-C=O)200,162,158,156,143,135,134,133,132,128,127,124,111,41,38,28476
    5c12.78(1H,s,-OH),7.36-8.06(7H,m,Ph-H),5.54(2H,s,-NH2),3.29(2H,t,-SCH2),3.07(3H,s,-NCH3),2.97(2H,t,-CH2-C=O)200,161,159,156,144,138,134,133,132,128,127,124,118,110,41,38,28554
    5d12.77(1H,s,-OH),10.68(1H,s,Ph-OH),7.18-7.86(8H,m,Ph-H),5.48(2H,s,-NH2),3.17(2H,t,-SCH2),3.09(3H,s,-NCH3),2.93(2H,t,-CH2-C=O)200,163,159,156,144,135,133,132,129,127,124,122,118,110,41,38,28474
    5e12.83(1H,s,-OH),7.21-7.87(8H,m,Ph-H),5.64(2H,s,-NH2),3.22(2H,t,-SCH2),3.11(3H,s,-NCH3),2.95(2H,t,-CH2-C=O),1.51(3H,s,Ph-CH3)200,160,156,144,143,135,134,133,132,129,127,124,118,110,42,38,28,21472
    5f12.84(1H,s,-OH),7.66-8.26(7H,m,Ph-H),5.52(2H,s,-NH2),3.27(2H,t,-SCH2),3.07(3H,s,-NCH3),2.98(2H,t,-CH2-C=O)200,159,156,144,138,136,134,133,132,130,128,127,110,41,38,28526
    5g12.80(1H,s,-OH),7.32-7.86(4H,m,Ph-H),7.16-7.66(3H,d,thiophene-H),5.44(2H,s,-NH2),3.27(2H,t,-SCH2),3.11(3H,s,-NCH3),2.98(2H,t,-CH2-C=O)192,159,156,144,134,133,132,129,127,124,110,40,37,27464
    5h12.78(1H,s,-OH),7.34-7.88(4H,m,Ph-H),5.50(2H,s,-NH2),3.23(2H,t,-SCH2),3.10(3H,s,-NCH3),2.95(2H,t,-CH2-C=O),2.69(4H,t,-CH2-N-CH2),1.33(4H,t,pyrrolidine-CH2-CH2)175,159,156,144,142,135,134,132,129,127,124,110,49,38,32,29,25451
    5i12.82(1H,s,-OH),7.34-7.85(7H,m,Ph-H),5.58(2H,s,-NH2),3.19(2H,t,-SCH2),3.11(3H,s,-NCH3),2.89(2H,t,-CH2-C=O),1.35-1.95(6H,m,-CH2-CH2-CH2)200,159,156,148,144,142,135,134,132,129,127,126,124,110,40,38,33,28,25498
    5j12.86(1H,s,-OH),7.26-7.82(8H,m,Ph-H),5.62(2H,s,-NH2),3.32-4.42(6H,m,piperidine-H),3.29(2H,t,-SCH2),3.03(3H,s,-NCH3),2.77(2H,t,-CH2-C=O),172,159,156,144,135,134,132,129,127,126,124,111,49,48,38,32,29513
    6a12.78(1H,s,-OH),7.65-7.94(9H,m,Ph-H),3.23(2H,t,-SCH2),3.07(3H,s,-NCH3),2.75(2H,t,-CH2-C=N)165,159,156,144,135,132,129,128,127,124,111,37,33,31440
    6b12.68(1H,s,-OH),7.46-7.84(8H,m,Ph-H),3.31(2H,t,-SCH2),3.12(3H,s,-NCH3),2.79(2H,t,-CH2-C=N)165,160,159,156,144,135,133,132,131,129,127,124,116,111,37,33,31458
    6c12.74(1H,s,-OH),7.30-7.96(7H,m,Ph-H),3.29(2H,t,-SCH2),3.03(3H,s,-NCH3),2.69(2H,t,-CH2-C=N)165,159,156,144,138,136,135,132,128,124,120,118,110,37,33,31536
    6d12.78(1H,s,-OH),10.66(1H,s,Ph-OH),7.12-7.76(8H,m,Ph-H),3.19(2H,t,-SCH2),3.11(3H,s,-NCH3),2.73(2H,t,-CH2-C=N)165,163,159,156,144,135,132,129,127,124,121,118,110,37,33,31456
    6e12.73(1H,s,-OH),7.18-7.87(8H,m,Ph-H),3.27(2H,t,-SCH2),3.07(3H,s,-NCH3),2.75(2H,t,-CH2-C=N),1.47(3H,s,Ph-CH3)165,159,156,144,141,135,132,131,129,127,124,110,42,37,33,31,21454
    6f12.74(1H,s,-OH),7.56-8.18(7H,m,Ph-H),3.19(2H,t,-SCH2),3.01(3H,s,-NCH3),2.68(2H,t,-CH2-C=N)165,159,156,144,138,136,135,134,132,130,129,126,110,37,33,31508
    6g12.82(1H,s,-OH),7.44-7.84(4H,m,Ph-H),7.10-7.62(3H,d,thiophene-H),3.20(2H,t,-SCH2),2.993H,(s,-NCH3),2.68(2H,t,-CH2-C=N)165,159,156,144,134,132,129,127,126,124,110,37,34,31446
    6h12.74(1H,s,-OH),7.44-7.78(4H,m,Ph-H),3.23(2H,t,-SCH2),3.04(3H,s,-NCH3),2.75(2H,t,-CH2-C=N),2.58(4H,t,-CH2-N-CH2),1.66(4H,t,pyrrolidine-CH2-CH2)159,156,149,144,134,132,129,127,124,110,49,37,31,30,26433
    6i12.76(1H,s,-OH),7.44-7.84(7H,m,Ph-H),3.23(2H,t,-SCH2),3.13(3H,s,-NCH3),2.63(2H,t,-CH2-C=N),1.35-1.87(6H,m,-CH2-CH2-CH2)165,159,156,149,146,144,135,132,129,127,124,110,37,33,31,25480
    6j12.82(1H,s,-OH),7.22-7.78(8H,m,Ph-H),3.36-4.44(6H,m,piperidine-H),3.25(2H,t,-SCH2),3.07(3H,s,-NCH3),2.73(2H,t,-CH2-C=N),159,156,144,140,135,134,132,130,129,126,123,111,45,37,32,27,22495
    下载: 导出CSV

    Table  3   Anti-cell proliferative activity of the tested compounds against Capan-1, SMMC-7721 and L1210 tumor cells($\bar{x}\pm s $, n=3)

    Compd. IC50/(μmol/L)
    Capan-1 SMMC-7721 L1210
    6a 15.7±1.4 18.2±1.7 14.6±1.5
    6b 9.8±1.0 8.6±0.9 2.6±0.3
    6c 9.6±1.0* 2.1±0.2* 8.7±0.8*
    6d 10.8±1.1* 11.6±1.2 10.2±1.0*
    6e 14.6±1.5 15.3±1.5 16.2±1.6
    6f 4.8±0.5* 8.7±0.7* 9.4±0.9*
    6g 11.4±1.2 14.1±1.4 15.8±1.6
    6h 11.8±1.2 13.6±1.4* 13.8±1.4
    6i 11.7±1.2 10.7±1.2* 9.2±0.9*
    6j 12.8±1.3 11.6±1.2 13.6±1.4
    Doxorubicin 3.5±0.6 2.7±0.2 1.4±0.2
    1 >100 >100 >100
    2 80.2±8.1 78.5±7.3 77.4±7.3
    3 65.5±6.6 71.7±7.2 73.6±7.5
    4 64.6±6.5 70.3±7.0 72.5±7.2
    5a 15.2±1.4 17.2±1.7 15.6±1.6
    5b 10.2±1.0 9.2±0.9 2.4±0.3
    5c 9.8±1.0* 6.2±0.6* 6.7±0.8*
    5d 10.6±1.1* 10.8±1.2 9.8±1.0*
    5e 15.6±1.5 15.1±1.5 15.4±1.5
    5f 7.6±0.7* 8.2±0.7* 8.8±0.9*
    5g 12.2±1.2 14.3±1.4 14.2±1.4
    5h 12.6±1.2 11.2±1.1* 13.6±1.4
    5i 12.7±1.3 11.6±1.2* 8.6±0.9*
    5j 11.8±1.2 13.6±1.4 15.2±1.5
    *P<0.05 vs doxorubicin
    下载: 导出CSV
  • [1]

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020[J]. CA Cancer J Clin, 2020, 70(1): 7-30. doi: 10.3322/caac.21590

    [2]

    Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249. doi: 10.3322/caac.21660

    [3] Guo ZR. R&D of imrecoxib based on pharmacophore and scaffold hopping[J]. Acta Pharm Sin(药学学报), 2018, 53(8): 1383-1386.
    [4]

    Brew DRM, Glasser FP. Synthesis and characterisation of magnesium silicate hydrate gels[J]. Cem Concr Res, 2005, 35(1): 85-98. doi: 10.1016/j.cemconres.2004.06.022

    [5]

    Campbell IB, MacDonald SJF, Procopiou PA. Medicinal chemistry in drug discovery in big pharma: past, present and future[J]. Drug Discov Today, 2018, 23(2): 219-234. doi: 10.1016/j.drudis.2017.10.007

    [6]

    Xin H, Gao X. Application of azulene in constructing organic optoelectronic materials: new tricks for an old dog[J]. ChemPlusChem, 2017, 82(7): 945-956. doi: 10.1002/cplu.201700039

    [7]

    Xin HS, Hou B, Gao XK. Azulene-based π-functional materials: design, synthesis, and applications[J]. Acc Chem Res, 2021, 54(7): 1737-1753. doi: 10.1021/acs.accounts.0c00893

    [8]

    Fu XY, Han H, Zhang D, et al. A polycyclic aromatic hydrocarbon diradical with pH-responsive magnetic properties[J]. Chem Sci, 2020, 11(21): 5565-5571. doi: 10.1039/D0SC00770F

    [9]

    Murai M, Amir E, Amir RJ, et al. Azulene-based conjugated polymers: unique seven-membered ring connectivity leading to stimuli-responsiveness[J]. Chem Sci, 2012, 3(9): 2721-2725. doi: 10.1039/c2sc20615c

    [10]

    Koch M, Blacque O, Venkatesan K. Syntheses and tunable emission properties of 2-alkynyl azulenes[J]. Org Lett, 2012, 14(6): 1580-1583. doi: 10.1021/ol300327b

    [11]

    Ince M, Bartelmess J, Kiessling D, et al. Immobilizing NIR absorbing azulenocyanines onto single wall carbon nanotubes—from charge transfer to photovoltaics[J]. Chem Sci, 2012, 3(5): 1472. doi: 10.1039/c2sc20071f

    [12] Wang X, Zhao XM, Zhang PP, et al. Synthesis and antitumor activity of 1, 2-benzothiazines imidazolo[1,2-b][1,3,4]triazazole derivatives[J]. J China Pharm Univ (中国药科大学学报), 2019, 50(5): 540-543.
图(1)  /  表(3)
计量
  • 文章访问数:  171
  • HTML全文浏览量:  75
  • PDF下载量:  63
  • 被引次数: 0
出版历程
  • 收稿日期:  2023-12-04
  • 刊出日期:  2024-10-24

目录

/

返回文章
返回
x 关闭 永久关闭