CN101434525B - 4-(4-羟基-3-甲氧基苯甲基)姜黄素及其用于制备抗肿瘤药物的应用 - Google Patents
4-(4-羟基-3-甲氧基苯甲基)姜黄素及其用于制备抗肿瘤药物的应用 Download PDFInfo
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Abstract
本发明涉及合成抗肿瘤药物，具体涉及合成4-(4-羟基-3-甲氧基苯甲基)姜黄素及其用于制备抗肿瘤药物的应用。该化合物由2，4-戊二酮与香草醛先经Knovenagel缩合后，催化氢化后得到3-(4-羟基-3-甲氧基苯甲基)-2，4-戊二酮，3-(4-羟基-3-甲氧基苯甲基)-2，4-戊二酮再与香草醛经羟醛缩合制得4-(4-羟基-3-甲氧基苯甲基)姜黄素。该化合物用于制备治疗白血病、皮肤癌、胃癌、结肠癌、肝癌、乳腺癌、***癌或其他恶性肿瘤的药物。
Description
技术领域
本发明涉及合成抗肿瘤药物，具体涉及合成4-(4-羟基-3-甲氧基苯甲基)姜黄素及其用于制备抗肿瘤药物的应用。
背景技术
姜黄素在印度、中国、日本、韩国等地有上千年的食用和药用记载。目前国内外研究发现姜黄素具有抗肿瘤、抗炎、抗血管生成、抗氧化和神经保护等多种活性。但是姜黄素水溶性差，其水溶液不稳定，尤其在中性至碱性pH值条件下更不稳定，姜黄素口服后在体内代谢快，生物利用度低，血药浓度较低，已成为限制其临床应用的主要因素。通过结构改造合成姜黄素衍生物，增强活性、水溶性有重要意义。目前姜黄素类似物抗肿瘤方面研究主要集中在抑制NF-κB和AP-1因子，抗血管生成活性和抗雄激素的体外研究，姜黄素类似物抗肿瘤方面国外专利授权的有：Vander Jagt等用对NF-κB和AP-1因子抑制，筛选抗肿瘤活性姜黄素类似物(US20070060644)，Lee等的雄激素受体拮抗剂(US006790979)，Snyder等的抗肿瘤和抗血管生成活性姜黄素类似物(US006664272)。
国内外对姜黄素的结构改造路线主要有：改变苯环上取代基种类和位置、β-二酮缩合或为单酮、改变中间不饱和共扼连接链、还原不饱和双键、4位活泼亚甲基取代等，对活性研究仍处于体外实验阶段。
本发明通过在姜黄素母体4位引入活性结构单元3，4-二取代苯甲基合成新的姜黄素类似物，并评价其抗肿瘤活性。
发明内容
本发明的目的之一在于提供4-(4-羟基-3-甲氧基苯甲基)姜黄素，其结构式为：
本发明目的之二在于提供4-(4-羟基-3-甲氧基苯甲基)姜黄素的制备方法。本发明化合物4-(4-羟基-3-甲氧基苯甲基)姜黄素可由2，4-戊二酮与香草醛先经Knovenagel缩合后得到3-(4-羟基-3-甲氧基苯亚甲基)-2，4-戊二酮(中间体A)，催化氢化3-(4-羟基-3-甲氧基苯亚甲基)-2，4-戊二酮后得到3-(4-羟基-3-甲氧基苯甲基)-2，4-戊二酮(中间体B)，3-(4-羟基-3-甲氧基苯甲基)-2，4-戊二酮再与香草醛经羟醛缩合制得4-(4-羟基-3-甲氧基苯甲基)姜黄素。其反应示意式如下所示：
本发明目的之三在于提供4-(4-羟基-3-甲氧基苯甲基)姜黄素用于制备抗肿瘤药物的应用。
4-(4-羟基-3-甲氧基苯甲基)姜黄素，可用于但不局限于制备治疗白血病、皮肤癌、胃癌、结肠癌、肝癌、乳腺癌或***癌药物。
4-(4-羟基-3-甲氧基苯甲基)姜黄素能够显著抑制多种人肿瘤细胞的增殖。根据表二可以看到，该化合物对本实验中的七种细胞株都表现出比母体姜黄素更强的抑制作用，尤其是K562、B16这二株细胞株，该化合物对它们的增殖抑制作用明显比姜黄素的好，其半数抑制浓度约为姜黄素的1/4和1/7。以上结果表明4-(4-羟基-3-甲氧基苯甲基)姜黄素体外肿瘤细胞增殖抑制作用比其母体姜黄素的抑制作用强。
具体实施方式
实施例1 4-(4-羟基-3-甲氧基苯甲基)姜黄素的合成。
合成原料3-羟基-4-甲氧基苯甲醛(香草醛)、2，4-戊二酮、三氧化二硼、硼酸三正丁酯、正丁胺、哌啶均为国药集团化学试剂有限公司。催化氢化装置(美国Parr 1100)，核磁共振波谱仪(Unity 500，美国Varian公司，500MHz)，离子阱质谱仪(DECAX-30000，美国Thermo Finnigan公司)；显微熔点仪(X-4，上海精密仪器厂)。
250ml单口烧瓶中加入2，4-戊二酮10g(0.1mol)，乙醇100ml，加入催化量哌啶，香草醛15g(0.1mol)，室温下搅拌反应48小时，浓缩移去溶剂，重结晶得浅黄色粉末中间体A12.0g。
250ml催化氢化反应瓶中加入丙酮100ml，中间体A10g，10％钯碳1g，25PSI下加压催化氢化反应1小时，反应液过滤，滤液浓缩后重结晶得浅棕色油状固体中间体B8.8g。
中间体B2.36g(10mmol)与三氧化二硼0.49g(7mmol)溶于乙酸乙酯10ml中，40℃搅拌反应0.5小时；加入香草醛3.04g(20mmol)、，硼酸三正丁酯11ml(40.5mmol)，室温下搅拌反应0.5小时，滴入正丁胺0.2ml(2mmol)与乙酸乙酯10ml的混合液，0.5小时滴加完，室温下搅拌反应48小时，加入0.5M盐酸15ml，升温至60℃反应1小时，反应液用乙酸乙酯萃取，饱和食盐水洗，无水硫酸镁干燥，浓缩后用乙醇重结晶，得桔红色粉末2.50克(产率50％)。mp203-205℃，分子式C29H28O8，1H NMR(DMSO)δ(ppm)3.69(s，3H)，3.79(s，3H)，3.82(s，3H)，3.99(s，2H)，6.78(d，2H，J＝7.5Hz)，6.60-7.27(m，9H)，7.58(d，2H，J＝15.0Hz)，17.9(s，1H)；ESI-MS(M-H)503.5。
实施例2 4-(4-羟基-3-甲氧基苯甲基)姜黄素抑制肿瘤细胞K562，HL-60，B-16，SW480，HepG2，MGC80-3，SH-SY5Y的体外生长活性：
2.1.细胞系
K562：人类慢性粒细胞白血病急变细胞系
HL-60：人类急性髓系白血病细胞系
B16：小鼠黑色素瘤B16细胞株。
SW480：人结肠癌细胞
HepG2：人肝肿瘤细胞
MGC80-3：人胃癌细胞
SH-SY5Y：人神经母细胞瘤细胞
以上细胞均来源于中科院上海细胞库。
2.2细胞培养
细胞培养液配方见表1，细胞在37℃，5％CO2孵育箱中培养，取对数生长期细胞用于增殖、凋亡实验。
表1培养液配方
细胞株 培养液
K562 RPM11640培养液+10％小牛血清
HL60 RPM11640培养液+10％小牛血清
B16 RPM11640培养液+10％小牛血清
SW480 DMEM+10％胎牛血清
HepG2 RPM11640培养液+10％小牛血清
MGC80-3 RPM11640培养液+10％小牛血清
SH-SY5Y RPM11640培养液+10％小牛血清
2.3 MTT法观察4-(4-羟基-3-甲氧基苯甲基)姜黄素对细胞增殖的抑制作用
将处于对数生长期的细胞，按密度为悬浮细胞50000个/孔、贴壁细胞8000～12000个/孔接种于96孔板里。实验组(贴壁细胞待贴壁后)分别加入不同浓度的4-(4-羟基-3-甲氧基苯甲基)姜黄素和姜黄素，对照组不加药，另设空白组(只加培养基，无细胞)，每组设三个平行孔，37℃培养48h，加入5mg/ml的MTT溶液20ul/孔，继续培养4h后，离心弃上清，加入DMSO150ul，振荡10min，充***解后，用全自动酶标仪(美国BIO-RAD公司生产)检测570nm处的吸光度(OD570)值。根据吸光度计算细胞生长抑制率。
细胞生长抑制率＝[对照孔OD值-实验孔OD值]/[对照孔OD值-空白孔OD值]×100％
以同一药物的不同浓度对肿瘤细胞生长抑制率作图，可得到剂量反应曲线，根据线性回归方程求出该药物的半数抑制浓度IC50，即细胞存活率减少50％时的药物浓度。
2.4结果
4-(4-羟基-3-甲氧基苯甲基)姜黄素能够显著抑制多种人肿瘤细胞的增殖，根据表2，我们可以看到，该化合物对本实验中的七种细胞株都表现出比母体姜黄素更强的抑制作用，尤其是K562、B16这二株细胞株，该化合物对它们的增殖抑制作用明显比姜黄素的好，其半数抑制浓度约为姜黄素的1/4和1/7。以上结果表明4-(4-羟基-3-甲氧基苯甲基)姜黄素体外肿瘤细胞增殖抑制作用比其母体姜黄素的抑制作用强。
表2
4-(4-羟基-3-甲氧基苯甲基)姜黄素和姜黄素对体外培养细胞的增殖抑制作用
Claims (4)
1.4-(4-羟基-3-甲氧基苯甲基)姜黄素，其结构式为：
2.一种权利要求1所述的4-(4-羟基-3-甲氧基苯甲基)姜黄素的制备方法，包括如下步骤：由2，4-戊二酮与香草醛先经Knovenagel缩合后得到3-(4-羟基-3-甲氧基苯亚甲基)-2，4-戊二酮，催化氢化3-(4-羟基-3-甲氧基苯亚甲基)-2，4-戊二酮后得到3-(4-羟基-3-甲氧基苯甲基)-2，4-戊二酮，3-(4-羟基-3-甲氧基苯甲基)-2，4-戊二酮再与香草醛经羟醛缩合制得4-(4-羟基-3-甲氧基苯甲基)姜黄素。
3.权利要求1所述的4-(4-羟基-3-甲氧基苯甲基)姜黄素用于制备抗肿瘤药物的应用。
4.如权利要求3所述的4-(4-羟基-3-甲氧基苯甲基)姜黄素用于制备抗肿瘤药物的应用，其特征在于：所述的抗肿瘤药物为治疗白血病、皮肤癌、胃癌、结肠癌、肝癌的药物。
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| CN101570496B (zh) * | 2009-06-12 | 2012-08-15 | 乐山师范学院 | 姜黄素-4-含氮类衍生物及其制备方法和用途 |
| CN104030904B (zh) * | 2014-03-07 | 2017-01-18 | 福建医科大学 | 4‑芳甲基姜黄素类似物作为Hsp90抑制剂的应用 |
| US9402834B2 (en) | 2014-10-21 | 2016-08-02 | Ions Pharmaceutical S.À R.L. | Human therapeutic agents |
| US9907786B2 (en) | 2014-10-21 | 2018-03-06 | Ions Pharmaceutical S.À R.L. | Therapeutic compositions containing harmine and isovanillin components, and methods of use thereof |
| US10092550B2 (en) | 2014-10-21 | 2018-10-09 | Ions Pharmaceutical S.À R.L. | Therapeutic compositions containing curcumin, harmine, and isovanillin components, and methods of use thereof |
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| US6664272B2 (en) * | 1999-12-03 | 2003-12-16 | Emory University | Curcumin analogs with anti-tumor and anti-angiogenic properties |
| US6790979B2 (en) * | 2002-04-17 | 2004-09-14 | University Of North Carolina At Chapel Hill | Curcumin analogues and uses thereof |
| CN101003470A (zh) * | 2007-01-22 | 2007-07-25 | 温州医学院生物与天然药物开发中心有限公司 | 姜黄素单羰基结构类似物及其用途 |
| CN101076336A (zh) * | 2004-10-15 | 2007-11-21 | 北卡罗来纳查佩尔山大学 | 新的姜黄素类似物及其用途 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US6664272B2 (en) * | 1999-12-03 | 2003-12-16 | Emory University | Curcumin analogs with anti-tumor and anti-angiogenic properties |
| US6790979B2 (en) * | 2002-04-17 | 2004-09-14 | University Of North Carolina At Chapel Hill | Curcumin analogues and uses thereof |
| CN101076336A (zh) * | 2004-10-15 | 2007-11-21 | 北卡罗来纳查佩尔山大学 | 新的姜黄素类似物及其用途 |
| CN101003470A (zh) * | 2007-01-22 | 2007-07-25 | 温州医学院生物与天然药物开发中心有限公司 | 姜黄素单羰基结构类似物及其用途 |
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