CN102775429B - 不饱和去甲基斑蝥酸银配聚物的制备和用途 - Google Patents
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Abstract
本发明涉及一种不饱和去甲基斑蝥酸银配位聚合物的合成方法和用途，该物质外观呈无色块状晶体，分子式{[Ag(C8H7O5)]·H2O}n，n为聚合度，结晶水数量可变。化学名为：聚[[[μ3‑(5,6‑η):κO2:κO2‑(±)‑(1S，2S，3R，4R)–3–羧基–7‑氧代二环‑[2.2.1]庚烷‑5‑烯‑2–羧负离子]银(I)]一水合物]，结构如下（结晶水数量可变）：
Description
技术领域
本发明涉及药物无机化学领域，具体涉及一类含银的不饱和去甲基斑蝥酸配聚物的制备及用途。
背景技术
金属元素在生命中扮演了重要的角色。生物体中的金属大都以阳离子形式存在，因为只有阳离子才能在体液中溶解。金属阳离子是缺电子的，而大多数生物分子都是富电子的，如蛋白质、DNA等，因此，带相反电荷的金属离子与生物分子有结合或相互作用的倾向。这种类似的倾向也存在于金属离子和一些对生命有重要价值的小分子之间。金属离子中值得注意的是银，其配合物作为一类近年来被广泛研究的潜在药物，显示出诱人的应用前景，主要是因为它们对一些癌细胞表现出强烈毒性的同时，对正常细胞的毒性很小[W.J. Youngs,A. R. Knapp,P. O. Wagers, C. A. Tessier, Dalton Trans. 41 (2012)327–336.]，在这方面优于金属铂。
去甲斑蝥素就是把2、3位上的两个甲基去掉，其临床毒性远小于斑蝥素，仍有很好抗肿瘤效果，从二十世纪八十年代开始在中国用于人类癌症尤其是肝癌的临床治疗[Kok,S. H.; Cheng, S. J.; Hong, C. Y.; Lee, J. J.; Lin, S. K.; Kuo, Y. S.; Chiang,C. P.; Kuo, M. Y., Cancer Lett. 2005, 217, 43–52.]。体外实验证实，去甲斑蝥素对多种癌细胞[如A2780 (Human ovarian carcinoma), G401 (human kidney carcinoma),HT29 (human colorectal carcinoma), H460 (human lung carcinoma), L1210 (murineleukemia)]的半数生长抑制浓度（GI50，the concentration that induces 50% growthinhibition compared with untreated control cells.）均略大于斑蝥素[Matthew E.Hart, A. Richard Chamberlin, Cecilia Walkom, Jennette A. Sakoff and AdamMcCluskey, Bioorganic & Medicinal Chemistry Letters 14 (2004) 1969–1973.]。临床实验也证实了去甲斑蝥素的药用价值。Wang G. S.等人对285名一级肝癌（primaryhepatoma）病人用去甲斑蝥素治疗，对照102名病人的传统化疗方法（如：5FU,hydroxycamptotherine, vincristine, thiophosphoramide and mitomycin），发现均可以延长病人的存活时间，从4.7-11.1个月不等，有17–30%的病人存活时间可以延长一年以上[Wang G. S., J. Ethnopharmacol, 1989, 26(2): 147.]。和用斑蝥素治疗的病人相比，用去甲斑蝥素治疗的病人不会出现骨髓抑制（myelosuppression）现象从而导致造血功能受到抑制，恰恰相反，去甲斑蝥素反而能刺激骨髓造血[Liu X-H, Balzsek I, ComissoM, Legras S, Marion S, Quittet P, Anjo A, Wang G-S, Eur J Cancer 31A(1995):953–963.]。这种反常的刺激也是短暂的，大概持续一个星期左右，在良好的护理下，白细胞水平会恢复到正常值。一个有趣的现象是，在老鼠身上的实验证实，去甲斑蝥素能阻止环磷酰胺类化疗药物引起的骨髓抑制现象，即可以抵制由其他化疗药物引起的白血球减少的现象。
本课题组曾经首次合成过一种Ag+和不饱和去甲斑蝥素的配聚物，详细研究过其晶体结构[Wang Feng-Yan, Jiang Xue-Bing, Tan Xue-Jie, Xing Dian-Xiang, Acta Crystallographica C67 (2011), m218-m220.]。七个月后，重庆大学的龚云等人又详细研究了该化合物的电催化性质[Gong, Yun; Wu, Tao; Li, Jinghua; Lin, Jianhua.，Inorganic Chemistry Communications(2012),19 39-42.]，并对合成方法作了一些改进。本发明在以上工作的基础上进一步改进了合成方法，并且研究了其体外抗肿瘤活性，发现该化合物在医药领域具有很好的应用前景。
发明内容
本发明的内容是合成了一种不饱和去甲基斑蝥酸银配位聚合物，外观呈无色块状晶体，分子式{[Ag(C8H7O5)]·H2O}n，n为聚合度，结晶水数量可变。化学名为：聚[[[μ3-(5,6-η):κO2:κO2 - (±) - (1S，2S，3R，4R) – 3 – 羧基 – 7 - 氧代二环 - [2.2.1]庚烷 - 5 -烯- 2 – 羧负离子]银(I)] 一水合物]，结构如下（结晶水数量可变）：
1、合成方法：
配聚物{[Ag(C8H7O5)]·H2O}n合成方法上的特征在于：以去甲基不饱和斑蝥酸{即：7 - 氧代二环 - [2.2.1]庚烷 - 5 - 烯 - 2, 3 - 二羧酸}或去甲基不饱和斑蝥素{即：7 - 氧代二环 - [2.2.1]庚烷 - 5 - 烯 - 2,3-外型-二羧酸酐}和银离子为原料，在合适的溶剂中混合，自然挥发。步骤如下：
1）将配体去甲基不饱和斑蝥酸和AgNO3加入溶剂中，配成合适浓度的溶液，然后按一定比例混合，过滤后常温常压下自然挥发；
2）一段时间后可得到晶体状物，分离出即为产物；
优选的，配体去甲基不饱和斑蝥酸和AgNO3的摩尔比为：2∶1 ~ 1∶2；
优选的，所述溶剂选自：水，甲醇、乙醇。
2、体外抗肿瘤活性：
将处于对数期生长的A549肺癌细胞，用0.25%胰酶消化细胞，使其成为单细胞，用含10%胎牛血清的F12K培养液制成浓度为1.25×107个/L的单细胞悬液，将细胞接种于96孔培养板中，每孔200μL（每孔2.5×103个细胞）。将96孔细胞培养板置于CO2培养箱中，在37℃，5%CO2条件下，培养48h。
当孔内细胞长满（90%满即可）时，按实验分组加入不同剂量的配合物溶液（200μL/孔），使待测化合物的终浓度分别为5μM、10μM、30μM、50μM、100μM，每组设3个复孔，培养96h。
各个孔中分别加入20μL浓度为0.5g/L的MTT，继续培养4h，使MTT还原为甲瓒（Formazan）。吸出全部上清液后，每孔加入200μL的DMSO，震摇15min，使甲瓒充分溶解后，运用酶联免疫检测仪测定490nm处的吸光度（OD值）。然后按照下式进行计算：
细胞抑制率%=（对照组OD值 - 实验组OD值）/ 对照组OD值 ×100%
测试结果表明，配合物分子对肺癌细胞A549的IC50（药物的半数抑制浓度）为7.28μM。这表明配合物分子对肺癌细胞具有很好的抑制效果，与顺铂对A549肺癌细胞的抑制效果（IC50=7.0μM）相当。
具体实施方式
为了更好的理解本发明内容，下面通过几个具体实施例进一步说明本发明的技术方案。以下实施例并不限定本发明。
实施例1
将配好的配体去甲基不饱和斑蝥酸与硝酸银的0.01mol/L无水乙醇溶液，各取20mL，分别过滤后以1:1的摩尔比混合于烧杯内，常温下静置24-72小时，得到无色透明块状晶体，即为目标产物。
Claims (1)
1.一种不饱和去甲基斑蝥酸银配位聚合物在制备预防和/或治疗肺癌药物中的应用，其中所述配位聚合物的结构式为：
分子式为{[Ag(C8H7O5)]·H2O}n，研究发现其对A549肺癌细胞具有抑制效果，其半数抑制浓度为7.28μM。
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|---|---|---|---|---|
| CN1500789A (zh) * | 2002-11-19 | 2004-06-02 | 北京大学 | 含去甲基斑蝥酸根(DCA)的铜(Ⅱ)、镓(Ⅲ)及稀土离子(Ln3+)混配配合物ML(DCA) |
| CN1686102A (zh) * | 2005-04-08 | 2005-10-26 | 中山大学 | 斑蝥素衍生物在制备抗肿瘤药物中的应用 |
| CN1861610A (zh) * | 2005-05-11 | 2006-11-15 | 武德柱 | 去甲斑蝥素－钕的合成 |
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1500789A (zh) * | 2002-11-19 | 2004-06-02 | 北京大学 | 含去甲基斑蝥酸根(DCA)的铜(Ⅱ)、镓(Ⅲ)及稀土离子(Ln3+)混配配合物ML(DCA) |
| CN1686102A (zh) * | 2005-04-08 | 2005-10-26 | 中山大学 | 斑蝥素衍生物在制备抗肿瘤药物中的应用 |
| CN1861610A (zh) * | 2005-05-11 | 2006-11-15 | 武德柱 | 去甲斑蝥素－钕的合成 |
Non-Patent Citations (2)
| Title |
|---|
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