CN115721652B - 别一叶萩碱或其衍生物的应用 - Google Patents
别一叶萩碱或其衍生物的应用 Download PDFInfo
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- CN115721652B CN115721652B CN202211576268.0A CN202211576268A CN115721652B CN 115721652 B CN115721652 B CN 115721652B CN 202211576268 A CN202211576268 A CN 202211576268A CN 115721652 B CN115721652 B CN 115721652B
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Abstract
本发明公开了别一叶萩碱或其衍生物的应用，属于医药技术领域。本发明发现别一叶萩碱及其衍生物可应用于制备治疗白血病和/或卵巢癌的药物。本发明所述的化合物对P‑糖蛋白高表达的卵巢细胞有抗增殖效果，表明P‑糖蛋白介导的耐药较难发生。其中BA‑2和BA‑3表现出低浓度促进髓系白血病细胞分化和高浓度促进髓系白血病细胞凋亡的双重效应，与已有抗肿瘤药物相比，肿瘤细胞对此类药物较难发生耐药。
Description
技术领域
本发明属于医药技术领域，具体涉及别一叶萩碱或其衍生物的应用。
背景技术
肿瘤机体在各种致瘤因子作用下，局部组织细胞增生所形成的新生物，是严重危害人类健康的疾病，亦是导致人类死亡的第二罪魁涡首(Siegel,R.L.et al.,CACancerJ.Clin.,2022,72,7-33)。肿瘤细胞的典型特征为凋亡受阻、恶性增殖(Douglas Hanahan,Cancer Discov.,2022；12:31-46.)，白血病细胞的典型特征为凋亡受阻、恶性增殖、分化阻滞(Chuan-Xu Liu et al.,Nat.Chem.Biol.,2012,8,486-493)。因此，寻找能够促进肿瘤细胞凋亡，抑制肿瘤细胞恶性增殖，或者促进肿瘤细胞分化的药物是治疗肿瘤的重要手段。
尽管新的抗肿瘤技术如免疫治疗、细胞治疗等不断兴起，但是小分子抗肿瘤药物仍然是治疗肿瘤的重要基石。
一叶秋(Securinegasufruticosa(Pall.)Rehd)为大戟科(Euphorbiaceae)叶底珠属植物。一叶萩有活血舒筋、健脾益肾等功效，用于治疗风湿腰痛、四肢麻木和小儿疳积等。文献报道，一叶萩植株含一叶萩碱(securinine，CAS编号：5610-40-2)、别一叶萩碱(allosecurinine，CAS编号：1857-30-3)等一叶萩碱型生物碱类化合物。一叶萩碱为中枢神经兴奋剂，临床上主要用于小儿麻痹后遗症、面神经麻痹等疾病的治疗。其在肿瘤活性方面的活性也有较多的研究。现有技术关于别一叶萩碱的研究较少。
发明内容
为解决现有技术的缺点和不足之处，提供别一叶萩碱或其衍生物在制备抗肿瘤药物中的应用。
本发明的另一目的在于提供一组别一叶萩碱衍生物。
本发明的再一目的在于提供上述别一叶萩碱衍生物的制备方法。
为了实现上述发明目的，本发明采用以下技术方案：
别一叶萩碱或其衍生物在制备抗肿瘤药物中的应用，其中，别一叶萩碱衍生物为具有式1所示结构的化合物：
式中，R1代表取代或者未取代的苯基、萘基、单或稠杂环基中的任意一种；数字1为手性中心的位置，手性碳原子的构型可以为R或S构型中的一种。
进一步地，所述的取代的基团为卤素、硝基、氰基、甲砜基、苯基、烷基、环烷基中的任意一种。
进一步地，R1代表2-硝基苯基、3-硝基苯基、4-硝基苯基、2，4-二硝基苯基、3-氰基苯基、4-氰基苯基、2-氟苯基、3-氟苯基、4-氟苯基、2，4-二氟苯基、对-三氟苯基、2-氯苯基、4-氯苯基、2-溴苯基、4-溴苯基、苯基、4-苯基苯基、4-叔丁基苯基、4-甲基苯基、2-甲基苯基、2-苯并噻唑基、3-苯并噻吩基、对甲砜基苯基中的任意一种。
进一步地，所述的别一叶萩碱衍生物，其形式为光学异构体或光学纯单体。
进一步地，所述的别一叶萩碱或其衍生物优选为化合物BA-1、BA-2、BA-3、BA-4、BA-5、BA-6、BA-7、BA-8、BA-9、BA-10、BA-11、BA-12、BA-13、BA-14、BA-15、BA-16、BA-17、BA-18、BA-19、BA-20、BA-21、BA-22或BA-23；更优选为BA-2或BA-3；化合物BA-1～BA-23分别为具有如下所示结构的化合物：
进一步的，所述的别一叶萩碱或其衍生物包括别一叶萩碱、别一叶萩碱衍生物以及它们在药学上可接受的盐。
更进一步地的，所述的药学上可接受的盐的阴离子为无机阴离子或有机阴离子；无机阴离子为氯离子、溴离子、碘离子、硫酸根离子、硝酸根、亚硝酸根、磷酸根或磷酸氢根等；有机阴离子为乙酸根、丙酸根、肉桂酸根、苯甲磺酸根、柠檬酸根、乳酸根或葡萄糖酸根等。
进一步的，所述的抗肿瘤药物为促进Bax和/或p21蛋白活性的药物。
进一步的，所述的抗肿瘤药物为拮抗Bcl-2、XIAP、PARP、YAP1、c-Myc、STAT3和/或p-STAT3蛋白表达引起的肿瘤恶性增殖的药物。
进一步的，所述的抗肿瘤药物为治疗卵巢癌的药物。
更进一步的，所述的治疗卵巢癌的药物为具有抑制卵巢癌细胞增殖功能的药物。
进一步的，所述的抗肿瘤药物为治疗白血病的药物。
更进一步的，所述的治疗白血病的药物为具有促进白血病细胞分化和凋亡双重功能的药物。
进一步的，在所述的应用中，别一叶萩碱或其衍生物可以采用常用的技术将其与可药用的赋形剂制成多种剂型，包括固体剂型，半固体剂型，液体剂型和气雾剂型。这几类剂型中的具体剂型包括片剂、丸剂、颗粒剂、糖锭剂、膏剂、溶液剂、栓剂、注射剂、吸入剂和喷雾剂。其中，喷雾剂是通过一个加压器和一个喷射器或者一个干粉吸入装置而实现的。可以用作喷射器里合适的喷射剂如二氯二氟甲烷、氟三氯甲烷、二氯四氟乙烷、二氧化碳和二甲醚等。喷雾剂给药的剂量可以通过喷射器的阀门来调节。这些剂型即能用于局部或者全身给药又能用于速释或缓释给药，此类药物的给药方式有很多，除了上述方式，还有口腔给药、面颊给药、直肠给药、腹膜给药、皮表给药、皮下注射给药和气管内给药等。
皮下注射给药时，可以用水溶性或脂溶性的溶剂将此类化合物配制成溶液剂、混悬剂和乳剂。脂溶性溶剂具体包括植物油及类似油类、合成脂肪酸甘油酯、高级脂肪酸酯及乙二醇酯。
口腔给药时，可以采用常用的技术将其与可药用的赋形剂制成复合物。这些赋形剂可以将这些化合物制成多种可以被病人接受的剂型，如片剂、丸剂、混悬剂、凝胶剂等。口服制剂的配制有多种方法，如先把化合物和固体赋形剂混匀，充分研磨混合物，适当添加辅料，加工处理成颗粒。可以用于制成口服剂型的辅料包括：糖类如乳糖、这趟、甘露醇或山梨醇；纤维素类如玉米淀粉、小麦淀粉、马铃薯淀粉、明胶、西黄蓍胶、甲基纤维素、羟甲基纤维素、羧甲基纤维素纳、聚乙烯吡咯酮等。
一组别一叶萩碱衍生物，为上述应用中所述的别一叶萩碱衍生物。
上述别一叶萩碱衍生物的制备方法，是将别一叶萩碱和含有R1基团的的醛进行Baylis–Hillman反应，获得目标产物；具体包括如下步骤：
S1、将别一叶萩碱溶解于有机溶剂中，在催化剂作用下，和含有R1基团的醛充分反应，获得混合溶液；
S2、将混合溶液先进行淬灭，然后进行萃取、有机层浓缩后得到粗产物，最后分离纯化，即获得所述的别一叶萩碱衍生物。
进一步的，步骤S1中所述的有机溶剂为无水二氯甲烷、甲醇中的任意一种。
进一步的，步骤S1中所述的催化剂为四氯化钛、甲醇钠中的任意一种。
进一步的，步骤S1中所述的别一叶萩碱、含有R1基团的醛、催化剂的摩尔比为1:1.5:1.8～2。
进一步的，步骤S1中所述的反应的条件为：温度为-2±1℃、时间12±1小时。
进一步的，步骤S2中所述的淬灭的具体步骤为：向混合溶液加入饱和碳酸氢钠，调节pH为9±0.5。
进一步的，步骤S2中所述的萃取采用的试剂为二氯甲烷。
本发明相对于现有技术具有如下的优点及效果：
本发明以天然产物为先导化合物，利用有机化学和药物化学手段进行结构修饰研究，从中寻找新药先导化合物，是开展创新药物研究的创新模式之一。本发明以天然别一叶萩碱为前体化合物进行化学修饰，得到了一系列的新型别一叶萩碱衍生物。通过卵巢癌细胞体外模型的药效学评价，发现别一叶萩碱和多个新型别一叶萩碱衍生物对P-糖蛋白高表达的卵巢细胞有抗增殖效果，表明P-糖蛋白介导的耐药较难发生；同时通过白血病细胞体外模型的药效学评价，发现部分新型别一叶萩碱衍生物表现出低浓度促进髓系白血病细胞分化和高浓度促进髓系白血病细胞凋亡的双重效应，与已有白血病治疗药物相比，肿瘤细胞对本发明药物较难发生耐药。
本发明提供了一种全新结构的化合物，所采用的合成路线应用了绿色化学反应，更环保、更具有原料经济性。这些化合物可用于开发治疗白血病和卵巢癌的新药。
附图说明
图1为别一叶萩碱衍生物的合成路线图。
图2为化合物BA-2和BA-3诱导髓系白血病细胞分化作用图；其中，(a)、(b)、(c)、(d)分别对应NB-4细胞、HL60细胞、THP-1细胞、KG-1细胞采用不同浓度BA-2和BA-3诱导3天的CD11b阳性细胞百分数。
图3为化合物BA-3作用于白血病细胞48小时后细胞凋亡图；其中，(a)、(c)、(e)、(g)、(i)、(k)分别对应NB-4细胞、HL60细胞、THP-1细胞、KG-1细胞、U937细胞、K562细胞对照组，(b)、(d)、(f)、(h)、(j)、(l)分别对应NB-4细胞、HL60细胞、THP-1细胞、KG-1细胞、U937细胞、K562细胞BA-3处理组。
图4为化合物BA-3作用于白血病细胞48小时后细胞DNA含量图；其中，(a)、(c)、(e)、(g)、(i)、(k)分别对应NB-4细胞、HL60细胞、THP-1细胞、KG-1细胞、U937细胞、K562细胞对照组，(b)、(d)、(f)、(h)、(j)、(l)分别对应NB-4细胞、HL60细胞、THP-1细胞、KG-1细胞、U937细胞、K562细胞BA-3处理组。
图5为化合物BA-3作用于白血病细胞48小时后细胞周期图；其中，(a)、(c)、(e)、(g)、(i)、(k)分别对应NB-4细胞、HL60细胞、THP-1细胞、KG-1细胞、K562细胞、U937细胞对照组，(b)、(d)、(f)、(h)、(j)、(l)、(m)分别对应NB-4细胞、HL60细胞、THP-1细胞、KG-1细胞、K562细胞、U937细胞(1μM)、U937细胞(2.5μM)BA-3处理组，(n)对应统计图。
图6为化合物BA-3作用于白血病细胞48小时后细胞线粒体膜电位图；其中，(a)、(b)、(c)、(d)分别对应THP-1细胞对照组、1μM处理组、2.5μM处理组、5μM处理组组，(e)、(f)、(g)、(h)分别对应KG-1细胞对照组、0.1μM处理组、1μM处理组、2.5μM处理组，(i)、(j)、(k)、(l)分别对应U937细胞对照组、1μM处理组、2.5μM处理组、5μM处理组组。
图7为别BA-3作用于NB4细胞48小时后蛋白表达图；其中，(a)、(b)、(c)、(d)、(e)、(f)、(g)、(h)、(i)分别对应Bax蛋白、Bcl-2蛋白、XIAP蛋白、YAP1蛋白、c-Myc蛋白、Caspase3蛋白、Caspase9蛋白、STAT3蛋白、p-STAT3蛋白。
图8为别BA-3作用于THP-1细胞48小时后蛋白表达图；其中，(a)、(b)、(c)、(d)、(e)、(f)、(g)、(h)、(i)分别对应Bax蛋白、Bcl-2蛋白、c-Myc蛋白、p21蛋白、Caspase3蛋白、Caspase9蛋白、STAT3蛋白、p-STAT3蛋白、PARP蛋白。
图9为别BA-3作用于KG-1细胞48小时后蛋白表达图；其中，(a)、(b)、(c)、(d)、(e)、(f)、(g)、(h)、(i)分别对应Bax蛋白、Bcl-2蛋白、XIAP蛋白、c-Myc蛋白、p21蛋白、Caspase3蛋白、Caspase9蛋白、STAT3蛋白、p-STAT3蛋白。
图10为别BA-3作用于U937细胞48小时后蛋白表达图；其中，(a)、(b)、(c)、(d)、(e)、(f)、(g)、(h)、(i)分别对应Bax蛋白、Bcl-2蛋白、c-Myc蛋白、p21蛋白、Caspase3蛋白、Caspase9蛋白、STAT3蛋白、p-STAT3蛋白、PARP蛋白。
图11为别BA-3作用于K562细胞48小时后蛋白表达图；其中，(a)、(b)、(c)、(d)、(e)、(f)、(g)、(h)、(i)分别对应Bax蛋白、Bcl-2蛋白、XIAP蛋白、c-Myc蛋白、p21蛋白、Caspase3蛋白、Caspase9蛋白、STAT3蛋白、p-STAT3蛋白。
图12为别BA-2作用于SKOV-3细胞48小时后蛋白表达图；其中，(a)、(b)、(c)、(d)、(e)、(f)分别对应Bax蛋白、Bcl-2蛋白、STAT3蛋白、XIAP蛋白、Caspase9蛋白、CleavedCaspase9蛋白。
图13为别BA-2作用于SKOV-3/Taxol细胞48小时后蛋白表达图；其中，(a)、(b)、(c)、(d)、(e)、(f)分别对应Bax蛋白、Bcl-2蛋白、STAT3蛋白、p-STAT3蛋白、Caspase9蛋白、Cleaved Caspase9蛋白。
图14为别一叶萩碱和BA-1～BA-23对拓扑异构酶I活性研究结果图；其中，泳道1：DNA、泳道2：DNA+拓扑异构酶Ⅰ、泳道3：DNA+拓扑异构酶Ⅰ+喜树碱、泳道A：DNA+拓扑异构酶I+别一叶萩碱、泳道B～Z：DNA+拓扑异构酶I+化合物BA-1～BA-23。
具体实施方式
下面结合实施例和附图对本发明作进一步详细的描述，但本发明的实施方式不限于此。
实施例1：BA-1的制备
别一叶萩碱和2-硝基苯甲醛发生Baylis–Hillman：称取别一叶萩碱(150mg,0.69mmol)加入含有5mL无水无氧二氯甲烷的双颈瓶中，转移至2℃搅拌溶解。再加入2-硝基苯甲醛(1.04mmol)，搅拌溶解。最后加入1.242mmol四氯化钛启动反应，点TLC板监测反应，约12个小时后反应不再进行，停止反应。滴加饱和碳酸氢钠溶液调节pH至9左右，后抽滤，滤渣用二氯甲烷冲洗。收集的滤液用无水硫酸钠干燥5分钟再减压旋干得到粗产物。硅胶柱层析分离纯化，得到黄色固体BA-1，产率为71％。1H NMR(400MHz,CDCl3)δ8.02(d,J＝8.1Hz,1H),7.97(d,J＝7.9Hz,1H),7.70(t,J＝7.7Hz,1H),7.52(t,J＝7.8Hz,1H),6.62(dd,J＝9.6,5.1Hz,1H),6.31(s,1H),6.14(d,J＝9.3Hz,1H),3.86(t,J＝5.1Hz,1H),3.61(d,J＝13.3Hz,1H),2.73–2.60(m,3H),1.89(d,J＝9.9Hz,1H),1.67(s,2H),1.26(d,J＝11.8Hz,6H).13C NMR(101MHz,CDCl3)δ172.15,160.73,147.93,136.10,133.78,129.03,125.04,121.73,90.64,64.91,60.95,58.62,43.33,42.23,31.48,30.10,29.67,21.69,20.32,18.22.HR-ESIMS m/z 369.1440[M+H]+,calcd for C20H21N2O5 +369.1445.
实施例2：BA-2的制备
别一叶萩碱和3-硝基苯甲醛发生Baylis–Hillman，制备方法同实施例1，原料用量摩尔比与实施例1相同，得到黄色固体BA-2，产率为73％。1H NMR(400MHz,CDCl3)δ8.29(s,1H),8.16(d,J＝8.3Hz,1H),7.79(s,1H),7.55(t,J＝7.9Hz,1H),6.85–6.75(m,2H),5.84(s,1H),3.91(s,1H),3.63(dd,J＝13.3,3.8Hz,1H),2.76–2.66(m,3H),1.25(s,8H).13C NMR(101MHz,CDCl3)δ171.94,161.36,148.44,143.77,132.38,129.69,123.00,120.96,90.68,68.37,61.15,58.74,43.53,42.40,31.50,30.12,29.69,21.87,20.92,18.28.HR-ESIMS m/z 369.1437[M+H]+,calcd for C20H21N2O5 +369.1445.
实施例3：BA-3的制备
别一叶萩碱和4-硝基苯甲醛发生Baylis–Hillman，制备方法同实施例1，原料用量摩尔比与实施例1相同，得到黄色固体BA-3，产率为75％。1H NMR(400MHz,CDCl3)δ8.19(d,J＝8.6Hz,2H),7.62(d,J＝6.8Hz,2H),6.82–6.66(m,2H),5.80(d,J＝12.0Hz,1H),3.86(s,1H),3.57(d,J＝13.1Hz,1H),2.74–2.58(m,3H),1.89(d,J＝8.5Hz,1H),1.64(d,J＝13.1Hz,3H),1.24(s,4H).13C NMR(101MHz,CDCl3)δ171.96,161.30,148.96,148.79,147.42,126.68,123.83,121.97,121.48,90.53,68.15,61.11,58.64,43.40,42.27,31.45,29.64,21.74,20.64,18.17.HR-ESIMS m/z 369.1455[M+H]+,calcd for C20H21N2O5 +369.1445.
实施例4：BA-4的制备
别一叶萩碱和2,4-二硝基苯甲醛发生Baylis–Hillman，制备方法同实施例1，原料用量摩尔比与实施例1相同，得到黄色固体BA-4，产率为60％。BA-4.1H NMR(400 MHz,CDCl3)δ8.79(d,J＝18.9 Hz,1H),8.51(t,J＝7.2 Hz,1H),8.34(t,J＝9.1 Hz,1H),6.87–6.69(m,1H),6.41(d,J＝8.9 Hz,1H),6.25(d,J＝9.3 Hz,1H),3.91(dt,J＝18.8,5.1 Hz,1H),3.57(dd,J＝12.9,4.4 Hz,1H),2.65(dtd,J＝35.0,10.6,10.1,3.7 Hz,3H),1.89(t,J＝9.8Hz,1H),1.64(s,3H),1.38–1.22(m,4H).13C NMR(101 MHz,CDCl3)δ171.82,161.74,149.41,147.17,143.23,130.92,127.45,121.24,120.42,90.74,63.94,60.83,58.64,43.39,42.39,29.64,21.68,20.68,18.17.HR-ESIMS m/z 437.2375[M+Na]+,calcd forC20H20N3NaO7 +437.1154.
实施例5：BA-5的制备
别一叶萩碱和3-氰基苯甲醛发生Baylis–Hillman，制备方法同实施例1，原料用量摩尔比与实施例1相同，得到黄色固体BA-5，产率为67％。BA-5.1H NMR(400 MHz,CDCl3)δ7.75(s,1H),7.68(d,J＝7.9 Hz,1H),7.59(d,J＝7.6 Hz,1H),7.47(t,J＝7.8 Hz,1H),6.83–6.70(m,2H),3.93(s,1H),3.62(d,J＝9.5 Hz,1H),2.80–2.64(m,3H),1.92(d,J＝10.0 Hz,1H),1.66(s,3H),1.25(s,5H).13C NMR(101 MHz,CDCl3)δ171.89,160.87,142.93,131.66,130.55,129.49,122.07,119.11,113.08,90.53,68.36,61.04,58.66,43.41,42.22,31.49,30.11,29.68,22.68,20.76,18.15.HR-ESIMS m/z 349.1599[M+H]+,calcdfor C21H21N2O3 +349.1545.
实施例6：BA-6的制备
别一叶萩碱和4-氰基苯甲醛发生Baylis–Hillman，制备方法同实施例1，原料用量摩尔比与实施例1相同，得到黄色固体BA-6，产率为68％。BA-6.1H NMR(400MHz,CDCl3)δ7.60(d,J＝22.5Hz,2H),6.74(d,J＝15.0Hz,1H),5.77(s,1H),3.88(s,1H),3.59(d,J＝13.1Hz,1H),2.68(d,J＝25.1Hz,2H),1.89(d,J＝10.0Hz,1H),1.63(s,2H),1.30(d,J＝46.7Hz,10H).13C NMR(101MHz,CDCl3)δ171.94,161.04,148.42,146.95,132.45,126.58,122.46,121.61,111.67,90.47,68.37,61.06,58.62,43.37,42.20,31.79,31.46,29.66,21.68,20.64,18.14.HR-ESIMS m/z349.1539[M+H]+,calcd for C21H21N2O3 +349.1545.
实施例7：BA-7的制备
别一叶萩碱和2-氯苯甲醛发生Baylis–Hillman，制备方法同实施例1，原料用量摩尔比与实施例1相同，得到黄色固体BA-7，产率为70％。1H NMR(400MHz,CDCl3)δ7.75(d,J＝7.6Hz,1H),7.40–7.32(m,2H),7.30(d,J＝7.6Hz,1H),6.59(dd,J＝9.4,5.2Hz,1H),6.04–5.93(m,2H),3.84(t,J＝5.0Hz,1H),3.64(d,J＝9.5Hz,1H),2.73–2.61(m,3H),1.89(d,J＝9.9Hz,1H),1.67(d,J＝4.3Hz,3H),1.25(s,4H).13C NMR(101MHz,CDCl3)δ172.69,160.70,147.78,138.00,132.08,129.60,129.31,128.04,127.17,121.64,90.68,65.62,61.20,58.64,43.38,42.24,29.69,21.79,20.92,18.27.HR-ESIMS m/z 358.1201[M+H]+,calcdfor C20H21ClNO3 +358.1204.
实施例8：BA-8的制备
别一叶萩碱和4-氯苯甲醛发生Baylis–Hillman，制备方法同实施例1，原料用量摩尔比与实施例1相同，得到黄色固体BA-8，产率为72％。1H NMR(400MHz,CDCl3)δ7.33(d,J＝10.1Hz,4H),6.69(d,J＝11.3Hz,2H),5.68(s,1H),3.82(s,1H),3.57(d,J＝13.3Hz,1H),2.66(d,J＝24.1Hz,3H),1.88(d,J＝10.4Hz,1H),1.64(s,3H),1.44–0.91(m,6H).13C NMR(101MHz,CDCl3)δ172.12,160.90,147.90,140.09,133.75,128.79,127.42,122.22,90.40,70.38,61.54,59.23,43.40,42.21,22.25,20.73,18.23.HR-ESIMS m/z 358.1203[M+H]+,calcd for C20H21ClNO3 +358.1204.
实施例9：BA-9的制备
别一叶萩碱和2-溴苯甲醛发生Baylis–Hillman，制备方法同实施例1，原料用量摩尔比与实施例1相同，得到黄色固体BA-9，产率为68％。1H NMR(400MHz,CDCl3)δ7.74(d,J＝7.9Hz,1H),7.56(t,J＝8.1Hz,1H),7.40(t,J＝7.5Hz,1H),7.26(q,J＝4.0Hz,1H),6.59–6.48(m,1H),6.03–5.90(m,2H),4.09(s,1H),3.74(d,J＝13.3Hz,1H),2.89(d,J＝10.4Hz,1H),2.79–2.57(m,2H),1.95(d,J＝10.3Hz,1H),1.71(s,2H),1.25(s,5H).13C NMR(101MHz,CDCl3)δ172.29,159.76,145.01,139.42,132.92,129.71,128.38,127.81,122.74,122.01,90.22,67.69,60.93,58.56,43.09,41.60,29.69,21.01,20.74,17.67.HR-ESIMS m/z404.0677[M+H]+,calcd for C20H21BrNO3 +404.0679.
实施例10：BA-10的制备
别一叶萩碱和4-溴苯甲醛发生Baylis–Hillman，制备方法同实施例1，原料用量摩尔比与实施例1相同，得到黄色固体BA-10，产率为73％。1H NMR(400MHz,CDCl3)δ7.48(d,J＝6.5Hz,2H),7.30(d,J＝6.8Hz,2H),6.80–6.69(m,1H),6.64(d,J＝9.3Hz,1H),5.68(s,1H),3.86(t,J＝5.1Hz,1H),3.60(d,J＝8.4Hz,1H),2.78–2.58(m,3H),1.89(d,J＝9.9Hz,1H),1.66(s,2H),1.25(s,5H).13C NMR(101MHz,CDCl3)δ172.15,160.45,148.10,140.51,131.77,127.76,122.11,121.95,90.46,68.79,61.12,58.67,43.44,42.27,31.49,30.11,29.68,21.84,20.76,18.79.HR-ESIMS m/z 404.0696[M+H]+,calcd for C20H21BrNO3 +404.0679.
实施例11：BA-11的制备
别一叶萩碱和2-氟苯甲醛发生Baylis–Hillman，制备方法同实施例1，原料用量摩尔比与实施例1相同，得到黄色固体BA-11，产率为70％。1H NMR(400MHz,CDCl3)δ7.71–7.50(m,1H),7.35–7.24(m,1H),7.17(t,J＝7.5Hz,1H),7.02(t,J＝9.4Hz,1H),6.74–6.60(m,1H),6.52(d,J＝9.3Hz,1H),5.99(s,1H),3.82(s,1H),3.59(d,J＝12.9Hz,1H),2.69(s,3H),1.66(s,3H),1.26(d,J＝11.9Hz,4H).13C NMR(101MHz,CDCl3)δ172.21,160.92,160.44,158.46,147.53,130.86,129.70,128.75,128.33,127.94,127.13,124.46,124.36,90.45,68.11,63.44,63.29,61.43,58.65,43.36,42.15,31.46,30.30,29.65,23.69,21.79,20.62,18.23.HR-ESIMS m/z342.1499[M+H]+,calcd for C20H21FNO3 +342.1500.
实施例12：BA-12的制备
别一叶萩碱和3-氟苯甲醛发生Baylis–Hillman，制备方法同实施例1，原料用量摩尔比与实施例1相同，得到黄色固体BA-12，产率为73％。1H NMR(400MHz,CDCl3)δ7.32(d,J＝8.9Hz,1H),7.17(t,J＝9.6Hz,1H),6.99(t,J＝8.6Hz,1H),6.74–6.64(m,1H),5.73(s,1H),3.94(s,1H),3.64(d,J＝13.3Hz,1H),2.80–2.64(m,2H),1.92(d,J＝10.0Hz,1H),1.67(s,2H),1.44–1.17(m,8H),1.07(t,J＝13.1Hz,1H),0.86(d,J＝7.1Hz,1H).13C NMR(101MHz,CDCl3)δ172.12,143.97,129.26,123.87,121.63,116.31,113.45,90.96,68.69,61.02,58.66,43.36,42.07,30.21,22.36,20.72,18.65.HR-ESIMS m/z 342.1497[M+H]+,calcdfor C20H21FNO3 +342.1500.
实施例13：BA-13的制备
别一叶萩碱和4-氟苯甲醛发生Baylis–Hillman，制备方法同实施例1，原料用量摩尔比与实施例1相同，得到黄色固体BA-13，产率为75％。1H NMR(400MHz,CDCl3)δ7.37(s,1H),7.02(s,1H),6.69(s,1H),5.69(s,1H),4.25–3.24(m,3H),2.65(d,J＝25.9Hz,2H),1.87(s,1H),1.64(s,2H),1.24(s,8H).13C NMR(101MHz,CDCl3)δ172.12,160.15,147.52,137.42,128.05,127.83,122.39,122.11,115.61,115.40,90.31,68.91,61.09,58.62,43.33,42.12,29.65,21.73,20.69,18.18.HR-ESIMS m/z 342.1510[M+H]+,calcd forC20H21FNO3 +342.1500.
实施例14：BA-14的制备
别一叶萩碱和2,4-二氟苯甲醛发生Baylis–Hillman，制备方法同实施例1，原料用量摩尔比与实施例1相同，得到黄色固体BA-14，产率为75％。1H NMR(400MHz,CDCl3)δ7.59(q,J＝8.4Hz,1H),6.92(t,J＝8.4Hz,1H),6.79(t,J＝9.6Hz,1H),6.75–6.68(m,1H),6.53(d,J＝9.3Hz,1H),5.91(s,1H),3.85(t,J＝5.1Hz,1H),3.62(d,J＝9.0Hz,1H),2.77–2.59(m,3H),1.87(d,J＝9.9Hz,1H),1.66(s,2H),1.42–1.10(m,5H).13C NMR(101MHz,CDCl3)δ172.17,161.01,160.59,148.10,128.95,124.42,124.25,121.77,120.60,103.94,90.59,63.13,61.08,58.06,43.46,42.28,29.68,21.89,20.70,18.30.HR-ESIMS m/z 360.1413[M+H]+,calcd for C20H20F2NO3 +360.1406.
实施例15：BA-15的制备
别一叶萩碱和4-三氟甲基苯甲醛发生Baylis–Hillman，制备方法同实施例1，原料用量摩尔比与实施例1相同，得到黄色固体BA-15，产率为74％。1H NMR(400MHz,CDCl3)δ7.58(d,J＝8.4Hz,2H),7.53(d,J＝8.3Hz,2H),6.80–6.66(m,2H),5.74(s,1H),4.65(s,1H),3.85(s,1H),3.55(d,J＝13.1Hz,1H),2.65(dt,J＝30.1,10.2Hz,3H),1.87(d,J＝10.0Hz,1H),1.61(s,2H),1.35–0.93(m,4H).13C NMR(101MHz,CDCl3)δ171.94,160.56,147.25,145.75,130.16,129.81,126.23,125.53,122.59,90.22,68.56,61.00,58.60,43.23,41.94,21.40,20.53,17.93.HR-ESIMS m/z 392.1481[M+H]+,calcd for C21H21F3NO3 +392.1468.
实施例16：BA-16的制备
别一叶萩碱和4-甲砜基苯甲醛发生Baylis–Hillman，制备方法同实施例1，原料用量摩尔比与实施例1相同，得到黄色固体BA-16，产率为60％。1H NMR(400MHz,CDCl3)δ7.86(d,J＝4.9Hz,2H),7.61(d,J＝8.4Hz,2H),6.82–6.73(m,1H),5.75(d,J＝9.1Hz,1H),4.43(s,1H),3.85(s,1H),3.56(t,J＝13.6Hz,1H),3.02(s,3H),2.64(dd,J＝44.7,7.8Hz,3H),1.85(dd,J＝23.6,11.3Hz,1H),1.63(d,J＝13.9Hz,3H),1.41–0.89(m,4H).13C NMR(101MHz,CDCl3)δ171.86,161.10,148.08,147.87,139.66,127.64,127.60,127.05,126.93,122.29,90.40,68.71,68.42,61.05,60.91,58.62,53.41,44.41,43.34,42.15,29.60,21.61,20.61,18.10.HR-ESIMS m/z402.1330[M+H]+,calcd for C20H24NO5S+402.1370.
实施例17：BA-17的制备
别一叶萩碱和苯甲醛发生Baylis–Hillman，制备方法同实施例1，原料用量摩尔比与实施例1相同，得到黄色固体BA-17，产率为70％。1H NMR(400MHz,CDCl3)δ7.41(d,J＝7.8Hz,2H),7.34(t,J＝7.1Hz,2H),7.29(d,J＝6.0Hz,1H),6.66(s,2H),5.70(s,1H),3.81(s,1H),3.56(d,J＝9.8Hz,1H),2.73–2.55(m,3H),1.88(d,J＝9.9Hz,1H),1.64(s,2H),1.35–1.14(m,4H).13C NMR(101MHz,CDCl3)δ172.21,160.06,147.15,141.47,128.64,128.03,126.06,122.50,90.27,69.48,61.08,59.01,43.29,42.07,29.65,21.70,20.68,18.15.HR-ESIMS m/z 324.1603[M+H]+,calcd for C20H22NO3 +324.1594.
实施例18：BA-18的制备
别一叶萩碱和2-甲基苯甲醛发生Baylis–Hillman，制备方法同实施例1，原料用量摩尔比与实施例1相同，得到黄色固体BA-18，产率为65％。1H NMR(400MHz,CDCl3)δ7.22(q,J＝7.6Hz,2H),7.11(d,J＝7.6Hz,1H),6.71(dd,J＝9.4,5.2Hz,1H),6.56(d,J＝9.3Hz,1H),5.65(s,1H),3.88(t,J＝4.9Hz,1H),3.65(dd,J＝13.0,4.4Hz,1H),2.77–2.62(m,3H),2.34(s,3H),1.89(d,J＝9.8Hz,1H),1.68(s,2H),1.46–1.05(m,8H).13C NMR(101MHz,CDCl3)δ172.54,160.06,141.12,138.44,128.94,128.65,127.01,123.67,122.20,90.51,80.92,69.66,61.05,58.73,43.49,42.29,29.69,21.88,21.49,21.01,18.30.HR-ESIMS m/z338.1756[M+H]+,calcd for C21H24NO3 +338.1751.
实施例19：BA-19的制备
别一叶萩碱和4-甲基苯甲醛发生Baylis–Hillman，制备方法同实施例1，原料用量摩尔比与实施例1相同，得到黄色固体BA-19，产率为66％。1H NMR(400MHz,CDCl3)δ7.29(d,J＝8.0Hz,2H),7.17(d,J＝7.8Hz,2H),6.72–6.65(m,1H),6.56(d,J＝9.1Hz,1H),5.66(s,1H),3.90(s,1H),3.66(d,J＝13.1Hz,1H),2.74(s,1H),2.66(d,J＝10.0Hz,1H),2.34(s,3H),1.89(d,J＝10.0Hz,1H),1.68(s,2H),1.27(d,J＝12.1Hz,8H).13C NMR(101MHz,CDCl3)δ190.91,140.81,140.54,138.25,138.08,129.45,126.27,122.38,69.62,61.00,58.72,43.46,42.04,31.50,30.12,29.70,23.09,22.21,21.76,21.19,20.95,18.21.HR-ESIMS m/z 338.1763[M+H]+,calcd for C21H24NO3 +338.1751.
实施例20：BA-20的制备
别一叶萩碱和4-苯基苯甲醛发生Baylis–Hillman，制备方法同实施例1，原料用量摩尔比与实施例1相同，得到黄色固体BA-20，产率为68％。1H NMR(400MHz,CDCl3)δ7.41–7.30(m,4H),6.77–6.61(m,2H),5.67(s,1H),3.88(s,1H),3.65(d,J＝13.3Hz,1H),2.77–2.62(m,3H),1.91(d,J＝9.8Hz,1H),1.69(s,2H),1.30(s,7H),1.25(s,3H).13C NMR(101MHz,CDCl3)δ172.33,160.05,151.27,147.35,138.17,126.06,125.70,122.28,90.52,69.63,61.06,58.75,43.53,42.98,42.35,34.58,31.31,29.70,29.32,21.93,21.02,18.31.HR-ESIMS m/z 400.1917[M+H]+,calcd for C26H26NO3 +400.1907.
实施例21：BA-21的制备
别一叶萩碱和4-叔丁基苯甲醛发生Baylis–Hillman，制备方法同实施例1，原料用量摩尔比与实施例1相同，得到黄色固体BA-21，产率为71％。BA-21.1H NMR(400MHz,CDCl3)δ7.50–7.27(m,4H),6.77–6.59(m,2H),5.67(s,1H),3.88(s,1H),3.65(d,J＝13.3Hz,1H),2.80–2.59(m,3H),1.91(d,J＝9.8Hz,1H),1.69(s,3H),1.30(s,9H),1.25(s,4H).13C NMR(101MHz,CDCl3)δ172.46,160.08,152.65,147.54,138.17,126.77,126.06,125.70,122.28,90.52,68.15,61.61,59.85,43.53,42.98,35.35,29.70,21.93,21.02,18.70.HR-ESIMS m/z 380.2230[M+H]+,calcd for C24H30NO3 +380.2220.
实施例22：BA-22的制备
别一叶萩碱和苯并噻吩2-甲醛发生Baylis–Hillman，制备方法同实施例1，原料用量摩尔比与实施例1相同，得到黄色固体BA-22，产率为58％。1H NMR(400MHz,CDCl3)δ7.86(s,2H),7.44(s,1H),7.35(s,2H),6.63(t,J＝8.3Hz,1H),6.30(d,J＝9.3Hz,1H),6.05(s,1H),3.83(s,1H),3.66(d,J＝13.3Hz,1H),2.66(d,J＝17.6Hz,3H),1.85(d,J＝9.8Hz,1H),1.64(s,3H),1.37–1.24(m,6H).13C NMR(101MHz,CDCl3)δ172.65,161.19,148.46,140.78,136.93,135.76,124.71,124.22,124.02,122.92,122.55,121.66,120.60,90.70,64.78,61.53,59.51,43.50,42.57,29.69,21.95,21.13,19.10.HR-ESIMS m/z 380.1330[M+H]+,calcd for C22H22NO3S+380.1335.
实施例23：BA-23的制备
别一叶萩碱和苯并噻唑7-甲醛发生Baylis–Hillman，制备方法同实施例1，原料用量摩尔比与实施例1相同，得到黄色固体BA-23，产率为55％。1H NMR(400MHz,CDCl3)δ7.98(d,J＝8.1Hz,1H),7.88(d,J＝8.0Hz,1H),7.47(t,J＝7.7Hz,1H),7.40(d,J＝7.8Hz,1H),6.79(s,2H),6.07(d,J＝8.4Hz,1H),3.92(s,1H),3.69(d,J＝13.3Hz,1H),2.74(s,1H),2.69(d,J＝3.8Hz,1H),1.97(d,J＝7.0Hz,1H),1.66(s,2H),1.43–1.12(m,6H).13C NMR(101MHz,CDCl3)δ172.29,171.91,162.81,152.65,135.36,126.23,125.38,123.26,122.20,121.95,119.44,90.86,66.84,61.20,58.81,43.56,42.54,29.73,21.90,20.98,18.30.HR-ESIMS m/z 381.1280[M+H]+,calcd for C21H21N2O3S+381.1267.
实施例24：抗肿瘤活性测定
所有细胞在37℃，5％CO2恒温培养箱中培养。人急性早幼粒细胞白血病细胞NB4、人组织细胞淋巴瘤细胞U937、人慢性髓原白血病细胞K562、人B细胞淋巴瘤细胞SUDHL-2培养基组成：RPMI-1640培养基+10％FBS+1％双抗。人原髓细胞白血病细胞HL60、急性髓系细胞白血病细胞KG-1培养基组成：IMDM培养基+20％FBS+1％双抗。人单核细胞白血病细胞THP-1培养基组成：RPMI-1640培养基+10％FBS+0.05mMβ-巯基乙醇+1％双抗。人卵巢癌细胞SKOV3培养基组成：高糖DMEM培养基+10％FBS+1％双抗。人卵巢癌紫杉醇耐药细胞SKOV3-Taxol培养基组成：高糖DMEM培养基+10％FBS+1％双抗+40ng/mL紫杉醇。
(1)MTT实验步骤：将处于对数生长期的SKOV3、SKOV-3/Taxol细胞进行消化离心，弃上清，重悬细胞并计数，按照1×105/mL的细胞密度接种于96孔板中，过夜培养至细胞贴壁。次日将旧培养基吸除，加入100μL含药液的培养基，于培养箱中培养特定时间72h后，每孔加入20μL MTT溶液(5mg/mL)，培养箱中孵育4小时，吸除上清，每孔加入120μL DMSO，振摇5分钟，用酶标仪在490nm波长处测定吸光值。计算抑制率【＝(OD空白-OD实验)/OD空白×100％】和IC50(利用GraphPad软件计算)。MTT结果表明，别一叶萩碱及其衍生物均能移植卵巢癌细胞生长，且别一叶萩碱衍生物抗卵巢癌活性均比别一叶萩碱好，对P-糖蛋白高表达的卵巢癌细胞株具有较好的效果。其中活性最好的化合物BA-2对卵巢癌细胞的IC50为3.11-3.50μM，和阳性药紫杉醇相当。
(2)CCK8实验步骤：将处于对数生长期的NB4、HL60、THP-1、KG-1、U937、K562、SUDHL-2细胞进行离心，弃上清，重悬细胞并计数，按照1×105/mL的细胞密度接种于96孔板中，每孔50μL细胞悬液，再加入50μL含药液的培养基，于培养箱中培养特定时间72h后，每孔加入10μL CCK8溶液，培养箱中孵育2小时，用酶标仪在450nm波长处测定吸光值。计算抑制率【＝(OD空白-OD实验)/(OD空白-OD培养基)×100％】和IC50(利用GraphPad软件计算)。CCK8结果表明，别一叶萩碱及其衍生物均表现出优秀的抗肿瘤活性，其中活性最好的化合物BA-3对髓系白血病细胞的IC50为1.06-3.95μM，与阳性对照喜树碱相当。
表1.BA-1～BA-23抗肿瘤活性
实施例25：诱导白血病细胞分化研究
细胞培养方法参照实施例24。将1×105个细胞/孔种于6孔板，加入化合物(0.5,1,2.5μM)作用72h后1200rpm离心5min，弃上清，收集细胞，加入200μLCD11b-PE抗体稀释液，混匀37℃避光孵育30min。孵育结束后离心收集细胞，PBS洗涤三次，弃上清，收集细胞，最后加入200μL PBS重悬。设置合适的流式细胞仪检测参数，上机检测。结果表明，化合物BA-2和BA-3在低浓度(0.5或1μM)下可以明显诱导白血病细胞往粒细胞方向分化，且促进KG-1往粒细胞分化活性比阳性对照全反式维甲酸强，促进HL60细胞往粒细胞方向分化和阳性药全反式维甲酸效果相当(图2)。
实施例26：诱导白血病细胞凋亡研究
细胞(NB4,HL60,THP-1,KG-1,U937,K562)培养方法参照实施例24。将处于对数期的细胞种于6孔板，1×105个细胞/孔，加入化合物作用48h后，1000rpm离心5min，弃上清，收集细胞，加入100μL Annexin V Binding Buffer重悬细胞，再加入2.5μL的Annexin V-FITCReagent和2.5μL的PI Reagent。轻柔涡旋混匀后，室温避光孵育20min后加入400μLAnnexin V Binding Buffer，混匀样本。设置合适的流式细胞仪检测参数，上机检测。结果表明，BA-3(2.5μM)可以明显诱导白血病细胞进入凋亡(图3)。
实施例27：诱导对白血病细胞DNA含量和细胞周期的影响研究
细胞(NB4,HL60,THP-1,KG-1,U937,K562)培养方法参照实施例24。将处于对数期的细胞种于6孔板，1×105个细胞/孔，加入化合物作用48h后，1000rpm离心5min，弃上清，收集细胞，加入500μL 70％预冷乙醇4℃固定过夜，离心收集细胞，再加入100μL RNase A溶液，重悬细胞，37℃水浴30min。再加入400μL PI染色液混匀，4℃避光孵育30min。设置合适的流式细胞仪检测参数，上机检测。结果表明，BA-3作用后的白血病细胞，明显出现Sub-G1峰，即出现凋亡峰(图4)。同时化合物BA-3可以导致NB4,HL60,THP-1,K562细胞S期阻滞，化合物BA-3可以导致U937细胞G2期阻滞。表明化合物BA-3抑制肿瘤细胞周期进而抑制肿瘤细胞增殖(图5)。
实施例28：对白血病细胞线粒体膜电位影响研究
细胞(THP-1,KG-1,U937)培养方法参照实施例24。将处于对数期的细胞种于6孔板，1×105个细胞/孔，加入化合物作用48h后，1200rpm离心5min，弃上清，收集细胞，加入0.5mL JC-1染色工作液，颠倒数次混匀。细胞培养箱中37℃孵育20min后600×g 4℃离心4min，收集细胞。用JC-1染色缓冲液洗涤2次，最后用200μL JC-1染色缓冲液重悬后，设置合适的流式细胞仪检测参数，上机检测。结果表明，BA-3作用后的THP-1,U937,KG-1细胞线粒体膜电位发生明显的翻转，表明BA-3促进了肿瘤细胞线粒体途径介导的凋亡(图6)。
实施例29：对癌细胞蛋白表达的影响研究
细胞(NB4,THP-1,KG-1,U937,K562,SKVO-3,SKVO-3/Taxol)培养方法参照实施例24。将处于对数期的细胞种于6孔板，1×105个细胞/孔，加入化合物作用48h后，收集细胞，蛋白样品的提取，BCA法测蛋白浓度，蛋白样品的变性，电泳，转膜，5％脱脂奶粉封闭，一抗、二抗孵育，显影，于超灵敏化学发光仪检测化学发光，得到条带，用Carestream软件分析处理条带。结果表明BA-2或者BA-3促进肿瘤细胞中的抑癌蛋白Bax,p21的表达，具有明显浓度依赖性。BA-2或者BA-3还抑制了肿瘤细胞中促癌蛋白Bcl-2,XIAP,PARP,YAP1,c-Myc,STAT3,p-STAT3的表达，也具有浓度依赖性(图7-图13)。总之，BA-2或者BA-3通过抑制STAT3通路进而发挥抗肿瘤作用。
实施例30：对拓扑异构酶I抑制作用研究
反应总体积为20微升，加样顺序为buffer、BSA、Topo I、化合物或者CPT混匀，先孵育20分钟，后再加入DNA混匀，放入37℃启动反应，历时30min。反应结束后每个样品取出8微升，加入2微升5x DNA loading buffer混匀后上样，1％琼脂糖凝胶电泳(99V电压40分钟)。电泳结束后将胶浸泡于含0.5μg/ml EB的1x TAE缓冲液中染色半个小时，后水洗20min，直接凝胶成像得结果。结果发现化合物别一叶萩碱和BA-1～BA-23对拓扑异构酶I活性均没有影响(图14)。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受所述的实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。
Claims (4)
1.别一叶萩碱衍生物，其特征在于：所述的别一叶萩碱衍生物为化合物BA-1、BA-2、BA-3、BA-4、BA-5、BA-6、BA-7、BA-8、BA-9、BA-10、BA-11、BA-12、BA-13、BA-14、BA-15、BA-16、BA-17、BA-18、BA-19、BA-20、BA-21、BA-22或BA-23；化合物BA-1～BA-23分别为具有如下所示结构的化合物：
。
2.别一叶萩碱、别一叶萩碱衍生物以及它们在药学上可接受的盐在制备抗肿瘤药物中的应用，其特征在于：其中，
所述的别一叶萩碱衍生物为化合物BA-1、BA-2、BA-3、BA-4、BA-5、BA-6、BA-7、BA-8、BA-9、BA-10、BA-11、BA-12、BA-13、BA-14、BA-15、BA-16、BA-17、BA-18、BA-19、BA-20、BA-21、BA-22或BA-23；化合物BA-1～BA-23分别为具有如下所示结构的化合物：
所述的抗肿瘤药物为如下任意一种或多种：
I.治疗卵巢癌的药物；
II.治疗白血病的药物。
3.根据权利要求2所述的应用，其特征在于：
所述的别一叶萩碱衍生物为化合物BA-2或BA-3。
4.根据权利要求2所述的应用，其特征在于：
所述的药学上可接受的盐的阴离子为无机阴离子或有机阴离子；无机阴离子为氯离子、溴离子、碘离子、硫酸根离子、硝酸根、亚硝酸根、磷酸根或磷酸氢根；有机阴离子为乙酸根、丙酸根、肉桂酸根、苯甲磺酸根、柠檬酸根、乳酸根或葡萄糖酸根。
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| CN112237583A (zh) * | 2019-07-16 | 2021-01-19 | 暨南大学 | 一叶萩碱链连二聚化合物sn3-l6或其药用盐在制备抗白血病药物中的应用 |
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