CN1185244C - Rebescensine A derivatives and preparing process thereof - 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。
The present invention provides an oridonin derivative as shown in the following general formula by changing the tension and solubility of α-exocyclic methylene cyclopentanone without destroying the active center of oridonin. Material: This oridonin derivative has higher anti-tumor cell activity. At the same time, the present invention also provides a preparation method of the above compound.
Description
本发明涉及新的冬凌草甲素衍生物及其制备方法。The present invention relates to novel oridonin derivatives and a preparation method thereof.
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。Among the more than 100 diterpenoid components that have been isolated from the plant of the genus Camellia, more than 30 have certain antitumor activity. Among them, there are about 17 species with the oridonin (kaurene type) type, and among them, oridonin has the highest content in plants, and its activity research is also the most on oridonin. Oridonin is a diterpene compound with α-methylene cyclopentanone. Its anticancer activity is definite and has been extensively studied by domestic and foreign scholars, such as Zhang Tanmu Research Group of Henan Medical University (see: a, Wang Jinying, Lin Chen, Zhang Tanmu, Acta Chinese Pharmacology, 1985, 6, 195.; b, Wu Kongming, Zhang Tanmu, Wang Qingduan, Cancer Prevention and Treatment Research, 1994, 21(4), 208.), and Japanese scholar Fujita research group (see: Eiich Fujita , Yoshimitsu Nagao, Kimiyoshi Kaneko, Shozo Nakazawa, and Hiroyuki Kuroda, Chem.Pharm.Bull., 29, 3208 (1981)), have done a lot of pharmacological experiments to it, proving that oridonin has definite in vitro As well as the anti-tumor activity in the body, its anti-tumor spectrum is also relatively wide, such as human nasopharyngeal cancer cells, human liver cancer cells, human cervical cancer cells, esophageal cancer cells, etc., all have obvious killing effects. But their activities are not high, and their IC50 are greater than 1μg/ml. During the in vivo anti-Ehrlich ascites cancer research in mice, it was found that all compounds with α-ring exomethylene cyclopentanone units in the structure have anti-tumor activity, while compounds without this unit have no activity. Japanese scholar Fujita and others believe that the active center of this type of diterpenoids is α-exocyclic methylene cyclopentanone, and Japanese scholars have acylated the 14-position hydroxyl group. Among the acylated compounds, the acyl group at C16 The activity is the highest, and the activity in vivo is 30%-40% higher than that of oridonin. When summarizing the basis of previous work, we found that the antitumor activity of all these compounds was not high enough, and their use was limited due to their poor water solubility. Recently, Liu Chenjiang et al. (see: Liu Chenjiang, Zhao Zhihong, Chinese Journal of Pharmaceutical Sciences, 33, 577 (1998)) reviewed the research on Rubescens and Rubescensin in the past 30 years, and also affirmed Rubescensin A The exact anti-cancer efficacy and raised the existing questions. In conclusion, in order to develop oridonin into a new drug, it is necessary to improve its antitumor activity, reduce toxicity as much as possible and improve its solubility.
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。The purpose of the present invention is to provide a derivative of oridonin with higher antitumor activity by changing the tension and solubility of α-ring exomethylenecyclopentanone without destroying the active center of oridonin. material, and the preparation method of the compound is provided at the same time.
本发明是通过以下技术方案实现的。The present invention is achieved through the following technical solutions.
冬凌草甲素衍生物，其特征以下面通式表示：Oridonin A derivatives are characterized by the following general formula:
通式1 通式2General Formula 1 General Formula 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；In general formula 1: R 1 is H or C1-C12 alkyl or acyl, or glucosyl, or galactosyl, or xylosyl, R 2 is H or glucosyl, or galactosyl, or xylosyl Glycosyl, or Mannosyl;
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。In the general formula 2: R 1 is H or C1-C12 alkyl or acyl; R 2 and R 3 are respectively C2-C18 alkyl, or isopropylidene or benzylidene.
制备上述通式1所示化合物的方法是：The method for preparing compound shown in above-mentioned general formula 1 is:
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；a. Reaction of Rubescensin A with acetone in the presence of anhydrous ketone sulfate, and then selective acylation with a selective acylating agent to obtain the compound shown in formula 3 with unprotected Cl-OH; or After reacting Rubescensin A with acetone in the presence of anhydrous sulfuric acid ketone, and then acylation with Ac 2 O-pyridine to obtain the unprotected C6-OH compound shown in formula 4;
式3 式4Equation 3 Equation 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。b. React the compound shown in formula 3 or formula 4 with tetraacetylated or triacetylated bromosugar in the presence of a phase transfer catalyst, and then use a mild deprotection method to remove the protecting group of the sugar to obtain A compound represented by general formula 1.
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。The method for preparing the compound shown in the above general formula 2 is that Rubescensin A is first selectively etherified with a selective etherification reagent Bu 2 SnO/RX or reacted with acetone or benzaldehyde in the presence of an acid, and then The compound represented by general formula 2 can be obtained by reacting with an acylating reagent.
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。The compounds provided by the present invention are modified by acylation, etherification or glycosidation of the 1-, 6-, 7- and 14-position hydroxyl groups of Oridonin A without destroying the original basic skeleton. , especially by changing the tension and orientation of α-ring exomethylene cyclopentanone, it is found that the oridonin derivatives represented by the general formula 1 or 2 have higher antitumor activity. Therefore, compared with the prior art, Rubescensin A derivatives have very high anti-tumor cell activity, and the activity is generally 8-10 times higher than that of Rubescensin A. The inventor tested the anticancer activity of the compound provided by the present invention by using an in vitro activity assay method. Using oridonin as a positive control, it was found that the compound was effective against cancer cells such as human nasopharyngeal carcinoma, human cervical cancer, and esophageal cancer. The direct killing effect is 6-10 times higher than that of oridonin.
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：Example 1 When R 1 =R 2 =H, the preparation of oridonin derivatives represented by the general formula 1:
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℃。Add 5 grams of oridonin (0.0137mol) in a 250 milliliter single-necked flask equipped with a reflux condenser, dissolve it in 120 milliliters of acetone, add 2 grams of anhydrous copper sulfate, under argon protection, heat to 50 ° C, React for 1.5 hours, cool to room temperature, filter out copper sulfate, add dilute alkali solution, extract 3 times with CHCl 3 , then backwash 2 times with water, dry the organic layer with anhydrous Na 2 SO 4 , evaporate the solvent under reduced pressure , recrystallized from methanol to obtain 4.9 g of needle-like crystals, with a yield of 88.3%. mp: 219-221°C.
元素分析(％)：计算值：C：65.38，H：8.11；实测值：C：65.69，H：8.14。Elemental analysis (%): Calculated: C: 65.38, H: 8.11; Found: 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)。Spectral analysis: IRv (cm-1): 3314, 1710, 1648, 1451, 1381, 1080, 1067, 882; 1 H-NMR (CDCl 3 ) δppm: 6.14, 5.55 (each 1H, s, H17), 5.90 ( 1H, d, J=11Hz, C6-OH), 4.79 (1H, s, H14), 4.24, 4.04 (each 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 (each 3H, s, two methyl hydrogens of acetonide), 1.15 (6H, s, two methyl hydrogens of C4).
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。Example 2 When R 1 =H, R 2 , R 3 =isopropylidene, the preparation method of the oridonin derivative represented by the general formula 2 is the same as that of Example 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：Example 3 When R 1 ＝acetyl and R 2 ＝H, the preparation of oridonin derivatives represented by general formula 1:
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℃。Add 300 mg (0.74 mmol) of the compound prepared in Example 1 to a 50 ml single-necked flask, dissolve in 3 ml acetic anhydride and 6 ml pyridine, and stir for 10 hours; add saturated NaHCO solution and stir until no bubbles are emitted; Ethyl ester was extracted 3 times, the organic layer was washed repeatedly with water, and then dried with anhydrous NaSO 4 ; evaporated to dryness under reduced pressure, and finally recrystallized with methanol-water (1:1) to obtain 260 mg of prismatic crystals, the yield 78.5%, mp: 193-195°C.
元素分析：计算值：C：65.92，H：7.74；实测值：C：66.18，H：7.46。Elemental Analysis: Calculated: C: 65.92, H: 7.74; Found: 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)。Spectral data: IRv (cm-1): 3393, 1743, 1708, 1641, 1083, 1069, 965, 913. 1 H-NMR (CDCl 3 ) δppm: 6.16, 5.56 (each 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 (each 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, methyl hydrogen of acetyl group), 1.65, 1.34 (each 3H, s, two methyl hydrogens of acetonide base hydrogen), 1.18, 1.17 (each 3H, s, two methyl hydrogens of C4).
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。Example 4 When R 1 = acetyl group, R 2 , R 3 = isopropylidene group, the preparation method of the oridonin derivative shown in the general formula 2 is the same as that in Example 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：Example 5 When R 1 ＝H, R 2 ＝glucosyl, the preparation of Oridonin A derivative shown in the general formula 1:
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℃。Add compound 100mg (0.25mmol) prepared in embodiment 3 in the 100ml three-neck flask that reflux condenser, constant pressure funnel are housed, be dissolved in 20ml anhydrous chloroform, add appropriate amount of anhydrous calcium sulfate again; Electromagnetic stirring 0.5 hour, Add 2.5g of active Ag 2 CO 3 -diatomaceous earth (1:1) three times every 1 hour, add dropwise 30ml of a chloroform solution of tetraacetylbromoglucose, and react for 3 hours; filter, evaporate to dryness, and perform silica gel column chromatography 220 mg of 1-acetyl-6-O-glycosidated compound was isolated. Then, add 500 mg (0.51 mol) of this glycosidation compound in a 50 ml single-necked flask, dissolve in 25 ml of methanol, add 7 ml of ammonia, and react with electromagnetic stirring at room temperature for 24 hours; Recrystallization with acetone gave 220 mg of 6-O-glycosidated compound, yield 70%, mp: 181-183°C.
元素分析(％)：计算值：C：59.58，H：7.59；实测值：C：59.89，H：7.57。Elemental analysis (%): Calculated: C: 59.58, H: 7.59; Found: 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)。Spectral data: IRv (cm-1): 3468, 2945, 1737, 1703, 1651, 1370, 1056, 1039, 910. 1 H-NMR (CD3COCD3) δppm: 5.95, 5.46 (each 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 (each 3H, s, two methyl hydrogens of acetonide), 1.20, 1.16 (each 3H, s, two methyl hydrogens of C4).
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008022505A1 (en) * | 2006-08-18 | 2008-02-28 | Rui Jin Hospital Affiliated To Shanghai Jiao Tong University School Of Medicine | Use of rubescensine a and derivatives thereof in pharmacy |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1329083C (en) * | 2004-03-11 | 2007-08-01 | 上海第二医科大学附属瑞金医院 | Method for degrading AML 1-ETO fusion protein and used reagent |
| CN101003528B (en) | 2006-01-18 | 2010-05-26 | 郑州大学 | En-kaurene diterpenoids and derivatives thereof, preparation methods and uses thereof |
| CN102850369B (en) * | 2011-06-29 | 2014-12-17 | 中国药科大学 | Nitrogen monoxide donor-type oridonin 1,4-hydroxyl-modified derivative, and its preparation method and application |
| CN102847166B (en) * | 2012-10-11 | 2014-04-09 | 山东大学 | Prodrug of oridonin with polyethylene glycol serving as vector and preparation method thereof |
| WO2014165841A1 (en) | 2013-04-05 | 2014-10-09 | The Board Of Regents Of The University Of Texas System | Oridonin analogs, compositions, and methods related thereto |
| CN103896958B (en) * | 2014-04-22 | 2016-08-24 | 中国药科大学 | Oridonin and ent-6,7-open loop dammara ene-type derivative purposes in terms of preparing antituberculotic thereof |
| CN104327089A (en) * | 2014-10-16 | 2015-02-04 | 深圳市健元医药科技有限公司 | Water-soluble oridonin derivative and preparation method thereof |
| CN108864132B (en) * | 2018-08-09 | 2020-06-02 | 上海寰竞商务咨询有限公司 | Oridonin derivatives, and preparation method and application thereof |
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1999
- 1999-01-18 CN CNB991011791A patent/CN1185244C/en not_active Expired - Lifetime
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008022505A1 (en) * | 2006-08-18 | 2008-02-28 | Rui Jin Hospital Affiliated To Shanghai Jiao Tong University School Of Medicine | Use of rubescensine a and derivatives thereof in pharmacy |
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| Publication number | Publication date |
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| CN1255502A (en) | 2000-06-07 |
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