CN114805391B - 天然美登素类化合物及其在制药中的用途 - Google Patents
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Abstract
本发明属医药技术领域,涉及从滑桃树中分离得到的天然美登素类化合物及其在制药中的用途。具体涉及式(I)化合物甲基特利回生(methyltrewiasine,即4,24‑二氧杂‑9,22‑二氮杂四环[19.3.1.110,14.03,5]二十六烷美登素衍生物)和式(II)化合物N‑甲基特利福洛林(N‑methyltreflorine,即3,7,30‑三氧杂‑9,22,27‑三氮杂五环[20.8.2.16,10.117,21.02,4]三十四烷特利福洛林衍生物)。所述化合物从滑桃树干燥果实中提取得到,试验证实其具有很强的抗肿瘤活性,可用于制备抗肿瘤药物,尤其是抗人宫颈癌、人白血病和人乳腺癌肿瘤药物。
Description
技术领域
本发明属医药技术领域,涉及从滑桃树中分离得到的天然美登素类化合物及其在制药中的用途。具体涉及化合物甲基特利回生(methyltrewiasine,即4,24-二氧杂-9,22-二氮杂四环[19.3.1.110,14.03,5]二十六烷美登素衍生物)和化合物N-甲基特利福洛林(N-methyltreflorine,即3,7,30-三氧杂-9,22,27-三氮杂五环[20.8.2.16,10.117,21.02,4]三十四烷特利福洛林衍生物)及其在制备抗肿瘤药物中的用途。
背景技术
现有技术公开了美登素(Maytansine)是一种大环内酰胺类化合物,于1972年从卵叶美登木(Maytenus ovatus)中首次发现,是天然抗肿瘤活性成分(Journal of theAmerican Chemical Society 1972,94,1354.)。有研究从美登木属植物中又陆续发现了美登素的多种类似物以及从微生物中发现的安沙霉素(Ansamitocins)等,总称为美登素类化合物(Maytansinoids)。2013年初,首个美登素抗体偶联药物(Kadcyla)由美国食品药品监督管理局(FDA)批准上市,用于治疗HER2阳性的晚期(转移性)乳腺癌(Journal ofMedicinal Chemistry 2014,57,6949.)。美登素类化合物作为抗体偶联药物中极具潜力的效应分子,近年来一直是肿瘤靶向研究的热点(Journal of Cellular Physiology 2019,235,31.)。
研究实践表明,美登素类化合物来源主要有三个,一是从美登木中提取分离,但是含量极微;二是通过微生物发酵产生,但发酵产量低,纯化工艺复杂,回收率低;三是通过全合成获得,但是其立体构型难以控制,步骤繁琐且合成成本昂贵;因此,扩大美登素天然植物来源依然是本技术领域对该类化合物研究的重要方向。
滑桃树(Trewianudiflora)是大戟科(Euphorbiaceae)滑桃树属(Trewia)单种,为高大乔木,分布于亚洲南部(如印度、马来西亚)和东南部热带地区(如我国云南、广西和海南等地),是一速生树种,资源较为丰富。上世纪八九十年代,对印度产滑桃树和云南产滑桃树的研究表明,滑桃树种子中含有美登素类化合物(The Journal of Organic Chemistry1981,46,4398;Journal of the American Chemical Society 1982,104,4929;Journalof Natural Products 1983,46,660;中国药理学报1988,9,508;云南植物研究1991,13,432)。但滑桃树化学成分研究并不充分,其中的美登素类化合物有待深入研究。
基于现有技术的现状,本申请的发明人拟提供从滑桃树中提取的美登素类化合物及其在制药中的用途。
发明内容
本发明的目的是基于现有技术的现状,提供从滑桃树中提取的美登素类化合物及其在制药中的用途。
本发明从滑桃树干燥果实中分离得天然化合物,尤其是从滑桃树中提取获得结构如式(I)和(II)所示的美登素类化合物;
本发明的进一步目的是提供所述化合物的药用用途。本发明式(I)和(II)所示的化合物进行了试验,试验验证所述化合物对HeLa(宫颈腺癌细胞株)、MV-4-11(人髓性单核细胞白血病细胞株)、MCF-7(人乳腺癌细胞株)以及MCF-7/ADR(人乳腺癌阿霉素耐药细胞株)的细胞增殖具有显著强的抑制作用,可作为制备新的治疗肿瘤的药物或先导化合物。
本发明所述的化合物通过下述方法制得:
将滑桃树的干燥果实粉碎后,用有机溶剂或/和水提取制备得总提取物,所用的有机溶剂可采用醇类,如乙醇,甲醇等,其中优选95%(体积比)乙醇;将总提取物分散于水中,用乙酸乙酯萃取,减压回收溶剂,浓缩至干,即得到乙酸乙酯提取物;
将乙酸乙酯提取物进行大孔树脂HP-20柱层析,用含水乙醇梯度洗脱;其中60%(体积比)乙醇洗脱部位进行硅胶柱层析,用二氯甲烷-甲醇梯度洗脱;其中二氯甲烷-甲醇10:1洗脱部分经过高效液相制得式(II)所示化合物,采用波谱方法鉴定其结构为N-甲基特利福洛林(N-methyltreflorine,即3,7,30-三氧杂-9,22,27-三氮杂五环[20.8.2.16, 10.117,21.02,4]三十四烷特利福洛林衍生物);90%(体积比)乙醇洗脱部位经进行硅胶柱层析,用二氯甲烷-甲醇梯度洗脱;其中二氯甲烷-甲醇50:1洗脱部分经过高效液相制备得到式(I)所示化合物,用波谱方法鉴定其结构为甲基特利回生(methyltrewiasine,即4,24-二氧杂-9,22-二氮杂四环[19.3.1.110,14.03,5]二十六烷美登素衍生物)。
本发明对式(I)和(II)化合物进行了对HeLa、MV-4-11、MCF-7以及MCF-7/ADR四种肿瘤细胞株的细胞增殖抑制活性测试,结果表明,所述化合物均具有很强的抑制活性,所述的式(I)和(II)化合物可进一步制备作为研制新的治疗肿瘤的药物或先导化合物。
具体实施方式
下面结合具体实施实例对本发明作进一步阐述,但不限制本发明。
实施例1从滑桃树中提取本发明化合物
(1)提取:将干燥的滑桃树果实(10.7千克)粉碎后于室温下用95%的乙醇渗漉提取,减压浓缩得到浸膏,并将此浸膏分散于水中,用乙酸乙酯萃取,减压回收溶剂,浓缩至干,得到乙酸乙酯提取物420克;
(2)分离:将乙酸乙酯提取物420克进行大孔树脂HP-20柱层析,用乙醇-水(30:70→45:55→60:40→75:25→90:10→100:0)梯度洗脱,每个梯度用量50升,收集流份;其中大孔树脂乙醇-水60:40流份(43.2克)进行硅胶柱层析,以二氯甲烷-甲醇(30:1→15:1→10:1→8:1→5:1→2:1→1:1)梯度洗脱,每个梯度用量5升;其中二氯甲烷-甲醇10:1洗脱部分经过高效液相制备得到式(II)化合物10.2毫克(洗脱剂为乙腈-水42:58,保留时间为4.0分钟),即N-甲基特利福洛林(N-methyltreflorine,即3,7,30-三氧杂-9,22,27-三氮杂五环[20.8.2.16,10.117,21.02,4]三十四烷特利福洛林衍生物);大孔树脂乙醇-水90:10流份(15.0克)进行硅胶柱层析,以二氯甲烷-甲醇(100:1→50:1→1:1)梯度洗脱,每个梯度用量5升;其中二氯甲烷-甲醇50:1洗脱部分经过高效液相制备得到式(I)化合物8.2毫克(洗脱剂为乙腈-水55:45,保留时间为15.0分钟),即甲基特利回生(methyltrewiasine,即4,24-二氧杂-9,22-二氮杂四环[19.3.1.110,14.03,5]二十六烷美登素衍生物)。高相液相色谱仪为岛津Essentia LC-16,紫外检测波长为210nm和254nm;色谱柱为Kromasil C18(150×10mm,5μm),流速为3.0mL·min-1;
式(I)化合物的理化性质及光谱数据为:性状为无色晶体;分子式为C38H54ClN3O11,分子量为763;熔点:152-153℃;比旋光度值:[α]25 D-39.1(c 0.10,甲醇);紫外光谱最大吸收波长值(甲醇):206(3.49),232(3.35),250(3.29),282(2.69)nm;红外光谱最大吸收频率值(溴化钾):3431,2968,2928,1714,1654,1579,1420,1390,1342,1307,1185,1088,1038cm-1;高分辨电喷雾电离质谱(质荷比):正离子模式m/z 764.3504[M+H]+(示分子式C38H54ClN3O11);核磁共振氢谱和碳谱数据如表1所示;
式(II)化合物的理化性质及光谱数据为:性状为无色晶体;分子式为C37H50ClN3O12;分子量为763;比旋光度值:[α]25 D-106.8(c 0.10,甲醇);紫外光谱最大吸收波长值(甲醇):206(3.37),232(3.24),256(3.00),282(2.57)nm;红外光谱最大吸收频率值(溴化钾):3421,2938,1739,1696,1659,1582,1450,1420,1198,1088,986cm-1;高分辨电喷雾电离质谱(质荷比):正离子模式m/z 764.3137[M+H]+(示分子式C37H50ClN3O12);核磁共振氢谱和碳谱数据如表1所示。
表1是式(I)和(II)化合物的核磁共振氢谱和碳谱数据(400/150MHz,化学位移:ppm,溶剂:氘代氯仿)。
表1
实施例2
式(I)和(II)化合物对肿瘤细胞株HeLa、MV-4-11、MCF-7、MCF-7/ADR细胞增殖的抑制作用测试
采用四甲基偶氮唑盐(MTS)比色法测试式(I)和(II)化合物对四种肿瘤细胞株HeLa(宫颈腺癌细胞株)、MV-4-11(人髓性单核细胞白血病细胞株)、MCF-7(人乳腺癌细胞株)、MCF-7/ADR(人乳腺癌阿霉素耐药细胞株)细胞增殖的抑制作用(ACS MedicinalChemistry Letters 2018,9,502.);
在37℃和5%CO2下对细胞进行传代培养,选取对数生长期细胞,吸取培养基,轻轻吹打,计数,以5×104细胞密度接种在96孔板中,每孔接种90μL,加10μL化合物,每个化合物设浓度梯度,每个浓度设三个复孔。MV-4-11细胞株加入化合物的最大浓度是10nM,其它三个细胞株加入化合物的最大浓度都是1000nM,以5倍比进行稀释,DMSO的终浓度是0.2%。在5%CO2、37℃培养箱内培养72小时后加入20μL的MTS,37℃温育3小时后,使用SpectraMAX340分光光度计测定490nm光吸收值,以波长690nm作为参考,用graphpad软件经公式拟合得半数抑制浓度IC50值。DMSO作为阴性对照,美登素衍生物DM-1作为阳性对照(UnitedStates patent 2007,US 7276497.),实验结果显示,
式(I)和(II)化合物均表现出很强的抑制肿瘤细胞增殖活性,与阳性对照相当或强于阳性对照,结果如表2所示。
表2是式(I)和(II)化合物对肿瘤细胞株细胞增殖的抑制活性。
表2
a阳性对照
Claims (3)
1.式(I)和式(II)结构的美登素类化合物
所述式(I)化合物是甲基特利回生(methyltrewiasine,即4,24-二氧杂-9,22-二氮杂四环[19.3.1.110,14.03,5]二十六烷美登素衍生物),其分子式为C38H54ClN3O11;分子量为763;
所述式(II)化合物是N-甲基特利福洛林(N-methyltreflorine,即3,7,30-三氧杂-9,22,27-三氮杂五环[20.8.2.16,10.117,21.02,4]三十四烷特利福洛林衍生物),其分子式为C37H50ClN3O12;分子量为763。
2.权利要求1所述的式(I)化合物甲基特利回生(methyltrewiasine,即4,24-二氧杂-9,22-二氮杂四环[19.3.1.110,14.03,5]二十六烷美登素衍生物)在制备抗人宫颈癌、人白血病和人乳腺癌肿瘤药物中的应用。
3.权利要求1所述的式(II)化合物N-甲基特利福洛林(N-methyltreflorine,即3,7,30-三氧杂-9,22,27-三氮杂五环[20.8.2.16,10.117,21.02,4]三十四烷特利福洛林衍生物)在制备抗人宫颈癌、人白血病和人乳腺癌肿瘤药物中的应用。
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