CN105017352B - 一种吲哚生物碱苷及其应用 - Google Patents
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Abstract
本发明公开了一种吲哚生物碱苷及其应用,属于医药领域。该吲哚生物碱苷的结构式为
Description
技术领域
本发明属于医药技术领域,具体涉及一种新的吲哚生物碱苷类化合物及其用途。
背景技术
肿瘤是人体器官组织的细胞在外来和内在有害因素的长期作用下所产生的一种以细胞过度增殖为主要特点的新生物,在医学上可分为良性肿瘤和恶性肿瘤两大类。良性肿瘤对人体健康影响较小,而恶性肿瘤(又称癌症)则严重威胁着人类的健康。根据世界卫生组织和美国癌症协会的最新统计数据,癌症已成为人类死亡的首要病因,2008年全世界约有1270万新诊断癌症病例和760万癌症死亡病例(约占所有死亡人数的13%),且大约有70%的癌症死亡病例发生在中低收入国家。预计到2030年,癌症年诊断和死亡病例将分别高达2140万和1320万。
根据中国癌症基金会数据,我国恶性肿瘤死亡率属于世界较高水平,而且呈持续增长趋势。2006年第三次全国死因调查显示,我国恶性肿瘤死亡率比70年代中期增加了83.1%,比90年代初期增加了22.5%。脑血管疾病和恶性肿瘤是我国前两位死亡原因,分别占死亡总数的22.4%和22.3%。恶性肿瘤不仅严重影响我国人口健康,而且成为医疗费用上涨的重要因素。此外,由于中晚期恶性肿瘤患者治疗效果尚不满意,其不良预后往往波及亲友和家庭,影响社会稳定。
虽然世界卫生组织、各国政府和科研机构在肿瘤预防与治疗上投入了大量的人力、物力,开展了深入的研究工作,在肿瘤的诊断、手术、放射及化学疗法方面取得了很大的进展,但到目前为止,很多恶性肿瘤仍缺乏有效的治疗手段。利用各种手段寻找切实有效的抗肿瘤药物,已经成为世界范围内生命科学研究的热点课题。目前临床上用于肿瘤治疗的化学合成药物,大多数作用机理都涉及肿瘤细胞的核酸代谢,以DNA为作用靶点,虽然对于肿瘤治疗起十分重要的作用,但在抑制肿瘤细胞增殖的同时,也给病人正常组织器官带来了极大的损伤,严重影响了肿瘤患者的生存质量,致使许多肿瘤病人不是死于慢性消耗衰竭,而是死于放、化疗的毒性和副作用。因此,继续寻找和研制新型抗肿瘤药物仍是当前药物研究的主要方向之一。
中药及天然药物在保障人类健康、防治疾病方面具有悠久的历史,世界医药产业的发展实践证明,中药、天然药物历来是创新药物研究的重要源泉。许多天然药物具有毒副作用相对较小、作用原理独特等优点,已成为抗肿瘤新药研究与开发的重要对象,从天然药物中寻找高效低毒的抗肿瘤先导化合物已成为天然药物化学的重点研究方向之一。紫杉醇、喜树碱、长春花碱、斑蝥素等广泛应用于恶性肿瘤的治疗就是其中一些成功的例子。今天,从传统中药及天然药物中寻找抗肿瘤先导化合物依然是创新药物研究的一条重要捷径。
骆驼蓬(Peganum harmala)为蒺藜科(Zygophyllaceae)骆驼蓬属(Peganum)植物,是一种耐旱、耐寒、耐碱、耐瘠薄的草本植物,维吾尔语叫“阿地热斯芒”,主要分布于新疆、甘肃、宁夏、青海和内蒙古的荒漠或半荒漠地区。骆驼蓬是维吾尔族、蒙古族民间沿用已久的药材,药用部位为成熟种子。骆驼蓬性平,味苦、辛,有毒,具有坚固筋脉、助阳暖阴、消除黏稠体液、消散寒湿之气等功能,主治筋脉软弱、骨关节痛、咳嗽痰多、偏瘫健忘、神昏头痛等。骆驼蓬在现代临床上主要用于治疗胃癌、肝癌、结肠癌、乳腺癌等恶性肿瘤。临床上,骆驼蓬总碱制剂对食道癌、胃癌、喷门癌、结肠癌等恶性肿瘤的有效率达到85.7%,且已作为院内制剂在中国医科大学多家附属医院及新疆多家医院应用。
骆驼蓬种子中主要活性成分为生物碱苷类,现代药理研究表明,骆驼蓬生物碱具有显著的抗肿瘤活性。现有的研究中并未明确具体是何种生物碱苷类具有抗肿瘤活性,这使得临床应用时缺乏足够的指导,限制了其应用,无法有效避免副作用。
发明内容
本发明的目的在于提供一种新型的吲哚生物碱苷及其应用。
发明人通过长期研究,从骆驼蓬种子中分离鉴定了1个新的化合物该化合物对胃癌具有很好的抗肿瘤作用,同时对肝癌和乳腺癌具有一定的作用,该化合物具有高效、低毒的优点,有望开发为新的抗癌药物,特别是抗胃癌药物。
附图说明
图1为本发明化合物的1H-NMR图谱;
图2为本发明化合物的13C-NMR图谱;
图3为本发明化合物的HSQC图谱;
图4为本发明化合物的HMBC图谱。
具体实施方式
的提取及鉴定:
取10Kg的骆驼蓬种子,粉碎后用70%甲醇加热回流提取3次,每次2小时,合并提取液,用纱布过滤后减压回收溶剂,得到总浸膏,将总浸膏用4L水混悬,加入盐酸将pH调至1.0,用等体积氯仿萃取两次,除去脂溶性杂质,水层用氨水将pH调至7.0,依次用等体积的氯仿,正丁醇萃取三次,取有机层,分别减压浓缩回收溶剂,得到氯仿层浸膏220g,正丁醇层浸膏280g。
取正丁醇萃取物250克,通过采用硅胶柱色谱、氧化铝柱色谱、羟丙基葡聚糖凝胶(Sephadex LH-20)柱色谱、ODS中低压柱色谱、反相高效液相色谱等分离方法,分离得到本发明化合物。通过理化常数和现代波谱学手段(HR-MS,1D-NMR,2D-NMR)鉴定结构,化合物为系统命名为2-(indol-3-yl)ethyl-α-L-rhamnopyranosyl-(1→6)-β-D-glucopyranoside。
使用13C-NMR和1H-NMR对提纯得到的化合物进行结构鉴定,13C-NMR和1H-NMR谱分别如图1和2所示。图3为本发明化合物的HSQC图谱;图4为本发明化合物的HMBC图谱。
1H-NMR(500Hz,DMSO-d6)在芳香区给出5个氢,其中,δH7.52(1H,m),7.22(1H,m),7.06(1H,m),6.97(1H,m)构成一个AA’BB’自旋耦合系统,δH10.82是活泼氢信号,δH4.23(1H,d,J=7.8Hz)给出β-D-葡萄糖的端基质子信号,δH4.61(1H,d,J=1.0Hz)为另一个糖端基质子信号,δH1.13(3H,d,J=6.2Hz)提示结构中存在一个甲基。该化合物的13C-NMR(125Hz,DMSO-d6)数据与化合物2-(indol-3-yl)ethyl-β-D-glucopyranoside对比,除了δC100.9,75.4,72.1,70.5,70.2,17.9以及67.0以外,其他数据基本与化合物2-(indol-3-yl)ethyl-β-D-glucopyranoside一致,δC100.9给出鼠李糖的端基碳信号,其中糖链的碳信号与文献报道的α-L-鼠李糖(1→6)-β-D-葡萄糖糖链一致,对比本化合物和2-(indol-3-yl)ethyl-β-D-glucopyranoside可以发现,本化合物中葡萄糖的6位碳向低场位移了+6ppm,出现在67.1ppm,说明鼠李糖连在葡萄糖的C-6位,在HMBC中,葡萄糖的H-6(δH3.83,m)与δC100.9(Rha,C-1)相关,H-1”(δH4.61)与δC67.1(Glc-6)相关,进一步确定了鼠李糖连接在葡萄糖的C-6位。结合HSQC,HMB谱可对本发明化合物的信号进行归属。
综合上述信息,该化合物被鉴定为2-(indol-3-yl)ethyl-α-L-rhamnopyranosyl-(1→6)-β-D-glucopyranoside。
表1:化合物的氢和碳信号归属(DMSO-d6)
抑瘤试验:
本发明化合物对人体5个瘤株的体外抑瘤活性实验,这5个瘤株包括人胃癌细胞SGC7901、BGC-803,人肝癌细胞HepG2、Hep-3B,人乳腺癌细胞MCF-7。
(1)抑制肿瘤细胞增殖(MTT法)
将肿瘤细胞接种于96孔板中,培养24h后加入待测试样品,再培养48h后用MTT法测定样品对肿瘤细胞增殖的抑制率。细胞增殖抑制率按下述公式计算,并用CalcuSyn软件计算被测试样品的半数抑制浓度(IC50),IC50<20μg/mL的成分将被视为活性样品;
(2)诱导肿瘤细胞凋亡
将肿瘤细胞以2×105个/mL密度接种于6孔板中,每孔3mL。培养24h后加入样品,再培养24h,收集细胞,用PBS洗1次,1000×g离心5min,以1mL 3.7%多聚甲醛重悬细胞,室温固定1h,1000×g离心5min,弃去上清,用PBS洗1次,将细胞重悬于100μL PBS中,取细胞悬液10μL,加入2μL 1mmol/L Hoechst 33258,37℃染色15min,荧光显微镜下观察凋亡小体。
(3)实验结果:见表2和表3
表2本发明化合物对不同肿瘤细胞的抑制作用
表3本发明化合物在2μM浓度时对不同肿瘤细胞的凋亡诱导作用
注:显著诱导凋亡(++),一般诱导凋亡(+),未发现凋亡(—)。
实验结果表明:本发明新化合物具有显著的抗肿瘤作用,特别是对癌症,包括但不限于胃癌、肝癌、乳腺癌具有很好的治疗作用,且能显著诱导肿瘤细胞发生凋亡作用,实验数据表明,本发明化合物对人胃癌细胞株SGC7901和BGC-803的体外增殖抑制作用强于阳性药物顺铂。
Claims (3)
1.一种吲哚生物碱苷,其结构式为
。
2.吲哚生物碱苷在制备治疗肿瘤中药物中的应用,其中,吲哚生物碱苷的结构式如权利要求1所述。
3.根据权利要求2所述的应用,其特征在于:肿瘤选自胃癌、肝癌、乳腺癌。
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