CN114853802B - 一种谷内酯衍生物及其制备方法、药物组合物和应用 - Google Patents
一种谷内酯衍生物及其制备方法、药物组合物和应用 Download PDFInfo
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Abstract
本发明公开了一种谷内酯衍生物及其制备方法、药物组合物和应用，该谷内酯衍生物结构如式Ⅰ所示，R1为烷基或硅烷基。本发明通过半合成修饰的手段获得了一种新型谷内酯衍生物，制备过程简便易行，通过药理实验发现本发明提供的谷内酯衍生物均表现出强效的抑制多种肿瘤细胞增殖的活性，特别地，谷内酯衍生物表现出优异的强效的抗白血病细胞活性，具有明显的体外和体内的抗肿瘤活性，适合用于抗肿瘤药物的开发。
Description
技术领域
本发明属于化药领域，具体涉及一种谷内酯衍生物及其制备方法、药物组合物和应用。
背景技术
近年来，全世界恶性肿瘤的发病率和死亡率逐年递增，恶性肿瘤已成为人类死亡的主要因素。急性髓系白血病(AML)是成人最常见的血液系统恶性肿瘤之一，中位生存期为4个月，一年总体生存率小于10％，根治机会很小，其治疗受到长期生存的阻碍，大多数AML患者最终死于耐药性和复发，且随着年龄增长发病率有上升的趋势。尽管有先进的生物疗法，但AML的主要治疗方案几乎没有改变，且面临着复发和耐药的难题。目前缺乏更好的低毒高效的有效药物和可行的替代方案是AML治疗中亟待解决的问题。
白血病干细胞(leukemia stem cells，LSCs)是白血病细胞中存在的一种类似正常造血干细胞但数量较少且具有自我更新能力及分化潜能的细胞。95％以上的白血病干细胞处于G0期的“休眠”状态，在体内长期潜伏，能逃逸大多数临床上应用的细胞周期特异性化疗药物的杀伤，从而成为白血病复发和耐药的根源。只有有效清除LSCs才能从根本上治愈白血病。
谷内酯是甾体代谢途径的重要中间体，并成为多种天然产物化学合成原料或中间体。尽管其用于合成了大量具有多种多样生物活性的天然产物，但是目前仍没有谷内酯衍生物抗肿瘤活性研究相关报道，例如谷内酯在体外肿瘤细胞增殖试验中，对大多数癌细胞的杀伤能力不足，IC50值均大于100μM。
发明内容
为解决前述问题，本发明提供了一种谷内酯衍生物，含有作为活性成分的谷内酯衍生物的治疗癌症药物组合物，以及制备谷内酯衍生物的方法。
为了实现本发明的上述目的，本发明提供如下的技术方案：
一种谷内酯衍生物，其结构如式I所示：
所述R1为烷基或硅烷基。
优选地，上述谷内酯衍生物中R1的结构为5-23中的一种：
。
本发明还提供了上述谷内酯衍生物的制备方法，其合成路线如下所示：
经过发明人研究发现，上述谷内酯衍生物能够应用在制备治疗癌症、预防癌症和/或改善癌症症状的药物或食品中。可作为治疗癌症的药物组合物的活性成分，该要用组合物还包括溶剂或可药用载体。
上述癌症包括：妇科癌类，例如：卵巢癌、子宫颈癌、阴道癌、阴部癌、子宫/子宫内膜癌、妊娠滋养细胞肿瘤、输卵管癌、子宫肉瘤；内分泌癌类，例如：肾上腺皮质癌、脑垂体癌、胰癌、甲状腺癌、副甲状腺癌、胸腺癌、多发性内分泌肿瘤；骨癌类，例如：骨肉瘤、尤因肉瘤、软骨肉瘤等；肺癌类，例如：小细胞肺癌、非小细胞肺癌；脑和CNS肿瘤，例如：神经母细胞瘤、听神经瘤、神经胶瘤和其他脑肿瘤，脊髓肿瘤、乳癌、结肠直肠癌、晚期结肠直肠腺癌；胃肠癌类，例如：肝癌、肝外胆管癌、胃肠类癌性肿瘤、胆囊癌、胃癌、食道癌、小肠癌；泌尿生殖器癌类，例如：阴茎癌、翠丸癌、前列腺癌；头和颈部肿瘤类，例如：鼻癌、鼻窦癌、鼻咽癌、口腔癌、唇癌、唾腺癌、喉头癌、下咽癌、正咽癌；血癌类，例如：急性骨髓性白血病、急性淋巴性白血病、儿童白血病、慢性淋巴性白血病、慢性骨髓性白血病、发状细胞性白血病、急性早幼粒细胞白血病、血浆细胞性白血病；骨髓癌血液病症，例如：骨髓分化不良症候群、骨髓增生性病症、范禾尼贫血、再生障碍性贫血、特发性巨球蛋白血症；淋巴癌类，例如：霍奇金病、非霍奇金氏淋巴瘤、周围T-细胞林巴瘤、皮肤型T-细胞淋巴瘤、AIDS相关性淋巴瘤；眼癌类，包括：视网膜母细胞瘤、葡萄膜黑色素瘤；皮肤癌类，例如：黑色素瘤、非黑色素瘤皮肤癌、梅克尔细胞癌；软组织肉瘤类，例如：卡波希肉瘤、儿童软组织肉瘤、成人软组织肉瘤、泌尿系统癌症，例如：肾癌维尔姆斯肿瘤、膀肤癌、尿道癌和转移性细胞癌。优选用于乳腺癌、结直肠癌、肺癌的治疗。
本发明的有益效果为：本发明通过半合成修饰的手段获得了一种新型谷内酯衍生物，制备过程简便易行，通过药理实验发现本发明提供的谷内酯衍生物均表现出强效的抑制多种肿瘤细胞增殖的活性，特别地，谷内酯衍生物表现出优异的强效的抗白血病细胞活性，具有明显的体外和体内的抗肿瘤活性，适合用于抗肿瘤药物的开发。
附图说明
图1所示为谷内酯衍生物体内抗肿瘤作用结果图。
具体实施方式
以下将结合实施例和附图对本发明的构思及产生的技术效果进行清楚、完整的描述，以充分地理解本发明的目的、方案和效果。以下实施例中所用的试验试剂，如无特殊说明，均为常规生化试剂；所述实验方法，如无特殊说明，均为常规方法。
实施例1：化合物4的制备
化合物4的结构如下：
(1)化合物1的制备
化合物1的结构如下：
制备过程如下：
将三氟乙酸(66.6mL，900mmol)溶于二氯甲烷(300mL)中，在-10℃下向反应体系中缓慢加入硼氢化钠(4.54g，120mmol)，10分钟后，将谷内酯(6.67g，30.0mmol)的二氯甲烷(10mL)溶液缓慢滴加至上述反应体系中，0℃反应20分钟，随后缓慢加入碳酸钠中和反应体系，二氯甲烷洗涤后用饱和氯化钠溶液洗涤，收集有机相浓缩并干燥，柱层析纯化(二氯甲烷：甲醇＝40：1)得化合物1(白色固体，5.61g，83％)。
(2)化合物2的制备
化合物2的结构如下：
制备过程如下：
将化合物1(3.40g，15.2mmol)溶于二氯甲烷(4mL)中，在0℃下向反应体系中加入三乙胺(8.42mL，60.6mmol)和三氟甲磺酸三甲硅酯(6.74g，30.3mmol)，室温反应2h，加水淬灭反应后用二氯甲烷萃取，收集有机相浓缩并干燥，柱层析纯化(石油醚：乙酸乙酯＝15：1)得化合物2(白色固体，3.19g，71％)。
(3)化合物4的制备
制备过程如下：
氮气环境下，将化合物2(3.05g，10.3mmol)溶于四氢呋喃(50mL)中，在-78℃下向反应体系中加入双(三甲基硅基)胺基锂(20.6mL，20.6mmol，1M in THF)，1h后，加入N,N-二甲基亚甲基碘化铵(4.72g，25.7mmol)，室温反应2h，加水淬灭反应后用乙酸乙酯萃取，收集有机相浓缩并干燥后溶于二氯甲烷(60mL)和饱和碳酸氢钠(30m L)的混合溶液中，随后加入间氯过杨苯甲酸(3.04g，20.6mmol)，5分钟后萃取，收集有机相浓缩并干燥后溶于四氢呋喃中，在0℃下加入四丁基氟化铵(13.4mL，13.4mmol，1M in THF)，30分钟后加入饱和氯化铵溶液淬灭反应，用乙酸乙酯萃取，收集有机相浓缩并干燥，柱层析纯化(石油醚：乙酸乙酯＝3：2)得化合物4(白色固体，1.31g，54％)。
对化合物4进行检测，其检测结果如下：1H NMR(400MHz,Chloroform-d)δ6.41(s,1H),5.55(s,1H),4.61(s,1H),3.68(t,J＝9.8Hz,1H),δ2.71–2.51(m,2H),2.09–2.02(m,1H),2.01–1.93(m,2H),1.84–1.73(m,1H),1.72–1.59(m,2H),1.51–1.39(m,2H),1.30(ddd,J＝26.2,12.1,6.1Hz,2H),0.79(s,3H).13C NMR(100MHz,CDCl3)δ166.2,132.0,128.9,81.1,79.6,43.1,39.9,34.1,31.3,30.9,29.6,27.5,22.2,10.3。
实施例2：化合物5的制备
化合物5的结构如下：
制备过程如下：
0℃下，向化合物4(236mg，1.00mmol)的二氯甲烷(5mL)溶液中加入咪唑(340mg，5.00mmol)和三甲基氯硅烷(327mg，3.00mmol)，1h后过滤随后收集有机相浓缩并干燥，柱层析纯化(石油醚：乙酸乙酯＝60：1)得化合物5(白色固体，256mg，83％)。
对化合物5进行检测，其检测结果如下：1H NMR(400MHz,Chloroform-d)δ6.42(s,1H),5.54(d,J＝2.7Hz,1H),4.62(d,J＝3.6Hz,1H),3.59(t,J＝7.5Hz,1H),2.71–2.47(m,2H),2.28(d,J＝6.5Hz,1H),2.05–1.70(m,4H),1.55–1.22(m,5H),0.75(d,J＝5.3Hz,3H),0.05(s,9H).13C NMR(100MHz,CDCl3)δ166.2,132.2,128.8,81.1,79.9,43.1,39.5,34.2,31.3,31.1,30.1,27.6,22.3,10.5,0.3。
实施例3：化合物6的制备
化合物6的结构如下：
制备过程如下：
使用叔丁基二甲基氯硅烷(453mg，3.00mmol)，按照实施例2所述化合物5的合成步骤获得目标化合物6(白色固体，302mg，61％)。
对化合物6进行检测，其检测结果如下：1H NMR(400MHz,Chloroform-d)δ6.41(s,1H),5.53(s,1H),4.61(s,1H),3.60(t,J＝8.8Hz,1H),2.79–2.46(m,2H),1.98(d,J＝15.2Hz,2H),1.89–1.73(m,1H),1.55(m,2H),1.46–1.38(m,1H),1.33(m,2H),1.26(m,2H),0.86(s,9H),0.75(s,3H),-0.02(s,6H).13C NMR(100MHz,CDCl3)δ166.1,132.1,128.6,81.0,79.8,43.3,39.3,34.1,30.1,29.7,27.5,25.8,22.3,18.1,10.5,-4.5,-4.9。
实施例4：化合物7的制备
化合物7的结构如下：
制备过程如下：
使用叔丁基二甲基氯硅烷(825mg，3.00mmol)，按照实施例2所述化合物5的合成步骤获得目标化合物7(白色固体，428mg，90％)。
对化合物7进行检测，其检测结果如下：1H NMR(400MHz,Chloroform-d)δ7.67–7.60(m,4H),7.46–7.31(m,6H),6.35(s,1H),5.48(s,1H),δ4.58(q,J＝2.9Hz,1H),3.69(t,J＝8.2Hz,1H),2.66–2.56(m,1H),2.49(dd,J＝16.1,2.6Hz,1H),1.94(dt,J＝15.0,3.4Hz,2H),1.83–1.70(m,1H),1.56–1.35(m,4H),1.19(dq,J＝11.8,6.6,6.0Hz,3H),1.06(s,9H),0.91(s,3H).13C NMR(100MHz,CDCl3)δ166.1,135.9,129.7,129.6,128.7,127.6,127.5,81.8,79.7,43.8,39.1,34.0,31.2,31.1,30.0,27.5,27.1,22.3,19.4,10.9。
实施例5：化合物8的制备
化合物8的结构如下：
制备过程如下：
使用三乙基氯硅烷(453mg,3.00mmol)，按照实施例2所述化合物5的合成步骤获得目标化合物8(白色固体，309mg，88％)。
实施例6：化合物9的制备
化合物9的结构如下：
制备过程如下：
使用三乙氧基氯硅烷(597mg，3.00mmol)，按照实施例2所述化合物5的合成步骤获得目标化合物9(白色固体，323mg，81％)。
实施例7：化合物10的制备
化合物10的结构如下：
制备过程如下：
使用三苯基氯硅烷(885mg，3.00mmol)，按照实施例2所述化合物5的合成步骤获得目标化合物10(白色固体，450mg，91％)。
对化合物10进行检测，其检测结果如下：1H NMR(400MHz,Chloroform-d)δ7.62(dt,J＝6.6,1.6Hz,6H),7.49–7.41(m,3H),7.37(m,6H),6.37(s,1H),5.50(s,1H),4.58(q,J＝2.8Hz,1H),3.85(t,J＝8.3Hz,1H),2.62(ddt,J＝16.0,5.3,2.9Hz,1H),2.51(dd,J＝16.0,2.6Hz,1H),2.00–1.88(m,2H),1.82–1.65(m,2H),1.59(m,1H),1.46(m,2H),1.29–1.13(m,3H),0.96(s,3H).13C NMR(100MHz,CDCl3)δ166.1,135.6,134.8,132.0,130.1,128.8,127.9,81.9,79.7,43.8,39.3,34.1,31.3,31.0,30.1,27.6,22.4,11.0。
实施例8：化合物11的制备
化合物11的结构如下：
制备过程如下：
使用异丙基二甲基氯硅烷(411mg，3.00mmol)，按照实施例2所述化合物5的合成步骤获得目标化合物11(白色固体，286mg，85％)。
对化合物11进行检测，其检测结果如下：1H NMR(400MHz,Chloroform-d)δ6.42(s,1H),5.55(s,1H),4.61(s,1H),3.59(t,J＝8.3Hz,1H),2.63(d,J＝3.9Hz,1H),2.55(d,J＝16.0Hz,1H),1.97(t,J＝13.0Hz,2H),1.89–1.72(m,2H),1.55(m,2H),1.47–1.23(m,5H),0.94(d,J＝2.9Hz,3H),0.92(d,J＝2.8Hz,3H),0.76(s,3H),-0.00(s,6H).13C NMR(100MHz,CDCl3)δ166.3,132.2,128.9,81.1,80.0,43.4,39.5,34.2,31.4,31.3,30.2,27.7,22.4,17.1,14.9,10.6,-3.4。
实施例9：化合物12的制备
化合物12的结构如下：
制备过程如下：
使用乙烯基二甲基氯硅烷(363mg，3.00mmol)，按照实施例2所述化合物5的合成步骤获得目标化合物12(白色固体，266mg，83％)。
对化合物12进行检测，其检测结果如下：1H NMR(400MHz,Chloroform-d)δ6.42(s,1H),6.08(dd,J＝19.9,14.8Hz,1H),5.97(dd,J＝14.8,4.4Hz,1H),5.74(dd,J＝19.9,4.4Hz,12H),5.56–5.52(m,1H),4.61(q,J＝2.8Hz,1H),3.61(t,J＝8.3Hz,1H),2.65(m,1H),2.56(m,1H),2.06–1.85(m,2H),1.89–1.71(m,2H),1.60–1.42(m,3H),1.36–1.31(m,1H),1.31–1.23(m,2H),0.76(s,3H),0.13(s,6H).13C NMR(100MHz,CDCl3)δ166.2,138.1,133.1,132.1,128.8,81.2,79.9,42.5,39.4,34.1,31.3,31.1,30.0,27.6,22.3,10.5,-1.4。
实施例10：化合物13的制备
化合物13的结构如下：
制备过程如下：
使用乙烯基苯基甲基氯硅烷(549mg,3.00mmol)，按照实施例2所述化合物5的合成步骤获得目标化合物13(白色固体，337mg，88％)。
实施例11：化合物14的制备
化合物14的结构如下：
制备过程如下：
使用正十八烷二甲基基氯硅烷(1.08g，3.00mmol)，按照实施例2所述化合物5的合成步骤获得目标化合物14(白色固体，421mg，77％)。
实施例12：化合物15的制备
化合物15的结构如下：
制备过程如下：
使用三甲氧基氯硅烷(471mg，3.00mmol)，按照实施例2所述化合物5的合成步骤获得目标化合物15(白色固体，253mg，71％)。
实施例13：化合物16的制备
化合物16的结构如下：
制备过程如下：
使用三正丙氧基氯硅烷(579mg，3.00mmol)，按照实施例2所述化合物5的合成步骤获得目标化合物16(白色固体，338mg，86％)。
对化合物16进行检测，其检测结果如下：1H NMR(400MHz,Chloroform-d)δ6.41(s,1H),5.54(s,1H),4.61(q,J＝2.8Hz,1H),3.58(t,J＝8.3Hz,1H),2.64(ddt,J＝16.0,5.3,2.9Hz,1H),2.56(m,1H),2.01–1.92(m,2H),1.86–1.70(m,2H),1.59–1.49(m,2H),1.38(m,2H),1.36–1.29(m,6H),1.28(m,2H),0.93(t,J＝7.3Hz,9H),0.74(s,3H),0.56–0.47(m,6H).13C NMR(100MHz,CDCl3)δ166.2,132.2,128.8,81.0,79.9,43.4,39.4,34.1,31.3,31.2,30.3,27.6,22.3,18.6,17.0,16.9,10.5。
实施例14：化合物17的制备
化合物17的结构如下：
制备过程如下：
使用(3-氯丙基)二甲基氯硅烷(513mg，3.00mmol)，按照实施例2所述化合物5的合成步骤获得目标化合物17(白色固体，278mg，75％)。
对化合物17进行检测，其检测结果如下：1H NMR(400MHz,Chloroform-d)δ6.42(t,J＝2.3Hz,1H),5.74–5.41(m,1H),4.62(d,J＝2.8Hz,1H),3.59(t,J＝8.3Hz,1H),3.50(t,J＝7.0Hz,2H),2.77–2.46(m,2H),1.98(tdt,J＝13.0,5.0,2.6Hz,2H),1.89–1.69(m,4H),1.60–1.48(m,2H),1.45–1.29(m,4H),0.75(s,3H),0.64(ddd,J＝10.6,5.9,1.6Hz,2H),0.06(s,6H).13C NMR(100MHz,CDCl3)δ166.2,131.2,128.9,81.2,79.8,48.0,43.2,39.5,34.1,31.2,30.1,29.8,27.6,27.1,22.3,14.6,10.6,-1.5。
实施例15：化合物18的制备
化合物18的结构如下：
制备过程如下：
使用环己基二甲基氯硅烷(531mg，3.00mmol)，按照实施例2所述化合物5的合成步骤获得目标化合物18(白色固体，305mg，81％)。
对化合物18进行检测，其检测结果如下：1H NMR(400MHz,Chloroform-d)δ6.42(t,J＝2.2Hz,1H),5.54(t,J＝1.8Hz,1H),4.62(d,J＝2.8Hz,1H),3.59(t,J＝8.3Hz,1H),2.72–2.46(m,2H),1.98(dddd,J＝13.3,10.8,4.6,2.3Hz,2H),1.82(dddd,J＝27.5,15.9,9.9,3.8Hz,2H),1.76–1.66(m,4H),1.60–1.49(m,2H),1.49–1.38(m,2H),1.37–1.31(m,2H),1.30–1.21(m,3H),1.17–0.98(m,3H),0.76(s,3H),0.62(tt,J＝12.2,3.0Hz,1H),-0.01(s,3H),-0.01(s,3H).13C NMR(100MHz,CDCl3)δ166.14,132.21,128.78,81.05,79.91,43.32,39.49,34.19,31.34,31.22,30.21,28.03,27.64,27.12,26.95,22.35,10.58,-3.15,-3.40。
实施例16：化合物19的制备
化合物19的结构如下：
制备过程如下：
使用三异丙基氯硅烷(579mg，3.00mmol)，按照实施例2所述化合物5的合成步骤获得目标化合物19(白色固体，318mg，81％)。
对化合物19进行检测，其检测结果如下：1H NMR(400MHz,Chloroform-d)δ6.42(s,1H),5.54(s,1H),4.61(s,1H),3.75(t,J＝8.7Hz,1H),2.65(d,J＝15.7Hz,1H),2.55(d,J＝15.6Hz,1H),2.18–1.86(m,4H),1.81(t,J＝14.0Hz,1H),1.65(m,1H),1.55–1.38(m,4H),1.30(m,3H),1.03(s,18H),0.79(s,3H).13C NMR(100MHz,CDCl3)δ166.2,131.2,128.8,81.4,79.8,43.9,39.4,34.2,31.6,31.3,30.7,27.7,22.4,18.2,18.2,12.4,10.6。
实施例17：化合物20的制备
化合物20的结构如下：
制备过程如下：
向化合物4(236mg，1.00mmol)的N,N’-二甲基甲酰胺(1mL)溶液中加入碳酸银(553mg，2.00mmol)和三苯基氯甲烷(1.12g，4.00mmol)，100℃反应12h后加水淬灭反应，用乙酸乙酯萃取，收集有机相并用饱和氯化钠溶液洗涤，随后浓缩并干燥，柱层析纯化(石油醚：乙酸乙酯＝20：1)得化合物20(白色固体，244mg，51％)。
对化合物20进行检测，其检测结果如下：1H NMR(400MHz,Chloroform-d)δ7.52–7.39(m,6H),7.28–7.15(m,9H),6.32(s,1H),5.43(s,1H),4.55(q,J＝2.8Hz,1H),3.56–3.48(m,1H),2.61–2.53(m,1H),2.44(d,J＝18.9Hz,1H),1.91(d,J＝2.6Hz,1H),1.83–1.75(m,1H),1.66–1.60(m,1H),1.21(m,4H),1.08(m,2H),1.03(s,7H).13C NMR(100MHz,CDCl3)δ166.4,145.8,132.3,129.7,129.1,128.1,126.8,86.5,82.7,80.0,44.5,39.4,34.2,31.9,31.6,28.8,28.0,23.1,12.1。
实施例18：化合物21的制备
化合物21的结构如下：
制备过程如下：
使用二(对甲氧基苯基)苯基氯甲烷(1.36g，4.00mmol)，按照实施例17所述化合物20的合成步骤获得目标化合物21(白色固体，237mg，44％)。
实施例19：化合物22的制备
化合物22的结构如下：
制备过程如下：
使用二苯基氯甲烷(812mg，4.00mmol)，按照实施例17所述化合物20的合成步骤获得目标化合物22(白色固体，197mg，49％)。
实施例20：化合物23的制备
化合物23的结构如下：
制备过程如下：
使用二苯基氯甲烷(372mg，4.00mmol)，按照实施例17所述化合物20的合成步骤获得目标化合物23(白色固体，164mg，56％)。
对化合物23进行检测，其检测结果如下：1H NMR(400MHz,Chloroform-d)δ6.42(s,1H),5.54(s,1H),4.62(q,J＝3.0Hz,1H),3.41(t,J＝8.2Hz,1H),2.70–2.61(m,2H),2.55(d,J＝17.2Hz,1H),1.98(t,J＝12.6Hz,2H),1.88–1.66(m,2H),1.62–1.48(m,2H),1.41–1.23(m,4H),1.11(s,9H),0.76(s,3H).13C NMR(100MHz,CDCl3)δ166.3,132.3,128.7,80.3,80.0,72.6,42.6,39.74,34.0,31.3,30.4,28.8,28.2,27.6,22.6,10.8。
实施例21：谷内酯衍生物的体外癌细胞抑制作用
采用四甲基偶氮唑蓝(MTT)比色法检测谷内酯衍生物对癌细胞的抑制作用。
MTT比色法实验步骤：将处于对数生长期的癌细胞按照每毫升5×104细胞数的密度接种至96孔细胞培养板中，调零孔为不含细胞的正常培养基。12小时后更换含不同浓度梯度异土谷内酯衍生物的培养基，调零孔更换正常培养基，每个浓度梯度设置5个复孔，置于37℃，5％CO2培养箱中培养。24小时后显微镜下观察细胞状态及生长变化。48小时后每孔加入四甲基偶氮唑蓝(凯基生物，5mg/mL)溶液,继续在37℃，5％CO2培养箱中培养，4小时后吸走培养基，每孔加入DMSO 100μL，使用酶标仪在570纳米波长下测量吸光度值，使用Graphpad软件进行数据统计分析，计算半数有效浓度(IC50，单位：μM)。抑制效果见下表1所示。
表1谷内酯衍生物对不同癌细胞系增殖的影响
综上所述，与天然的谷内酯相比，这些合成类似物的抗增殖作用普遍增强。其中，化合物19抗癌活性较强，具有极低的IC50，具备继续深入研究的价值，具有广谱的抗肿瘤活性，因此选择化合物19进行更深入的探究。
实施例22：化合物19敏感细胞株的筛选
经过前期一系列的实验探索，证明了化合物19具有良好的抗肿瘤活性和对肿瘤干细胞的杀伤作用，因此继续筛选敏感细胞株。通过对19种常见的肿瘤细胞系的MTT筛选，发现化合物19在Kasumi-1和WEHI-3细胞系上具有更敏感的作用，这表明化合物19在白血病细胞系上作用敏感。
表2化合物19对19种肿瘤细胞活力影响的测定
实施例23：谷内酯衍生物体内抗肿瘤作用
试验对象：本试验选用动物品系为Balb/c小鼠，18～22g，SPF级别。
试验接种内容：WEHI-3细胞尾静脉荷瘤
方法为小鼠皮下荷瘤法，WEHI-3细胞用胰岛素针进行小鼠尾静脉荷瘤。3天后，根据体重平均分为对照组及给药组，给药组每天按化合物19的100mg/kg和200mg/kg剂量给药，阳性药组按高三尖杉酯碱1mg/kg进行腹腔注射，治疗开始后每天测量小鼠体重。给药15天后，将小鼠带出动物房并取其脾、肝组织。
结果如图1所示，(A)为小鼠体长展示；(B)为小鼠体重定量分析；(C)为小鼠脾组织展示；(D)为小鼠脾重定量分析；(E)为小鼠肝组织展示；(F)为小鼠肝重定量分析。
结果表明，与对照组相比，化合物19能明显抑制肿瘤生长，且小鼠的生存状态良好，对小鼠体重几乎无影响。在保证关键器官安全的前提下，能有效地恢复AML小鼠模型的肿瘤发生，证明了治疗AML的可行性和良好的安全性。因此，化合物19能够显著抑制小鼠体内白血病细胞的生长，在有效剂量下无明显毒副作用，因此具有潜在的临床应用价值。
以上所述，只是本发明的较佳实施例而已，本发明并不局限于上述实施方式，只要其以相同的手段达到本发明的技术效果，都应属于本发明的保护范围。在本发明的保护范围内其技术方案和/或实施方式可以有各种不同的修改和变化。
Claims (7)
1.一种谷内酯衍生物，其特征在于，其结构如式Ⅰ所示：
所述R1的结构如化合物5-22中的一种：
。
2.一种权利要求1所述的谷内酯衍生物的制备方法，其特征在于，其合成路线如下所示：
当所述R1Cl为氯硅烷时，反应条件为咪唑，DCM，0℃；
当所述R1Cl为氯代烷时，反应条件为Ag2CO3,DMF,100℃。
3.权利要求1所述的谷内酯衍生物在制备治疗癌症、预防癌症和/或改善癌症症状的药物或食品中的应用。
4.根据权利要求3所述的应用，其特征在于，所述癌症包括白血病、乳腺癌、结直肠癌、肺癌、黑色素瘤、内分泌癌、骨癌、脑和CNS肿瘤、泌尿生殖器癌、头和颈部肿瘤、血癌、骨髓癌血液病症、淋巴癌、眼癌、皮肤癌、软组织肉瘤。
5.根据权利要求3所述的应用，其特征在于，所述癌症包括白血病、肺癌、淋巴癌、结直肠癌。
6.一种药物组合物，其特征在于，其活性成分为权利要求1所述的谷内酯衍生物。
7.根据权利要求6所述的药物组合物，其特征在于，还包括溶剂或可药用载体。
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