CN1185244C - 冬凌草甲素衍生物及其制备方法 - Google Patents
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Abstract
本发明在不破坏冬凌草甲素活性中心的前提下，通过改变α-环外亚甲基环戊酮的张力和溶解度，提供了一种如下面通式所示的冬凌草甲素衍生物：这种冬凌草甲素衍生物具有更高的抗肿瘤细胞活性。同时，本发明还提供了上述化合物的制备方法。
Description
本发明涉及新的冬凌草甲素衍生物及其制备方法。
从香茶菜属植物中已分离出的100多个二萜类成分中，有一定抗肿瘤活性的有30多个。其中具有冬凌草甲素(贝壳杉烯型)型的有17种左右，而它们在植物中的含量以冬凌草甲素为最高，其活性研究也以冬凌草甲素的为最多。冬凌草甲素是具有α-亚甲基环戊酮的二萜类化合物，其抗癌活性确切，已被国内外学者广泛研究，例如河南医科大学张潭木研究小组(见：a、王锦英，林晨，张潭木，中国药理学报，1985，6，195.；b、吴孔明，张潭木，王庆端，肿瘤防治研究，1994，21(4)，208.)，以及日本学者Fujita研究小组(见：Eiich Fujita，Yoshimitsu Nagao，Kimiyoshi Kaneko，Shozo Nakazawa，and Hiroyuki Kuroda，Chem.Pharm.Bull.，29，3208(1981))，对其均作了大量的药理实验工作，证明冬凌草甲素具有确切的体外以及体内的抗肿瘤活性，其抗瘤谱也较广，如人体鼻咽癌细胞，人体肝癌细胞，人体子宫颈癌细胞，食管癌细胞等均有明显的杀伤作用。但其活性均不高，其IC50都大于1μg/ml。在进行体内抗小鼠艾氏腹水癌的活性研究过程中发现，凡结构上具有α-环外亚甲基环戊酮单元的化合物都具有抗肿瘤活性，而没有该单元的化合物都没有活性。日本学者Fujita等人认为这类二萜类化合物的活性中心为α-环外亚甲基环戊酮，并且日本学者对14位羟基进行了酰化，酰化后的化合物当中以C16时的酰基活性为最高，体内活性较冬凌草甲素高出30％～40％。我们在总结前人工作基础时发现，所有这些化合物的抗肿瘤活性都不够高，并且由于水溶性差，因而限制了它的使用。最近刘晨江等人(见：刘晨江，赵志鸿，中国药学杂志，33，577(1998))又对冬凌草以及冬凌草甲素近30年的研究进行了综述，同样肯定了冬凌草甲素的确切的抗癌疗效，并提出了存在的问题。总之，欲将冬凌草甲素开发为新药，还需提高其抗肿瘤活性，并尽可能地降低毒性和改善其溶解性。
本发明的目的是在不破坏冬凌草甲素活性中心的前提下，通过改变α-环外亚甲基环戊酮的张力和溶解度，提供具有更高抗肿瘤活性的冬凌草甲素衍生物，同时提供该化合物的制备方法。
本发明是通过以下技术方案实现的。
冬凌草甲素衍生物，其特征以下面通式表示：
通式1 通式2
在通式1中：R1为H或C1～C12的烷基或酰基，或为葡萄糖基、或半乳糖基、或木糖基，R2为H或葡萄糖基、或半乳糖基、或木糖基，或甘露糖基；
在通式2中：R1为H或C1～C12的烷基或酰基；R2，R3分别为C2～C18的烷基，或为异丙叉基、苯甲叉基。
制备上述通式1所示化合物的方法是：
a、将冬凌草甲素在无水硫酸酮的存在下与丙酮反应，再用选择性酰化试剂进行选择性酰化即可得到式3所示的Cl-OH不被保护的化合物；或将冬凌草甲素在无水硫酸酮的存在下与丙酮反应后，再用Ac2O-吡啶酰化得到式4所示的C6-OH不被保护的化合物；
式3 式4
b、将式3或式4所示的化合物在相转移催化剂的存在下与四乙酰化或三乙酰化溴代糖进行反应，然后再用温和的脱保护方法将糖的保护基脱除即得到通式1所示的化合物。
制备上述通式2所示化合物的方法是，将冬凌草甲素用选择性醚化试剂Bu2SnO/RX首先进行选择性醚化或在酸的存在下与丙酮或苯甲醛反应，，再用酰化试剂与其反应即可得到通式2所示的化合物。
本发明所提供的化合物是在不破坏原有的基本骨架的基础上，通过对冬凌草甲素的1位、6位、7位和14位羟基进行酰化、醚化或糖苷化修饰改造，特别是通过改变α-环外亚甲基环戊酮的张力和导向性，从而发现以通式1或通式2所示的冬凌草甲素衍生物具有更高的抗肿瘤活性的。因此，与现有技术相比，冬凌草甲素衍生物具有很高抗肿瘤细胞活性，其活性一般高出冬凌草甲素的8-10倍。发明人采用体外活性测定法对本发明提供的化合物的抗癌活性进行了测试，以冬凌草甲素作阳性对照，发现该化合物对人体鼻咽癌、人体子宫颈癌、食管癌等癌细胞的直接杀伤作用较冬凌草甲素高出6-10倍。
实施例1 当R1＝R2＝H时，通式1所示的冬凌草甲素衍生物的制备：
在装有回流冷凝管的250毫升单口烧瓶中加入冬凌草甲素5克(0.0137mol)，溶于120毫升丙酮中，加入2克无水硫酸铜，氩气保护下，加热至50℃，反应1.5小时，冷至室温，滤去硫酸铜，加入稀碱溶液，用CHCl3萃取3次，再用水反洗2次，有机层用无水Na2SO4，干燥，减压蒸去溶剂后，用甲醇重结晶，得到针状晶体4.9克，产率88.3％.mp：219-221℃。
元素分析(％)：计算值：C：65.38，H：8.11；实测值：C：65.69，H：8.14。
光谱分析：IRv(cm-1)：3314，1710，1648，1451，1381，1080，1067，882；1H-NMR(CDCl3)δppm：6.14，5.55(各1H，s，H17)，5.90(1H，d，J＝11Hz，C6-OH)，4.79(1H，s，H14)，4.24，4.04(各1H，d，J＝10Hz，H20)，3.87(11H，dd，J＝10.4，8Hz，H6)，3.46(1H，m，H1)，3.06(1H，d，J＝9.2Hz，H13)，2.52(1H，dt，J＝8.8，13.6Hz，H12)，1.48-1.62(2H，m，H2)，1.65，1.32(各3H，s，缩丙酮的两个甲基氢)，1.15(6H，s，C4的两个甲基氢)。
实施例2 当R1＝H，R2，R3＝异丙叉基时，通式2所示的冬凌草甲素衍生物的制备方法同实施例1。
实施例3 当R1＝乙酰基、R2＝H时，通式1所示的冬凌草甲素衍生物的制备：
在50ml的单口烧瓶中加入实施例1所制备的化合物300mg(0.74mmol)，溶于3ml醋酸酐和6ml吡啶中，搅拌反应10小时；加入饱和NaHCO3溶液搅拌，直到无气泡放出为止；用乙酸乙酯萃取3次，将有机层用水反复洗涤，再用无水NaSO4干燥；减压蒸干至浆状，最后用甲醇-水(1∶1)重结晶，得棱柱状晶体260mg，产率78.5％，mp：193-195℃。
元素分析：计算值：C：65.92，H：7.74；实测值：C：66.18，H：7.46。
光谱数据：IRv(cm-1)：3393，1743，1708，1641，1083，1069，965，913。1H-NMR(CDCl3)δppm：6.16，5.56(各1H，s，H17)，5.80(1H，d，J＝9.2Hz，C6-OH)，4.76(1H，d，J＝1.2Hz，H14)，4.61(1H，dd，J＝5.6，11.2Hz，H1)，4.22，4.16(各1H，d，J＝10Hz，OCH2)，3.92(1H，t，J＝9.0Hz，H6)，3.05(1H，d，J＝9.2Hz，H13)，2.47(1H，m，H12)，1.98(3H，s，乙酰基的甲基氢)，1.65，1.34(各3H，s，缩丙酮的两个甲基氢)，1.18，1.17(各3H，s，C4的两个甲基氢)。
实施例4 当R1＝乙酰基，R2，R3＝异丙叉基时，通式2所示冬凌草甲素衍生物的制备方法同实施例3。
实施例5 当R1＝H、R2＝葡萄糖基时，通式1所示的冬凌草甲素衍生物的制备：
在装有回流冷凝管、恒压漏斗的100ml三口烧瓶中加入实施例3中所制备的化合物100mg(0.25mmol)，溶于20ml无水氯仿，再加入适量无水硫酸钙；电磁搅拌0.5小时，每隔1小时分三次加入2.5g活性Ag2CO3-硅藻土(1∶1)，滴加四乙酰溴代葡萄糖的氯仿溶液30ml，反应3小时结束；过滤，蒸干，硅胶柱层析分离得1-乙酰-6-O-糖苷化化合物220mg。然后，在50ml的单口烧瓶中加入这种糖苷化化合物500mg(0.51mol)，溶于25ml甲醇中，加入7ml氨水，室温电磁搅拌反应24小时；真空蒸干得淡黄色浆状物，色谱分离，用丙酮重结晶得6-O-糖苷化化合物220mg，产率70％，mp：181-183℃。
元素分析(％)：计算值：C：59.58，H：7.59；实测值：C：59.89，H：7.57。
光谱数据：IRv(cm-1)：3468，2945，1737，1703，1651，1370，1056，1039，910。1H-NMR(CD3COCD3)δppm：5.95，5.46(各1H，s，H17)，5.02(1H，d，J＝8Hz，H1)，4.91(1H，s，H14)，4.32(2H，m，H20，H6)，4.00(1H，d，J＝10Hz，H20)，3.91(1H，dd，J＝11.2，2.4Hz，H6)，3.71(1H，dd，J＝11.2，5.2Hz，H6)，3.50(1H，dd，J＝11.5，5.2Hz，H1)，3.41-3.20(4H，m，H3，H4，H5，H2)，2.96(1H，d，J＝8.8Hz，H13)，2.54(1H，m，H12)，1.62，1.26(各3H，s，缩丙酮的两个甲基氢)，1.20，1.16(各3H，s，C4的两个甲基氢)。
Claims (3)
1、冬凌草甲素衍生物，其特征以下面通式表示：
或
通式1 通式2
在通式1中：R1为H或C1～C12的烷基或酰基，或为葡萄糖基、或半乳糖基、或木糖基，R2为H或葡萄糖基、或半乳糖基、或木糖基，或甘露糖基；
在通式2中：R1为H或C1～C12的烷基或酰基；R2，R3分别为C2～C18的烷基，或为异丙叉基、苯甲叉基。
2、一种制备如权利要求1所述通式1所示化合物的方法，其特征在于：
a、将冬凌草甲素在无水硫酸酮的存在下与丙酮反应，再用选择性酰化试剂进行选择性酰化即可得到式3所示的C1-OH不被保护的化合物；或将冬凌草甲素在无水硫酸酮的存在下与丙酮反应后，再用Ac2O-吡啶酰化得到式4所示的C6-OH不被保护的化合物；
式3 式4
b、将式3或式4所示的化合物在相转移催化剂的存在下与四乙酰化或三乙酰化溴代糖进行反应，然后再用温和的脱保护方法将糖的保护基脱除即得到通式1所示的化合物。
3、一种制备如权利要求1所述通式2所示化合物的方法，其特征在于：将冬凌草甲素用选择性醚化试剂Bu2SnO/RX首先进行选择性醚化或在酸的存在下与丙酮或苯甲醛反应，再用酰化试剂与其反应即可得到通式2所示的化合物。
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2008022505A1 (fr) * | 2006-08-18 | 2008-02-28 | Rui Jin Hospital Affiliated To Shanghai Jiao Tong University School Of Medicine | Utilisation de rubescensine a et de ses dérivés en pharmacie |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1329083C (zh) * | 2004-03-11 | 2007-08-01 | 上海第二医科大学附属瑞金医院 | 一种降解aml1－eto融合蛋白的方法及所用试剂 |
| CN101003528B (zh) * | 2006-01-18 | 2010-05-26 | 郑州大学 | 对映贝壳杉烯类二萜化合物及其衍生物、其制备方法和用途 |
| CN102850369B (zh) * | 2011-06-29 | 2014-12-17 | 中国药科大学 | 一氧化氮供体型冬凌草甲素14位羟基修饰衍生物、其制备方法及用途 |
| CN102847166B (zh) * | 2012-10-11 | 2014-04-09 | 山东大学 | 一种聚乙二醇为载体的冬凌草甲素的前药及其制备方法 |
| CA2911620C (en) | 2013-04-05 | 2022-03-08 | The Board Of Regents Of The University Of Texas System | Oridonin analogs, compositions, and methods related thereto |
| CN103896958B (zh) * | 2014-04-22 | 2016-08-24 | 中国药科大学 | 冬凌草甲素及其ent-6,7-开环贝壳杉烯型衍生物在制备抗结核药物方面的用途 |
| CN104327089A (zh) * | 2014-10-16 | 2015-02-04 | 深圳市健元医药科技有限公司 | 水溶性冬凌草甲素衍生物及其制备方法 |
| CN108864132B (zh) * | 2018-08-09 | 2020-06-02 | 上海寰竞商务咨询有限公司 | 一类冬凌草甲素衍生物及其制备方法和用途 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2008022505A1 (fr) * | 2006-08-18 | 2008-02-28 | Rui Jin Hospital Affiliated To Shanghai Jiao Tong University School Of Medicine | Utilisation de rubescensine a et de ses dérivés en pharmacie |
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