CN110776542A - 一种从金花茶提取的化合物及其制备抗肿瘤药物应用 - Google Patents
一种从金花茶提取的化合物及其制备抗肿瘤药物应用 Download PDFInfo
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Abstract
本发明公开了一种从金花茶中提取分离的新型化合物金花茶酚E,并公开了金花茶酚E在制备抗肿瘤药物中的应用,金花茶提取物金花茶酚E抑制PIM1激酶的活性,能够抑制肿瘤细胞存活,抑制肿瘤细胞的克隆形成,抑制肿瘤细胞的增殖能力,并且能够诱导肿瘤细胞周期阻滞、细胞凋亡,具有抗肿瘤药物制备应用前景。
Description
技术领域
本发明属于天然提取化合物技术,具体涉及一种具有抗肿瘤活性的金花茶提取物金花茶酚E及其制药应用。
背景技术
癌症是全球范围内死亡率极高的一种疾病,且发病率仍在持续升高,最新全球癌症统计报告显示,2018年癌症新发病例1910万,癌症新增死亡病例870万。目前,癌症的治疗方法主要有化学药物治疗、放射治疗以及手术切除等,这些治疗方法在杀死肿瘤细胞的同时,通常也会对正常细胞造成损害,副作用极大。近年来,靶向疗法逐渐兴起,该疗法针对已经明确的与肿瘤密切相关的位点进行治疗,使肿瘤细胞特异性死亡,而不会波及肿瘤周围的正常组织细胞,有效降低毒副作用,大大提高了癌症患者的生存率。乳腺癌作为全球女性最常见的恶性肿瘤之一,其发病率居全球女性肿瘤的首位,在亚洲人群中以每年2%的速度增加。相较于其他亚型,三阴性乳腺癌侵袭性更强、预后更差,并且缺乏有效的分子靶点。随着分子生物学的发展及对肿瘤细胞信号通路的深入研究,一些参与调节肿瘤细胞信号转导的关键激酶逐渐成为抗肿瘤药物筛选的热门靶点。一些调节其重要信号通路的中药提取逐渐进入人们的视野,其中PIM1作为重要靶点在许多疾病的进展中发挥了重要的作用,在抗肿瘤方面发挥着药物研发的巨大潜质[1][2]。
根据世界卫生组织的报道,肿瘤即癌症是世界第二大死因,全球近六分之一的死亡是由癌症造成的。自20世纪40年代以来抗肿瘤药物发展迅速,目前国内外临床上广泛使用的抗肿瘤药物有100多种。经过70多年的发展,抗肿瘤药物在提高患者的生活质量及延长生存时间方面取得了明显进展。近10年FDA批准近40个抗肿瘤新分子实体药物上市。抗癌药物主要分为细胞毒类小分子药物及天然产物抗癌药物和分子靶向药物,以紫杉醇为代表,天然产物来源的化合物在抗肿瘤药物的研发占据了重要的位置,我国丰富的中药材是抗肿瘤药物的宝库,中药材发现抗肿瘤的天然活性物质也是当代中药研究的重要主题。
金花茶作为我国一级保护植物,具有极高的药用价值,近年来随着其提取工艺的进步,金花茶提取物由于其具有多样的生物活性而备受关注,其抗肿瘤作用的化学成分、药理作用及其机制受到了关注[3]。因此,本发明提取了一类金花茶化合物,并通过计算虚拟对接技术、酶学筛选技术、细胞水平的筛选技术发现了具有抗肿瘤活性的一种从金花茶提取的化合物,抗肿瘤实验结果显示化合物具有良好的抗癌活性。
参考文献:
[1]THEO CUYPERS H,SELTEN G,QUINT W,et al.Murine leukemia virus-induced T-cell lymphomagenesis:Integration of proviruses in a distinctchromosomal region[J].Cell,1984,37(1):141-150.
[2]WANG Z,BHATTACHARYA N,MEYER M K E,et al.PIM1Negatively Regulatesthe Activity of PTP-U2S Phosphatase and Influences Terminal Differentiationand Apoptosis of Monoblastoid Leukemia Cells[J].Archives of Biochemistry andBiophysics,2001,390(1):9-18.
[3]张武君,赵云青,刘保财,黄颖桢,陈菁瑛,邹福贤.金花茶成分及药理作用研究进展[J].亚热带农业研究,2018,14(01):66-72.
发明内容
发明目的:针对上述现有技术,本发明提供了一种具有抗肿瘤活性的金花茶提取的化合物及其制备抗肿瘤药物应用。
技术方案:本发明公开了一种具有抗肿瘤活性的金花茶提取物单体成分金花茶酚E,其结构如式I所示:
上述金花茶酚E,分子式为C39H32O15,代号YR-65,化学名为:Kaempferol 3-O-(3”,6”-O-trans-p-coumaroyl)-β-D-glucopyranoside。
本发明还进一步公开了所述金花茶酚E在制备治疗抗肿瘤药物中的应用。具体的,所述肿瘤为乳腺癌。
所述化合物I具有很好的酶学抑制作用。所述金花茶酚E对于乳腺癌细胞具有细胞毒作用,进一步研究发现此外在不同浓度下,金花茶酚E对乳腺癌细胞系具有生长抑制、周期阻断以及诱导肿瘤细胞凋亡的作用。
有益效果:本发明所述的金花茶提取化合物结构简单、提取路线简便、原料易得及反应条件温和,获得的化合物具有良好的PIM1酶学抑制效果和抗肿瘤活性,从而有效地抑制抗肿瘤关键靶点PIM1,进而杀死乳腺癌肿瘤细胞,具有抗肿瘤药物研发价值。
附图说明
图1是金花茶酚E电喷雾质谱;
图2是金花茶酚E对PIM1酶活的影响;
图3是金花茶酚E对MDA-MB-231和MDA-MB-468乳腺癌细胞存活的影响;
图4给予金花茶酚E干预后MDA-MB-231和MDA-MB-468乳腺癌细胞平板克隆实验;
图5给予金花茶酚E干预后MDA-MB-231和MDA-MB-468乳腺癌细胞生长曲线;
图6金花茶酚E诱导MDA-MB-231和MDA-MB-468乳腺癌细胞周期阻滞;
图7金花茶酚E诱导MDA-MB-231和MDA-MB-468乳腺癌细胞凋亡;
图8YR-65对MDA-MB-231和MDA-MB-468乳腺癌细胞核形态的影响。
具体实施方式
下面通过实施例对本发明作出详细说明。
药物来源:防城港普通种金花茶(Camellia nitidissima Chi);
2016年7月采摘于防城港,中国,广西。
试剂和仪器:
细胞株:
MDA-MB-231细胞:人乳腺癌细胞株,贴壁生长,购于中国科学院上海细胞库;
MDA-MB-468细胞:人乳腺癌细胞株,贴壁生长,购于中国科学院上海细胞库。
实施例1金花茶天然提取活性物提取工艺:
取金花茶干花6kg,粉碎到约40目后用95%的乙醇高温回流提取3次,每次时间分别为3h、2h、1h。合并提取液,用旋转蒸发仪50℃低压回收工业乙醇,得金花茶花乙醇提取浸膏1500g。加6L超纯水使其充分混悬后,加入等体积二氯甲烷萃取3次,40℃低压旋蒸去二氯甲烷后,得金花茶花二氯甲烷萃取部位52g,剩余水相部分再加入等体积水饱和乙酸乙酯萃取3次,40℃低压回收乙酸乙酯后,得金花茶花乙酸乙酯萃取部位266.2g;乙酸乙酯相经过硅胶柱柱层析分离得到17个组分。随后17个组分别分经过硅胶层析柱,Sephadex LH-20凝胶柱、C18色谱柱、MCI层析柱和HPLC制备柱处理分离后,从组分3中分离得到化合物23(6.8mg)、化合物31(82mg)和化合物36(5.6mg);从组分5中分离得到化合物44(7.4mg);从组分8中分离得到化合物37(1.9mg);从组分9中分离得到化合物14(21mg)和化合物43(2.5mg);从组分10中分离得到化合物1(2.57g)、化合物5(62mg)、化合物9(6mg)、化合物16(9mg)、化合物17(5mg)、化合物19(83mg)其中,化合物19即为金花茶酚E(nitidissimol D),其结构如式I所示:
该化合物为黄色无定型粉末状,可溶于甲醇,电喷雾质谱如图1所示,ESI-MS,m/z739.09[M-H]-。结合氢谱、碳谱、DEPT谱初步推断此化合物的分子式为C39H32O15。综合该化合物的氢谱和碳谱数据以及和相关文献对比的结果可以推测该化合物为Kaempferol3-O-(3”,6”-O-trans-p-coumaroyl)-β-D-glucopyranoside。其氢谱和碳谱具体归属如下:
1H-NMR(500MHz,CD3OD)δ:7.96(2H,d,J=8.8Hz,H-2’,6’),7.73(1H,d,J=15.9Hz,H-γ”’),7.49(2H,d,J=8.6Hz,H-2”’,6”’),7.41(1H,d,J=15.9Hz,H-γ””),7.30(2H,d,J=8.6Hz,H-2””,6””),6.86(2H,d,J=8.6Hz,H-3”’,5”’),6.81(2H,d,J=8.6Hz,H-3””,5””),6.80(2H,d,J=8.2Hz,H-3’,5’),6.49(1H,J=15.9Hz,H-β”’),6.24(1H,s,H-8),6.09(1H,J=15.9Hz,H-β””),6.04(1H,J=1.7Hz,H-6),5.68(1H,J=8.0Hz,H-1”),5.12(1H,t,J=9.2Hz,H-3”),4.39(1H,J=11.5Hz,Ha-6”),4.24(1H,dd,J=11.5,6.6Hz,Hb-6”),3.74(1H,m,H-4”),3.64(1H,m,H-5”),3.47(1H,m,H-2”).
13C-NMR(125MHz,CD3OD)δ:178.8(s,C-4),168.9(s,C-α”’),168.8(s,C-α””),165.2(s,C-7),162.5(s,C-5),161.0(s,C-4”’),160.9(s,C-4””),160.8(s,C-4’),158.8(s,C-2),158.0(s,C-9),147.1(d,C-γ”’),146.4(d,C-γ””),134.4(s,C-3),132.1(d,C-2’,6’),131.2(d,C-2””,6””),131.1(d,C-2”’,6”’),127.2(s,C-1”’),126.9(s,C-1””),122.8(s,C-1’),116.7(d,C-3””,5””),116.6(d,C-3”’,5”’),116.0(d,C-3’,5’),115.2(d,C-β”’),114.6(d,C-β””),105.7(s,C-10),100.4(d,C-1”),99.7(d,C-6),94.7(d,C-8),75.9(d,C-3”),75.5(d,C-5”),75.6(d,C-4”),71.8(d,C-2”),64.4(t,C-6”).
实施例2金花茶酚E对PIM1酶学水平抑制作用
(1)酶促步骤;
依次用激酶缓冲液稀释待测化合物(金花茶酚E、阳性参照十字孢碱(Staurosporine)、激酶、底物及ATP,以制备酶促步骤所需最终浓度为(2.5倍、5倍、5倍、5倍)的工作溶液。将待测物4μL、激酶、底物及ATP各2μL依次加入384孔板中(阴性对无化合物,加入4μL激酶缓冲液,空白对照无化合物和激酶,共加入6μL激酶缓冲液),保证所加试剂全部加至板底,避免挂壁,反应体系为10μL。最后以薄膜封板(防止蒸发及灰尘),室温孵育1h,每组均设置3复孔。
(2)终止步骤:
用检测缓冲液稀释Sa-XL665储备溶液(16.67μM),以制备浓度为试验所需最终浓度4倍的工作溶液,按照1/50的比例稀释STK-抗体储备溶液,以获得工作溶液。待激酶反应结束后,依次加入5μL的Sa-XL665及5μL的STK-Antibody(含EDTA),总反应体系为20μL,封板,室温终止反应1h。
(3)上机检测:
终止反应结束后,用酶标仪上机检测,分别检测620nm及665nm处的荧光度值,并计算665/620的比值。
(4)酶活抑制率计算:
根据反应原理,阴性对照组的酶促反应完全,即665/620的比值最大,而对于化合物组,比值越小说明酶促反应进行得越少,即酶活抑制越明显。空白对照孔读值最小,计算酶活抑制率时各组均要去除空白对照的影响。因此,酶活抑制率按照以下公式进行计算:
实验结果见图2,根据图示可见:对化合物分别设置一系列浓度梯度(0.001μM、0.01μM、0.1μM、1μM、5μM、10μM、100μM),考察其酶活抑制作用。结果表明化合物均呈浓度依赖性抑制PIM1激酶的活性,对PIM1的酶学水平IC50为:1.46±1.18μM。(阳性对照(十字孢碱)IC50为24.9);结果表明金花茶酚E具有较高的酶活抑制率。
实施例3金花茶酚E对人乳腺癌细胞株体外抑制作用
细胞株:人乳腺癌细胞株MDA-MB-231细胞,人乳腺癌细胞株MDA-MB-468细胞;
实验方法:MTT法;
实验步骤:
(1)取处于指数生长期状态良好的细胞一瓶,加入0.25wt%胰蛋白酶消化液,消化使贴壁细胞脱落,计数(2~4)×104个/mL,制成细胞悬液;
(2)取细胞悬液接种于96孔板上,180μL/孔,置恒温CO2培养箱中培养;
(3)24小时后,加入受试药物金花茶酚E(20μL/孔),培养72小时;
(4)将MTT试剂加入96孔板中,20μL/孔,培养箱中孵育4小时;
(5)吸去上清液,加入DMSO(150-200μL/孔),平板摇床上振摇至甲瓒完全溶解;
(6)用酶联免疫检测仪在波长为570nm处测定每孔的吸光值,并计算相应的细胞抑制率。
实验结果见图3,用终浓度为1.5、3、6、12、24、48、96μM金花茶酚E处理MDA-MB-231和MDA-MB-468乳腺癌细胞。MTT法检测细胞存活率,结果以半数致死浓度IC50±标准差(n=6)表示,随着剂量的增加,在两种乳腺癌细胞上均显示出明显的抑制乳腺癌细胞存活的作用,且在两株乳腺癌细胞中,金花茶酚E的IC50分别为10.98±2.55μM和11.39±3.06μM。
实施例4化合物金花茶酚E对乳腺癌细胞的生长抑制作用
实验步骤:
平板克隆形成实验
(1)取生长状态良好,处于对数期的细胞,进行消化、离心,细胞重悬后进行计数,取对应体积的细胞悬液于完全培养基中,吹打混匀后,将细胞悬液加入到6孔板中。每个孔2mL细胞悬液,含1000个细胞。上下左右晃匀六孔板,置于恒温CO2敷箱中培养。
(2)培养24h后,更换新鲜的完全培养基,并随机分为5组:阴性对照组、给药组(低、中、高剂量)、阳性对照组;继续于敷箱中培养,每3-4天更换一次培养基,至单个细胞团块至少含有50个细胞时,终止培养。
(3)取出六孔板,弃上清,并用PBS清洗一次,每孔加入4%的多聚甲醛,室温固定30min,弃固定液,每孔加入1mL 0.8%的结晶紫染液,室温避光染色30min;最后用小流量的自来水冲洗六孔板板底,洗掉结晶紫染液,空气干燥后进行拍照。
实验结果如图4所示,在克隆形成实验中,将MDA-MB-231细胞和MDA-MB-468细胞分别给予2.5μM、5μM、10μM剂量的金花茶酚E和0.05μM十字孢碱干预14天后,将克隆用结晶紫染色。结果显示随着剂量增加乳腺癌细胞的克隆形成能力受到抑制。
根据图示可见,化合物金花茶酚E可以明显抑制乳腺癌细胞的增殖。
生长曲线实验
(1)取生长状态良好,处于对数期的细胞,进行消化、离心,细胞重悬后进行计数,稀释成1-2×105个/mL,取所需体积的细胞悬液,重悬于完全培养基中,吹打均匀后,以500μL/孔,每孔5×104个细胞,接种于24孔板中,置恒温CO2敷箱中培养
(2)培养24h后,更换新鲜的低血清培养基,并随机分为5组:阴性对照组、给药组(低、中、高剂量)、阳性对照组,继续于敷箱中培养。
(3)将细胞消化下来,每天计数一次,连续6天。
实验结果如图5所示,MDA-MB-231和MDA-MB-468细胞分别给予2.5μM、5μM、10μM剂的金花茶酚E和0.05μM十字孢碱干预治疗,持续6天,并每天计数以绘制生长曲线。结果显示随着剂量增加乳腺癌细胞的增殖能力受到抑制。
根据图示可见,在两株乳腺癌细胞中,化合物金花茶酚E均可以明显抑制乳腺癌细胞的生长。
单染检测细胞周期分布
实验步骤:
(1)细胞接种:取对数期细胞进行消化处理,离心,重悬后进行细胞计数,调整细胞密度至合适浓度,乳腺癌细胞一般按照1.5×105个/mL接种于六孔板中,每孔一般加2mL,置37℃恒温敷箱中培养;
(2)给药:待细胞贴壁牢固后,更换低血清(2%)培养基,加药处理48h;
(3)细胞收集:药物处理48h后,收集细胞上清于15mL离心管中,用预冷的PBS洗一遍,并收集上清于同一离心管中。之后用胰酶消化细胞,用收集好的细胞上清终止消化,将细胞吹下后收集在同一离心管中;
(4)细胞固定:将离心管以1000rpm离心5min,弃上清,加入1mL1×PBS重悬细胞,并转移至1.5mL离心管中,以1000rpm离心5min,弃上清,轻弹离心管底部,震散细胞。每管加入200μL预冷的PBS,吹匀细胞,再加入800μL预冷的87.5%的乙醇(使乙醇最终含量为70%),吹打几秒后,置4℃过夜;
(5)染色:将固定好的细胞样品以1000rpm离心5min,弃上清,加入1mL预冷的PBS重悬,离心、弃上清。在避光条件下,每个样品加入0.5mL染液(染液配方:1个样品=0.5mL缓冲液+25μL 20×PI+10μL RNAse),室温避光染色30min;
(6)上机检测:染色结束,混合均匀,转移至流式管中,流式细胞仪检测。
实验结果如图6所示,将细胞分别给予2.5μM、5μM、10μM剂量的金花茶酚E和0.5μM紫杉醇干预48小时后,并通过PI染色和流式细胞仪分析细胞周期。结果显示随着剂量增加化合物能够诱导人乳腺癌癌细胞MDA-MB-231和MDA-MB-468发生G2/M期阻滞。根据图示可见,化合物金花茶酚E能够引起人乳腺癌癌细胞MDA-MB-231和MDA-MB-468发生G2/M期阻滞。
Annexin V/PI双染法检测细胞凋亡
实验步骤:
(1)细胞接种及给药,方法同细胞周期检测;
(2)细胞收集:取15mL离心管,收集细胞上清液,用4℃预冷的1×PBS洗涤,并收集上清于同一离心管中,用无EDTA的胰酶消化细胞,消化好后用细胞上清终止消化(切记一定不要过度消化,以免造成假阳性的结果),吹下细胞收集于同一离心管中,以1000rpm离心5min,弃上清,加入1mL预冷的PBS重悬,转移至1.5mL离心管中,离心、弃上清,重复用PBS清洗一次,离心、弃上清(注意弃净,可以大枪头套小枪头);
(3)染色:每管中加入100μL1×binding buffer吹匀细胞,再分别加入5μL FITCAnnexin V及5μL PI,涡旋混匀,避光反应15min;
(4)上机检测:每管再加入400μL 1×binding buffer,吹匀后,吸至流式管,进行检测,Annexin V-FITC的激发光为绿色荧光,PI的激发光为红色荧光(全程避光操作)。
实验结果如图7所示,将细胞分别给予2.5μM、5μM、10μM剂量的金花茶酚E和0.5μM紫杉醇干预48小时后,并通过Annexin V/PI染色分析细胞凋亡,并通过流式细胞术进行分析。果显示随着剂量增加该化合物能够诱导人乳腺癌癌细胞MDA-MB-231和MDA-MB-468细胞凋亡的增加。
根据图示可见,化合物金花茶酚E能够诱导乳腺癌细胞发生凋亡。
Hoechst染核实验实验步骤:
(1)样品准备:取生长状态良好,处于对数期的细胞,进行消化、离心,细胞重悬后进行计数,稀释成1×105个/mL,接种于含无菌爬片24孔板中,每孔500μL细胞悬液,待24h细胞贴壁后,换低血清培养基,并随机设置5组,分组同上,于恒温CO2敷箱中培养48h;
(2)细胞固定及打孔:弃上清,以4℃预冷的PBS清洗细胞爬片,然后每孔加入1mL预冷的4%的多聚甲醛进行固定,室温15min;弃固定液,用PBS洗2次,每孔加入500μL用PBS缓冲液稀释的0.5%Triton X-100,室温静置30min打孔;
(3)染核:弃掉0.5%Triton X-100,用PBS洗2次,避光条件下,每孔加入1mL 1×Hoechst 3342溶液(5μg/mL,用PBS稀释至该浓度),室温孵育30min。
(4)成像:弃去Hoechst 33342溶液,每孔加入1mL PBS洗涤细胞爬片两次,取出爬片,倒扣于滴有抗荧光猝灭剂的载玻片上,在340nm波长激发,在荧光倒置显微镜下观察拍照。随机拍摄不同视野,进行图像采集并合成分析。
实验结果如图8所示,将细胞分别给予2.5μM、5μM、10μM剂量的金花茶酚E和0.5μM紫杉醇干预48小时后,并进行Hoechst染色以检测腺癌的核形态变化。结果显示正常对照组细胞,细胞核形态为圆形,呈淡蓝色;细胞给药处理48h后,细胞核呈亮蓝色,致密浓染,细胞核形态出现皱缩,或呈碎片状,或呈月牙形,表明给药处理后,细胞可能发生了凋亡。
综上所述,化合物金花茶酚E具有很好的酶学抑制作用,并对于肿瘤具有细胞毒作用,进一步研究发现此外在不同浓度下,金花茶酚E对乳腺癌细胞系具有生长抑制、周期阻断以及诱导肿瘤细胞凋亡的作用。化合物金花茶酚E靶向PIM1并对乳腺癌细胞具有杀伤作用提示其可能在靶向药物研发上具有巨大潜力。
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