CN116693591A - 一个乌苏烷三萜咖啡酸酯化合物的制备与抗肿瘤应用 - Google Patents
一个乌苏烷三萜咖啡酸酯化合物的制备与抗肿瘤应用 Download PDFInfo
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Abstract
本发明涉及一个乌苏烷三萜咖啡酸酯化合物在制备抗肿瘤产品中的应用,属于中药、天然药物制药领域。以本发明乌苏烷三萜咖啡酸酯化合物为活性成分的抗肿瘤药物。
Description
技术领域:
本发明属于中药、天然药物制药领域,具体地,涉及以一个乌苏烷三萜咖啡酸酯化合物为活性成分的药物组合,及其在抗肿瘤剂中的应用。
技术背景:
三萜苯丙酸酸酯类化合物在植物界中分布广泛,主要分布于石松科石松属(Lycopodium),石杉科石杉属(Huperzia)、马尾杉属(Phlegmariurus),桦木科桦木属(Betula),兰科卷瓣兰属(Cirrhopetalum)、石仙桃属(Pholidota),夹竹桃科鸡蛋花属(Plumeria),菊科婆罗门参属(Tragopogon)等植物中(孙梦颖, 梁敬钰, 冯煦, 等. 三萜酚酸酯类化合物的研究进展[J]. 天然产物研究与开发, 2011, 23(2): 369-373)。迄今为止,未见山楂属(Crataegus)植物中三萜咖啡酸酯化合物类化合物的研究报道。
发明内容:
本发明旨在提供一个乌苏烷三萜咖啡酸酯化合物,以其为活性成分的药物组合物,他们的制备方法,以及它们在制备抗肿瘤剂中的应用。
本发明的上述目的是通过下面的技术方案得以实现的:
下述结构所示的乌苏烷三萜咖啡酸酯化合物,
。
化合物1的制备方法,取蔷薇科山楂属植物的枝叶、果实或全株,用有机溶剂氯仿或乙酸乙酯或丙酮或甲醇或乙醇或水直接冷浸或者热回流提取,或者先用上述有机溶剂或水冷浸或回流提取后再用乙酸乙酯萃取得到总浸膏,总浸膏经反复柱层析得到化合物1。
本发明化合物1的制备方法更具体地是用:
A:丙酮或甲醇或乙醇或水冷浸或热回流提取山楂属植物的果实或全株得到总浸膏,乙酸乙酯萃取得到乙酸乙酯浸膏,经反复柱层析可得到化合物1。
B:有机溶剂(如:氯仿、甲醇、乙醇、丙酮、二氯甲烷等)直接冷浸或热回流提取山楂属植物的果实或全株的粗粉得到总浸膏,总浸膏经反复柱层析可得到化合物1。
更具体地,化合物1的制备方法,是将山楂属植物的果实或全株阴干,粉碎到30目,用95%乙醇在室温条件下浸提3次,每次24 h,提取液合并,减压浓缩提取液得浸膏后用适量水混悬,再用乙酸乙酯分配数次,得乙酸乙酯萃取物,萃取物用适量氯仿∕丙酮溶解后用硅胶80-100目拌样,然后用200-300目硅胶进行柱层析划段粗分,以1 : 0-0 : 1氯仿∕丙酮或1 : 0-0 : 1氯仿∕甲醇进行梯度洗脱,得到8个主要部分,将9 : 1氯∕丙部分、8 : 2氯∕丙部分及7 : 3氯∕丙部分进行硅胶柱层析,以30 : 1-1 : 2石油醚∕丙酮进行梯度洗脱,得10个部分,再分别进行反复硅胶、MCI和Sephadex LH-20柱层析分别得化合物1。
抗肿瘤剂,含有化合物1和常规辅剂。
药物组合物,其中含有治疗有效量的化合物1和药学上可接受的载体。
化合物1在制备抗肿瘤剂中的应用。
所述的化合物在制备治疗肝癌、乳腺癌、宫颈癌、结肠癌的药物中的应用。
本发明用于抗肿瘤的药物组合物,其中含有化合物1和药学上可接受的载体。
本发明药物组合物中所述药学上可接受的载体是指药学领域常规的药物载体。本发明化合物可以组合物的形式通过口服、鼻吸入、直肠或肠胃外给药的方式施用于需要这种治疗的患者。用于口服时,可将其制成常规的固体制剂如片剂、粉剂、粒剂、胶囊等,制成液体制剂如油悬浮剂、糖浆、酏剂等;用于肠外给药时,可将其制成注射用的溶液等。优选的形式是片剂、胶囊和注射剂。
本发明药物组合物的各种剂型可以按照药学领域的常规生产方法制备。例如使活性成分与一种或多种载体混合,然后将其制成所需的剂型。
本发明的药物组合物优选含有重量比为0.1%-99.5%的活性成分,最优选含有重量比为0.5%-95%的活性成分。
本发明化合物的施用量可根据用药途径、患者的年龄、体重、所治疗的疾病的类型和严重程度等变化,其日剂量可以是0.01-10 mg/kg体重,优选0.1-5 mg/kg体重。可以一次或多次施用。
本发明的化合物显示出较好的肿瘤细胞毒活性。
本发明对化合物1进行了抗肿瘤细胞活性筛选,该类化合物显示较好的肿瘤细胞毒活性。在抗肿瘤活性应用中,化合物1是以如下的量施用于基材或一种群上,所述量的范围1-1000 µM,优选在10-200 µM,任选地与载体和/或媒体相结合。
具体实施方式:
下面用本发明的实施例来进一步说明本发明的实质性内容,可以使本专业人员更全面地理解本发明,但不以任何方式限制本发明。
实施例1:
本发明化合物1的提取、分离和纯化:
将滇西山楂的枝叶(10 kg)阴干,粉碎到30目,用95%乙醇在室温条件下浸提3次,每次50 L、24 h,提取液合并,减压浓缩提取液得浸膏(1.5 kg)。该浸膏用氯仿∕丙酮溶解后以适量80-100目硅胶吸附,然后用3.0 kg 200-300目硅胶进行柱层析划段粗分,以氯仿∕丙酮(1 : 0-0 : 1)进行梯度洗脱,得到8个主要部分,将8 : 2氯∕丙部分进行硅胶柱层析,以10 : 1-1 : 2石油醚∕丙酮进行梯度洗脱,得8个部分。其中第三洗脱部分进行反复硅胶(CHCl3/MeOH,80:1)和Sephadex LH-20 (CHCl3/MeOH,1:1)柱层析得化合物1。
实施例2:
本发明化合物1的物理和波谱数据:
化合物1:白色粉末。UV (MeOH),λ max/nm (log ε): 203 (4.40), 217 (4.36),243 (4.20), 296 (4.31), 328 (4.43)。MS, found m/z 619.4015 [M-H]-; calculatedfor C39H55O6 -, 619.4004。1H-NMR (400 MHz, CD3COCD3) δ: 7.55 (1H, d, J = 15.9 Hz,H-7'), 7.16 (1H, d, J = 2.1 Hz, H-2'), 7.05 (1H, dd, J = 8.2, 2.1 Hz, H-6'),6.87 (1H, d, J = 8.2 Hz, H-5'), 6.32 (1H, d, J = 15.9 Hz, H-8'), 5.16 (t, J =3.6 Hz, H-12), 4.64 (1H, d, J = 9.8 Hz, H-3), 3.87 (1H, brs, H-2), 3.55 (1H,d, J = 10.6 Hz, H-28a), 3.06 (1H, d, J = 10.6 Hz, H-28b), 2.04 (1H, overlap,H-1a), 1.99 (2H, m, H-11), 1.89 (1H, overlap, H-16a), 1.88 (1H, overlap, H-15a), 1.72 (1H, overlap, H-9), 1.64 (1H, overlap, H-7a), 1.63 (1H, overlap,H-22a), 1.56 (1H, m, H-6a), 1.48 (1H, m, H-6b), 1.42 (1H, overlap, H-19),1.41 (1H, overlap, H-21a), 1.40 (1H, overlap, H-18), 1.39 (1H, overlap, H-22b), 1.37 (1H, overlap, H-7b), 1.28 (1H, overlap, H-16b), 1.24 (1H, overlap,H-21b), 1.18 (3H, s, H-27), 1.09 (3H, s, H-25), 1.07(1H, overlap, H-1b), 1.04(1H, overlap, H-5), 1.03 (3H, s, H-26), 0.98 (1H, overlap, H-15b), 0.94 (3H,s, H-24), 0.93 (3H, d, J = 5.9 Hz, H-30), 0.89 (3H, s, H-23), 0.88 (1H,overlap, H-20), 0.85 (3H, d, J = 5.9 Hz, H-29); 13C-NMR (100 MHz, CD3COCD3) δ:48.7 (t, C-1), 66.8 (d, C-2), 84.9 (d, C-3), 40.2 (s, C-4), 55.7 (d, C-5),19.0 (t, C-6), 33.5 (t, C-7), 40.9 (s, C-8), 48.4 (d, C-9), 38.6 (s, C-10),24.2 (t, C-11), 125.3 (d, C-12), 140.1 (s, C-13), 42.9 (s, C-14), 26.7 (t, C-15), 23.8 (t, C-16), 38.8 (s, C-17), 55.1 (d, C-18), 40.2 (d, C-19), 40.4 (d,C-20), 31.5 (t, C-21), 36.3 (t, C-22), 29.1 (q, C-23), 18.3 (q, C-24), 17.4(q, C-25), 17.2 (q, C-26), 23.8 (q, C-27), 69.6 (t, C-28), 17.9 (q, C-29),21.7 (q, C-30), 127.7 (s, C-1'), 115.1 (d, C-2'), 146.3 (s, C-3'), 148.6 (s,C-4'), 116.3 (d, C-5'), 122.3 (d, C-6'), 145.2 (d, C-7'), 116.4 (d, C-8'),167.8 (s, C-9')。
实施例3:
本发明化合物的抗肿瘤细胞活性检测:
采用MTT法测定本发明化合物对人乳腺癌细胞株(MCF-7)、肝癌细胞株(HepG2)、宫颈癌细胞株(Hela)和结肠癌细胞株(HT-29)的细胞毒性。将100 μL对数期的细胞接种于96孔板中,每孔细胞为7×103个。培养24 h后,小心吸出旧培养液,每孔加入200 µL含有供试品的1640培养基(20 µL供试品工作液+180 µL含10% FBS的1640培养液),每个浓度设置4个复孔。阴性对照加入同等体积的相应溶媒,阳性对照加入多烯紫杉醇。将96孔板置于培养箱中孵育24 h。培养24 h后,每孔按培养液和CCK-8体积比为10:1的比例加入CCK-8溶液。继续培养2 h后,用酶标仪测定在450 nm处的吸光度。抑制率按以下公式计算:抑制率% = (1 −OT/OC) × 100;OT为实验组OD值,OC为阴性对照组OD值。而后以样品浓度为横坐标,以抑制率为纵坐标,作图并求出抑制率为50%时样品的浓度(IC50),样品活性结果即以半数抑制浓度(IC50)表示。
活性数据见表1。
表1 化合物1的肿瘤细胞毒活性数据
实施例4:
片剂:实施例1和2所得化合物1 10 mg,乳糖180 mg,淀粉55 mg,硬脂酸镁5 mg;
制备方法:将化合物、乳糖和淀粉混合,用丙二醇均匀湿润,把湿润后的混合物过筛并干燥,再过筛,加入硬脂酸镁,然后将混合物压片,每片重250 mg,化合物含量为10 mg。
实施例5:
安瓿剂:实施例1和2所得化合物1 2 mg;
制备方法:实施例1和2所得化合物1溶解于3 mL丙二醇中,过滤所得溶液,在无菌条件下装入安瓿瓶中。
实施例6:
胶囊剂:实施例1和2所得化合物1 10 mg,乳糖187 mg,硬脂酸镁3 mg;
制备方法:将化合物与助剂混合,过筛,均匀混合,把得到的混合物装入硬明胶胶囊,每个胶囊中200 mg,活性成分含量为10 mg。
Claims (5)
1.下述结构式所述的乌苏烷三萜咖啡酸酯化合物,
。
2.药物组合物,其中含有治疗有效量的权利要求1所述化合物和药学上可接受的载体。
3.抗肿瘤剂,其中含有权利要求1所述化合物和常规辅剂。
4.权利要求1所述化合物在制备抗肿瘤剂中的应用。
5.权利要求1所述化合物在制备治疗癌症的药物中的应用。
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