CN104513224B - 具有抗肿瘤活性的金刚烷型间苯三酚类化合物及其药用组合物 - Google Patents
具有抗肿瘤活性的金刚烷型间苯三酚类化合物及其药用组合物 Download PDFInfo
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- CN104513224B CN104513224B CN201510012264.3A CN201510012264A CN104513224B CN 104513224 B CN104513224 B CN 104513224B CN 201510012264 A CN201510012264 A CN 201510012264A CN 104513224 B CN104513224 B CN 104513224B
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- acid
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- diamantane
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- phloroglucinol
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Abstract
提供骈五元碳环的金刚烷型间苯三酚类化合物Rxc‑189或其药用盐，以其为有效成分和至少一种药学上可接受的载体组成的药物组合物，其制备方法，以及其在制备抗肿瘤药物中的应用。化合物Rxc‑189为骈五元碳环的金刚烷型间苯三酚类化合物，具有显著的体外细胞毒活性，化学结构新颖，活性强，作为抗肿瘤药物有较多优势。
Description
技术领域：
本发明属于药物技术领域，具体地说，涉及具有抗肿瘤活性的金刚烷型间苯三酚类活性化合物Rxc-189及其制备方法，以该化合物为活性成分的药物组合物，以及其在治疗肿瘤疾病中的应用。
背景技术：
金丝桃属(Hypericum)是藤黄科(Guttiferae)的一个大属，全世界约400种，除南北两极地或荒漠地及大部分热带低地外世界广布。我国约有55种8亚种，几产于全国各地，但主要集中在西南地区，其中云南约产27种4亚种，四川约产25种3亚种，贵州约产19种1亚种；有10余种为广布种。中国特有种类有32种，其中的19种分布于云南。除了用于观赏，金丝桃属植物具有抗抑郁、抗病毒、抗菌和抗肿瘤等多种药理活性。该属植物在国内外民间被广泛作为药用具有悠久的历史，国产金丝桃属植物有25种被民间作药用。其长期的民间药用基础，使得各国学者对该属植物展开了大量的研究工作，尤其是在药学研究方面。先后从不同的金丝桃属植物中发现了如金丝桃素类、槲皮苷、金丝桃苷、芦丁、黄烷酮醇类、黄酮类、酮类、香豆素类和间苯三酚衍生物(贯叶金丝桃素)等活性成分。其中间苯三酚类化合物结构类型十分丰富且多变，且多有全新骨架类型的化合物报道。但迄今为止，现有技术中尚未见有骈五元碳环的金刚烷型间苯三酚类化合物Rxc-189及其的生物活性的报道。
发明内容：
本发明的目的在于提供从近无柄金丝桃(Hypericum subsessile N.Robson)中分离得到的一类骈五元碳环金刚烷型间苯三酚类化合物，以其为有效成分的药物组合物，其制备方法，在制备药物中特别是在制备抗肿瘤药物中的应用。
为了实现本发明的上述目的，本发明提供了如下的技术方案：
下述结构式所示的骈五元碳环的金刚烷型间苯三酚类化合物Rxc-189或其药用盐，
如所述的药用盐，是指药学上可接受的盐，包括与有机酸或无机酸形成的盐，所述的有机酸为酒石酸、柠檬酸、甲酸、乙酸、乙二酸、丁酸、草酸、马来酸、琥珀酸、己二酸、藻酸、柠檬酸、天冬氨酸、苯苯磺酸、樟脑酸、樟脑磺酸、二葡糖酸、环戊烷丙酸、十二烷基硫酸、乙磺酸、葡庚糖酸、甘油磷酸、半硫酸、庚酸、己酸、延胡索酸、2‐羟基乙磺酸、乳酸、马来酸、甲磺酸、烟酸、2‐萘磺酸、扑酸、果胶酯酸、3‐苯基丙酸、苦味酸、新戊酸、丙酸、琥珀酸、酒石酸、硫代氰酸、对‐甲苯磺酸盐和十一烷酸盐，所述的无机酸为盐酸、氢溴酸、氢碘酸、硫酸或磷酸。
抗肿瘤的药物组合物，其包含所述的金刚烷型间苯三酚类化合物和至少一种药学上可接受的载体。
所述的金刚烷型间苯三酚类化合物在制备抗肿瘤的药物中的应用。
所述的金刚烷型间苯三酚类化合物的制备方法，取近无柄金丝桃地上部分，干燥，粉碎后用100％甲醇，每次50L，室温下冷浸三次，每次2天；提取液浓缩后浸膏用硅胶100-200目拌样过硅胶柱，分别以氯仿和乙酸乙酯洗脱，得氯仿部分，用聚酰胺粉80-100目拌样上MCI柱，以甲醇/水为流动相洗脱，以TLC进行检测，合并相同组分，得到5个组分A-E，其中组分C再过硅胶柱后得到组分C1-C7，C4组分经过HPLC分离纯化得到化合物Rxc-189。
本发明的骈五元碳环的金刚烷型间苯三酚类化合物Rxc-189及其药物组合物可以是任何合适形式，例如固体，半固体，液体或气溶胶形式。一般情况下，药物含有本发明的化合物或提取物作为活性成分，与适合外部，肠道，或肠胃外给药的有机或无机载体或赋形剂混合。活性成分可以是复方的，例如，与常规无毒药学可接受载体和/或赋形剂制成片剂、小药丸、胶囊、栓剂、阴道栓、溶液、乳液、混悬液和适合使用的其他形式。在组合物中使用的药学可接受载体包括，例如，水、葡萄糖、乳糖、阿拉伯胶、明胶、甘露糖醇、淀粉、三硅酸镁、滑石、玉米淀粉、角蛋白、胶态二氧化硅、马铃薯淀粉，和适合在制备固体、半固体、液体或气溶胶形式的制剂中使用的其他载体。组合物可以另外含有稳定剂，增稠剂，和/或着色剂和香料。
本发明的骈五元碳环的金刚烷型间苯三酚类化合物Rxc-189及其药学上可接受的盐及配糖体可经口或不经过口给药，给药量因药物不同而各有不同，对成人来说，每天1‐100mg较合适。
经口服给药时，首先使化合物与常规的药用辅剂如赋形剂、崩解剂、黏合剂、润滑剂、抗氧化剂、包衣剂、着色剂、芳香剂、表面活性剂等混合，将其制成颗粒剂、胶囊、片剂等形式给药；非经口给药时可以注射液、输液剂或栓剂等形式给药。制备上述制剂时，可使用常规的制剂技术。
附图说明：
图1为本发明化合物Rxc-189的立体构型；
图2为本发明流式细胞仪检测细胞周期图，Rxc-189引起HeLa细胞G2/M周期阻滞。
具体实施方式：
下面结合附图，用本发明的实施例来进一步说明本发明的实质性内容，但并不以此来限定本发明。
实施例1：
1、化合物Rxc-189的制备：
分离流程：干燥近无柄金丝桃地上部分19kg，粉碎后用100％甲醇(每次50L)室温下冷浸三次，每次2天。提取液浓缩后(浸膏约2.7kg)用硅胶(100-200目，约7kg)拌样过硅胶柱，分别以氯仿和乙酸乙酯洗脱，得氯仿部分共439g，用聚酰胺粉(80-100目)拌样上MCI柱，以甲醇/水为流动相洗脱，以TLC进行检测，合并相同组分，得到5个组分A-E，其中组分C再过硅胶柱后得到组分C1-C7，C4组分经过HPLC分离纯化得到化合物Rxc-189(12mg)。
Rxc-189结构解析：
化合物Rxc-189，无色块状晶体，m.p.95.4-98.6℃，(c 0.09,MeOH)。ESI-MS谱给出准分子离子峰为m/z 641[M+Na]+，结合高分辨正离子HR-ESI-MS(m/z[M+Na]+641.3458,calcd for 641.3454)和13C NMR、DEPT谱提供的信息，确定其分子式为C38H50O7，不饱和度为14。UV光谱在203(1.28),248(0.88)nm处有吸收，说明分子中存在共轭苯基。IR光谱显示存在羟基(3433cm-1，br)和羰基(1731and 1698cm-1)等基团。分析1H和13C NMR谱，再结合HSQC谱表明化合物Rxc-189中含有38个碳信号，其中包括9个甲基，5个亚甲基，11个次甲基；13个季碳(包括6个不饱和季碳)。
通过上述波谱数据的分析，化合物Rxc‐189的结构得到确定。最后，通过X‐单晶衍射分析进一步证实了以上分析，并确定了其立体构型(图1)，表‐1为Rxc-189的NMR波谱数据(CH3OH)。
表‐1.Rxc-189的NMR波谱数据(CH3OH)
2、采用MTT还原法验证Rxc-189的抗肿瘤活性
取对数生长期人癌细胞株(HepG2肝癌细胞、Eca109食道癌细胞株、HeLa宫颈癌细胞、A549非小细胞肺癌细胞)，采用含10％小牛血清的DMEM培养液培养，以1×106/mL接种于96孔板中，接种体积为100μL，置37℃、5％CO2孵箱中培养24h；分别设细胞对照组和8个浓度的实验组(100、50、25、12.5、6.25、3.125、1.6和0.8μg/mL)，每组3个复孔；培养24h后吸取培养液，实验组加入含不同浓度异Rxc-189的培养液100μL，细胞对照组加等体积培养液；置37℃、5％CO2孵箱中培养72h，加入MTT的磷酸缓冲液(5mg/mL)10μL/孔，继续培养4h，吸弃上清液，加DMSO 100μL/孔，轻微震荡10min，用酶标仪于检测波长540nm测定吸光度(OD)值，计算细胞IC50。检测结果见表2所示。
表2、Rxc-189抑制多种肿瘤细胞生长的IC50值(μM)
| 化合物 | HepG2 | Eca109 | HeLa | A549 |
| Rxc-189 | 1.58 | 0.07 | 3.54 | 7.52 |
| 依托泊苷 | >20 | 8.04 | 21.02 | >20 |
| 紫杉醇 | 0.84 | 0.61 | 0.69 | >20 |
由表1、表2可见：Rxc-189对HepG2肝癌细胞、、Eca109食道癌细胞株、HeLa宫颈癌细胞、A549非小细胞肺癌细胞的生长均具有明显抑制作用，强于阳性对照药依托泊苷，与紫杉醇抗肿瘤活性相当，可望作为活性成分用于制备抗肿瘤药物制剂，具有药用前景。
3、采用流式细胞术检测Rxc-189阻滞细胞周期的活性：
取对数生长期人癌细胞株HeLa宫颈癌细胞，采用含10％小牛血清的DMEM培养液培养，以1×106/mL接种于6孔板中，接种体积为2mL，置37℃、5％CO2孵箱中培养24h；每孔分别加入10、20、30μM化合物Rx-189继续培养24小时；胰酶消化后用4℃ 70％乙醇固定过夜；经PBS漂洗后，用5ug/mL碘化丙啶染色后用流式细胞仪检测细胞周期，其结果如图2所示。
图2为Rxc-189引起HeLa细胞G2/M周期阻滞。如图所示，随浓度增加，Rxc-189可将HeLa细胞G2/M周期从正常的31.7％增加到44.1％(20uM)和50.9％(30uM)。表明Rxc-189可有效诱导G2/M期的细胞周期阻滞，显示其可作为抗肿瘤化合物的潜力。
制剂实施例1：
按实施例1的方法先制得本发明的化合物Rxc-189，以及利用有机酸(酒石酸，柠檬酸，甲酸，乙二酸等)或无机酸(盐酸，硫酸，磷酸等)制成的盐，按常规加注射用水，精滤，灌封灭菌制成注射液。
制剂实施例2：
按实施例1的方法先制得本发明的化合物Rxc-189，以及利用有机酸(酒石酸，柠檬酸，甲酸，乙二酸等)或无机酸(盐酸，硫酸，磷酸等)制成的盐,将其溶于无菌注射用水中，搅拌使溶，用无菌抽滤漏斗过滤，再无菌精滤，分装于2安瓿中，低温冷冻干燥后无菌熔封得粉针剂。
制剂实施例3：
按实施例1的方法先制得本发明的化合物Rxc-189，以及利用有机酸(酒石酸，柠檬酸，甲酸，乙二酸等)或无机酸(盐酸，硫酸，磷酸等)制成的盐，与赋形剂重量比为9:1的比例加入赋形剂，制成粉剂。
制剂实施例4：
按实施例1的方法先制得本发明的化合物Rxc-189，以及利用有机酸(酒石酸，柠檬酸，甲酸，乙二酸等)或无机酸(盐酸，硫酸，磷酸等)制成的盐，按其与赋形剂重量比为1:5‐1:10的比例加入赋形剂，制粒压片。
制剂实施例5：
按实施例1的方法先制得本发明的化合物Rxc-189，以及利用有机酸(酒石酸，柠檬酸，甲酸，乙二酸等)或无机酸(盐酸，硫酸，磷酸等)制成的盐，按常规口服液制法制成口服液。
制剂实施例6：
按实施例1的方法先制得本发明的化合物Rxc-189，以及利用有机酸(酒石酸，柠檬酸，甲酸，乙二酸等)或无机酸(盐酸，硫酸，磷酸等)制成的盐，按其与赋形剂重量比为5:1的比例加入赋形剂，制成胶囊或颗粒剂或冲剂。
Claims (4)
1.下述结构式所示的骈五元碳环的金刚烷型间苯三酚类化合物Rxc-189，
2.抗肿瘤的药物组合物，其包含权利要求1所述的金刚烷型间苯三酚类化合物和至少一种药学上可接受的载体。
3.权利要求1所述的金刚烷型间苯三酚类化合物在制备抗肿瘤的药物中的应用。
4.权利要求1所述的金刚烷型间苯三酚类化合物的制备方法，其特征在于取近无柄金丝桃地上部分，干燥，粉碎后用100％甲醇，每次50L，室温下冷浸三次，每次2天；提取液浓缩后浸膏用硅胶100-200目拌样过硅胶柱，分别以氯仿和乙酸乙酯洗脱，得氯仿部分，用聚酰胺粉80-100目拌样上MCI柱，以甲醇/水为流动相洗脱，以TLC进行检测，合并相同组分，得到5个组分A-E，其中组分C再过硅胶柱后得到组分C1-C7，C4组分经过HPLC分离纯化得到化合物Rxc-189。
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