CN110577551A - 喜树碱-甘氨酸-5,6-二溴去甲斑蝥素结合物及其应用 - Google Patents
喜树碱-甘氨酸-5,6-二溴去甲斑蝥素结合物及其应用 Download PDFInfo
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- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
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Abstract
本发明提供了喜树碱‑甘氨酸‑5,6‑二溴去甲斑蝥素结合物I及其制备方法，其中，式I的R选自C1‑C6的烷基、取代烷基、环烷基、苄基或取代苄基。
Description
技术领域
本发明属于新药设计与合成领域，具体涉及一类新型的喜树碱-甘氨酸-5,6-二溴去甲斑蝥素结合物及其抗肿瘤应用。
背景技术
20-(S)-喜树碱(20-(S)-Camptothecin，简称CPT)最初是在20世纪60年代早期由美国药物化学家Wani团队从中国栱桐科植物喜树Camptotheca acuminate树皮的提取物中发现，喜树是一种阔叶树，在我国传统中医药应用较早。Vishnuvajjala和Garzon-Aburbeh等研究人员先后报道了由于毒性高以及生物利用度较低，喜树碱不能用作体内抗癌试剂。药物化学家为此进行了很多尝试，希望可以得到生物活性更高和稳定性增强的喜树碱衍生物。这些衍生物大多涉及喜树碱化学结构中A、B或C环修饰的产物，然而这些修饰中很少能增强喜树碱内酯环在生理条件下的稳定性。近来，药物学家开始更多地关注20-羟基的酯化，20S-羟基本身被认为增加了CPT的内酯环在中性pH下水解速率，通过移动内酯-羧酸平衡向有利于羧酸一侧进行；20-羟基的酯化可阻断这一过程，从而可以增加母体结构的稳定性和水溶性。一般来说，对于某种癌症或许有几个癌症基因或病理通路；而药物代谢仍然是导致大多数肿瘤治疗失败的原因，此外耐药性也是经常面临的难题。鉴于这些情况，需要设计双靶药物以达到最佳治疗效果。喜树碱是一种拓扑异构酶I抑制剂，去甲斑蝥素具有刺激骨髓产生白细胞独特特征，此外，去甲斑蝥素通过抑制蛋白磷酸酶发挥抑制癌细胞生长的作用。由于甘氨酸分子中同时含有活性NH和OH基团，选择甘氨酸作为连接剂以连接因此选择喜树碱和去甲斑蝥素，来构建抗癌双靶点药物结合物。
为了寻找药效更好，毒性更强的抗癌药物候选者，本发明设计了将喜树碱的20位-羟基和5,6-双脱氢去甲斑蝥素通过甘氨酸连接在一起的结构独特的喜树碱-甘氨酸-5,6-二溴去甲斑蝥素结合物，并设计合成方法高收率制备了目标衍生物。
发明内容
本发明提供了一种新型喜树碱-甘氨酸-5,6-二溴去甲斑蝥素结合物；其结构式如式I所示，其中，式I的R选自C1-C6的烷基、取代烷基、环烷基、苄基或取代苄基。
一种优选的实施方式，式I的R选自C1-C4的烷基、取代烷基、环烷基或苄基；更优选的，式I的R选自甲基、乙基、丙基、丁基、环丙基或苄基。
另一方面，本发明提供了喜树碱-甘氨酸-5,6-二溴去甲斑蝥素结合物I的合成方法，包括以下步骤：1)喜树碱与N-Boc-甘氨酸1在偶联剂及有机碱存在下在偶联剂及有机碱存在下通过酯化反应得到化合物2；2)化合物2在三氟乙酸催化下脱除Boc保护基团得到化合物3；3)与5,6-二溴去甲斑蝥素单酸酯II在偶联剂及有机碱存在下通过酯化反应得到喜树碱-甘氨酸-5,6-二溴去甲斑蝥素结合物I，合成路线见以下：
其中，合成路线中式II和式I的R保持一致，选自C1-C6的烷基、取代烷基、环烷基。
一种优选的实施方式，步骤1)中所述偶联剂选自1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(缩写为EDCI)、二环己基碳二亚胺(缩写为DCC)或N,N-二异丙基碳二亚胺(缩写为DIC)；步骤1)中的所述有机碱选自三乙胺、二异丙基胺、4-二甲氨基吡啶(缩写为DMAP)、1,4-二氮杂二环[2.2.2]辛烷(缩写为DABCO)等；所述溶剂选自卤代烃溶剂，如二氯甲烷、氯仿。
一种优选的实施方式，步骤2)中采用的溶剂选自二氯甲烷或氯仿。
一种优选的实施方式，步骤3)中所述偶联剂选自1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(缩写为EDCI)、二环己基碳二亚胺(缩写为DCC)或N,N-二异丙基碳二亚胺(缩写为DIC)；步骤1)中的所述有机碱选自三乙胺、二异丙基胺、4-二甲氨基吡啶(缩写为DMAP)、1,4-二氮杂二环[2.2.2]辛烷(缩写为DABCO)等；所述溶剂选自卤代烃溶剂，如二氯甲烷或氯仿。
在上述合成路线中，反应溶剂可依据反应对温度、溶剂极性的需求，从N,N-二甲基甲酰胺(缩写为DMF)、二甲基亚砜(缩写为DMSO)、二氯甲烷、氯仿、四氢呋喃或异丙醚中选取。
反应温度可依据反应类型适当选取。
反应时间可通过薄层层析TLC、高效液相色谱法HPLC或LC-MS液相质谱联用等监控手段追踪反应情况得出。
活性测试证明，本发明设计并合成得到喜树碱-甘氨酸-5,6-二溴去甲斑蝥素结合物I具有很好的抗肝癌效果。因此，第三方面，本发明提供了喜树碱-甘氨酸-5,6-二溴去甲斑蝥素结合物I用于制备抗肿瘤药物的用途；优选地，用于制备抗肝癌、胃癌、结肠癌和胰腺癌药物的用途。
本发明的有益之处在于：本发明提供了喜树碱-甘氨酸-5,6-二溴去甲斑蝥素结合物I，该衍生物整合了喜树碱与去甲斑蝥素衍生物两类活性药物片段，为新型双靶点肿瘤抑制剂。经活性测试证明该喜树碱-甘氨酸-5,6-二溴去甲斑蝥素结合物具有良好的抗肿瘤效果，尤其是肝癌、胃癌、结肠癌和胰腺癌活性高。此外，本发明制备喜树碱-甘氨酸-5,6-二溴去甲斑蝥素结合物I的方法，原料易得，成本低廉，合成反应目标产物收率高；易于制备得到。
具体实施方式
以下将通过具体实施例进一步阐述本发明，但并不用于限制本发明的保护范围。在不脱离本发明构思的前提下，本领域技术人员可对权利要求的各参数或条件做出的改进或组合，这些改进或组合也应视为本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。本发明中使用的溶剂及试剂来自国药集团上海试剂公司。除特别说明外，所用试剂均为化学纯。
实施例1、制备化合物II
参照文献，呋喃与顺丁烯二酸酐在四氢呋喃中反应得到5,6-双脱氢去甲斑蝥素4，2)然后在氯仿溶剂中，滴加液溴得到反式-5,6-二溴去甲斑蝥素5；3)最后5,6-二溴去甲斑蝥素与相应醇试剂ROH反应以较高收率生成相应的5,6-二溴去甲斑蝥素单酸单酯化合物II。
(1)、制备5-烯-去甲斑蝥素4
顺丁烯二酸酐12.02g，置于干燥研体中研细并溶解于乙醚90mL，缓慢滴加呋喃13mL。反应液在38℃反应1h后，溶液出现白色固体，且随反应时间增长，白色固体增多。反应至24h后抽滤，得目标化合物1(17.46g，85.75％)，为白色固体。熔点122～123℃，Rf0.52(展开剂石油醚∶AcOEt＝3∶1)；1HNMR(400MHZ,CDCl3)：δ3.18(s，2H)，5.47(s，2H)，6.58(s，2H)。
(1)、制备反式-5,6-二溴去甲斑蝥素5
室温下，取5-烯-去甲斑蝥素15.00g，加入三氯甲烷20mL在室温下搅拌成悬浮状，20min内边搅拌边用滴液漏斗滴加2.5mL三氯甲烷与0.5mL液溴的混合液。待反应结束后抽滤，用四氯化碳洗涤3次，得8.30g反式-5,6-二溴去甲斑蝥素5,为白色固体，收率85.4％。熔点：157～159℃，Rf:0.65(petroleum ether:ethyl acetate＝2:1).1HNMR(400MHZ,DMSO-d6)δ：5.20(d，J＝4Hz，1H)，5.02(s，1H)，4.51-4.57(m，2H)，3.87(s，2H)。13CNMR(100MHZ,DMSO-d6)δ：171.82，170.73，86.98，83.31，52.44，52.40，48.96，46.92。IR(KBr):v(cm-1):1782，1238，1085，972，917。
(3)、制备5,6-二溴去甲斑蝥素单酸甲酯IIa(R＝Me):
取反式-5,6-二溴去甲斑蝥素20.50g，置于圆底烧瓶中，加入5mL无水甲醇，室温下开始搅拌，在搅拌过程中缓慢加入无水甲醇5mL，反应5h后，抽滤，得产物白色固体，干燥后称重为472mg，收率86％。熔点：>240℃。Rf＝0.41(ethyl acetate:methanol＝3:1).1HNMR(400MHZ,DMSO-d6)δ:12.61(s，1H)，4.78(q，J＝4Hz，2H)，4.70(d，J＝4Hz，2H)，3.54(s，3H),3.23(s，2H)。13CNMR(100MHZ,DMSO-d6)δ：170.76，170.21，86.79，86.50，54.31，54.08，51.68，49.28，48.25。IR(KBr):v(cm-1):1730，1693,1435，1351,1273，1227，964,932，812,797.
(4)、制备5,6-二溴去甲斑蝥素单酸乙酯IIb(R＝Et):
取反式-5,6-二溴去甲斑蝥素20.5g，置于圆底烧瓶中，加入1.5mL无水乙醇，开始搅拌升高温度至78℃时溶液开始回流，然后缓慢逐滴滴加无水乙醇，直至溶液变得澄清。然后趁热抽滤，冷却结晶，抽滤，得一白色固体，干燥后称重为469mg，收率82％。熔点：164-165℃。Rf:0.65(ethyl acetate:methanol＝3:1).1HNMR(400MHZ,DMSO-d6)δ：12.66(s，1H)，4.74(d，J＝28Hz，2H)，4.42(s，1H)，4.00(q，J＝8Hz，2H)，3.54(t，J＝12Hz，1H),3.35(t，J＝12Hz，1H)，3.21(s，1H)，1.15(q，J＝4Hz，3H).13C NMR(100MHZ,DMSO-d6)δ：170.74，169.63，86.75，86.46，60.35，54.31，54.13，49.21，48.31，13.83。IR(KBr):v(cm-1):1779，1243，1084，969，916.
(5)、制备5,6-二溴去甲斑蝥素单酸苄酯IIc(R＝Bn):
在0℃下，取反式-5,6-二溴去甲斑蝥素20.2g，置于圆底烧瓶中，加入0.17mL三乙胺，0.13mL苄醇和4mL二氯甲烷，反应1h后，加热回流5h，冷却，减压除去溶剂，经柱层析得白色固体，干燥后称重为216mg，收率81％。熔点:137-139℃。Rf:0.76(ethyl acetate:methanol＝3:1).1HNMR(400MHZ,DMSO-d6)δ:12.74(br，1H)，7.37(s，5H)，5.06(t，J＝16Hz，1H)，4.95(t，J＝4Hz，2H)，4.80(d，J＝8Hz，1H)，4.43(d，J＝16Hz，2H)，3.60(d，J＝8Hz，1H)，3.39(t，J＝8Hz，1H)。13CNMR(100MHZ,DMSO-d6)δ：171.48,169.52,135.75,128.38,128.36,128.04,128.01,126.39,86.11,82.37,66.15,54.67,53.88,48.47,46.77。IR(KBr):v(cm-1):1785,1615,1238,1086,1007,970,919,852。
实施例2、制备喜树碱-甘氨酸-5,6-二溴去甲斑蝥素结合物I
喜树碱-甘氨酸-5,6-二溴去甲斑蝥素结合物I通过以下步骤制备得到：1)、喜树碱与N-Boc-甘氨酸1在偶联剂及有机碱存在下在偶联剂及有机碱存在下通过酯化反应得到化合物2；2)、化合物2在三氟乙酸催化下脱除Boc保护基团得到化合物3；3)、与5,6-二溴去甲斑蝥素单酸酯II在偶联剂及有机碱存在下通过酯化反应得到喜树碱-甘氨酸-5,6-二溴去甲斑蝥素结合物I。
化合物2(BOC-Gly-CPT)的制备
将CPT(160mg，0.46mmol)，N-Boc-甘氨酸(1，160mg，0.92mmol，2equ.)和DMAP(0.053g，0.45mmol，1.0equ.)溶于CH2Cl2(20mL)中。将反应混合物冷却至0℃。将DIC(0.52mL，3.35mmol，1.3equ.)逐滴加入到反应混合物中。将反应保持在冰浴中并连续搅拌1h，然后在室温下搅拌以避免副反应。使用TLC(CH2Cl2：CH3OH＝20：1)监测反应的进程。反应完成后，将反应混合物用水淬灭，分离有机相用MgSO4干燥。减压除去溶剂，通过MeOH/CHCl3＝1/9作为洗脱剂的快速柱色谱纯化粗产物，得到目标化合物2BOC-Gly-CPT(200mg，86.2％)，为黄色固体。Rf＝0.68(CH2Cl2:CH3OH＝20:1).1H NMR(400MHz,CDCl3)δ＝8.33(s,1H),8.18(d,J＝4Hz,1H),7.59-7.77(m,3H),7.24(d,J＝8Hz,1H),5.63(d,J＝8Hz 1H),5.34(d,J＝8Hz,2H),5.21(s,2H),4.30(s,3H),4.14(d,J＝4Hz,1H),4.01(d,J＝8Hz,1H),3.77-3.82(m,3H),2.08-2.25(m,5H),0.94(t,J＝8Hz,3H).13C NMR(100MHz,CDCl3)δ＝169.54,167.23,167.03,157.30,157.09,155.58,152.15,148.77,146.35,145.57,131.18,130.64,129.63,128.36,128.12,128.03,119.91,96.31,80.17,67.04,49.96,42.37,42.00,31.66,38.33,23.48,7.56.
化合物3(Gly-CPT)的制备
将上述步骤制备得到化合物2(150mg，0.30mmol)溶于50％TFA的CH2Cl2(20mL)中，并在回流下连续搅拌24h以脱除氨基酸上的Boc基团。除去溶剂后，加入冷无水乙醚(20mL)，有淡黄色固体沉淀产生。过滤收集沉淀，并使用冷乙醚(20mL×3)洗涤两次。粗产物用CH2Cl2稀释并用饱和NaHCO3洗涤。有机相用MgSO4干燥。除去溶剂后，通过使用CH2Cl2:CH3OH＝80:1作为洗脱剂的快速柱色谱法纯化残余物，得到标题产物3(64mg，53.4％)，为淡黄色固体。Rf＝0.32(CH2Cl2:CH3OH＝20:1).1H NMR(400MHz,DMSO-d6)δ＝8.63(s,1H),8.05-8.15(m,2H),7.87(t,J＝8Hz,2H),7.71(t,J＝8Hz,2H),7.43(s,1H),5.47-5.66(m,2H),5.32(s,2H),4.12-4.28(m,2H),2.20-2.32(m,2H),1.08(t,J＝8Hz,3H).13C NMR(100MHz,DMSO-d6)δ＝169.56,167.21,157.28,155.60,152.14,148.72,146.32,145.57,131.15,130.60,129.62,128.37,128.10,127.98,119.93,96.31,67.02,49.95,42.38,31.66,25.82,7.56.
喜树碱-甘氨酸-5,6-二溴去甲斑蝥素结合物Ia(R＝Me)的制备
将化合物3(120mg，0.30mmol)，化合物IIa(210mg，0.59mmol)，EDCI(124.0mg，1.29mmol)和DMAP(25mg，0.16mmol)悬浮于CH2Cl2(15ml)中，所得反应液在冰浴搅拌反应2h，随后室温下搅拌48h。加入CH2Cl2(40ml)以稀释反应混合物，然后用H2O(20mL×3)洗涤混合物，分液，有机层用MgSO4干燥。减压除去溶剂，残余物通过快速柱色谱纯化，用CH2Cl2:CH3OH＝50:1洗脱，得到目标化合物Ia(191mg，85.2％)，为淡黄色固体。M.p.213-215℃,Rf＝0.41(CH2Cl2:CH3OH＝20:1，紫外254nm下观察显色).1H NMR(400MHz,DMSO-d6)δ＝8.58(d,J＝8Hz,1H),8.15(dd,J＝8Hz,8Hz,1H),8.03(t,J＝8Hz,1H),7.83(t,J＝8Hz,1H),7.68(t,J＝8Hz,1H),7.03(d,J＝20Hz,1H),5.47(s,2H),5.30(d,J＝40Hz,1H),5.16(d,J＝16Hz,2H),4.99(d,J＝4Hz,1H),4.76(s,1H),4.5-4.6(m,3H),4.26(dd,J＝16Hz,4Hz,1H),3.72(t,J＝8Hz,1H),3.63(dd,J＝16Hz,4Hz,1H),3.34(s,2H),2.12(s,2H),0.89(s,3H).13C NMR(100MHz,DMSO-d6)δ＝176.19,175.91,175.07,174.67,166.96,166.87,165.96,165.90,156.78,156.75,152.63,148.24,146.48,146.41,144.83,144.71,131.95,131.87,130.84,130.71,130.09,130.06,129.51,129.29,128.89,128.82,128.34,128.30,128.12,128.09,119.57,119.44,95.35,95.23,86.82,86.67,82.93,82.90,77.16,77.09,66.90,53.95,53.80,53.56,50.58,50.56,48.26,48.24,46.61,46.55,30.95,7.88.IR(KBr)ν(cm-1)＝3446,3218,2989,1756,1716,1661,1606,1502,1401,1333,1254,1172,1057,995,763,617.
喜树碱-甘氨酸-5,6-二溴去甲斑蝥素结合物Ib(R＝Et)的制备
将(20S)-喜树碱氨基乙酸酯(150mg,0.37mmol)和化合物IIb(190mg,0.51mmol)溶解于二氯甲烷15mL，冰浴搅拌反应,随后逐滴加入EDCI(150g,0.74mmol)和DMAP(0.028g,0.22mmol)，冰浴反应2h，室温反应48h。加入CH2Cl2(40ml)以稀释反应混合物，然后用H2O(20mL×3)洗涤混合物，分液，有机层用MgSO4干燥。减压除去溶剂，残余物通过快速柱色谱纯化，用CH2Cl2:CH3OH＝50:1洗脱，得到目标化合物Ib(240mg，85.2％)，为淡黄色固体。M.p.208-210℃,Rf＝0.67(DCM:CH3OH＝20:1，紫外254nm下观察显色).1H NMR(400MHz,DMSO-d6)δ＝8.65(d,J＝4Hz,1H),8.17(dd,J＝8Hz,8Hz,1H),8.10(dd,J＝8Hz,4Hz,1H),7.86(t,J＝8Hz,1H),7.70(t,J＝8Hz,1H),7.04(d,J＝16Hz,1H),5.47(s,2H),5.34(d,J＝4Hz,1H),5.24(d,J＝8Hz,2H),4.99(d,J＝4Hz,1H),4.75(s,1H),4.49-4.63(m,3H),4.23(dd,J＝8Hz,8Hz,1H),3.72(t,J＝8Hz,1H),3.62(dd,J＝8Hz,8Hz,1H),3.33(s,2H),2.02-2.17(m,2H),1.12-1.34(m,3H),0.87(t,J＝8Hz,3H).13C NMR(100MHz,DMSO-d6)δ＝176.19,175.89,175.06,174.65,166.98,166.88,165.94,165.87,156.83,156.82,152.74,148.30,146.55,146.47,144.80,144.68,132.04,131.97,130.88,130.75,130.23,129.58,129.36,129.99,128.93,128.42,128.40,128.19,128.18,119.60,119.47,95.42,95.27,86.81,86.66,82.88,82.78,77.15,77.07,66.91,53.94,53.80,53.56,50.68,48.24,45.59,45.54,30.86,7.85.
喜树碱-甘氨酸-5,6-二溴去甲斑蝥素结合物Ic(R＝Bn)的制备
将(20S)-喜树碱氨基乙酸酯(200mg,0.49mmol)和化合物IIc(400mg,0.89mmol)溶解于二氯甲烷15mL，冰浴搅拌反应,随后逐滴加入DIC(0.31mL,2.05mmol)和DMAP(0.028g,0.22mmol)，冰浴反应2h，室温反应72h。加入CH2Cl2(40ml)以稀释反应混合物，然后用H2O(20mL×3)洗涤混合物，分液，有机层用MgSO4干燥。减压除去溶剂，残余物通过快速柱色谱纯化，用CH2Cl2:CH3OH＝80:1洗脱，得到目标化合物Ib(344mg，84.0％)，为淡黄色固体。M.p.191-193℃,Rf＝0.41(DCM:CH3OH＝20:1，紫外254nm下观察显色).1H NMR(400MHz,DMSO-d6)δ＝8.61(s,1H),8.09-8.16(m,2H),7.85(s,1H),7.68(s,1H),7.30(d,J＝12Hz),6.53(s,1H),5.45(d,J＝16Hz,8H),5.26(s,1H),3.65(s,6H),1.86(s,1H),0.87(s,5H).13CNMR(100MHz,DMSO-d6)δ＝172.93,157.23,156.56,152.97,150.43,148.36,131.98,130.81,130.25,129.46,128.93,128.83,128.58,128.37,128.08,119.49,109.99,97.15,87.05,72.82,66.67,65.69,50.68,49.16,30.72,23.73,8.22.IR(KBr)ν(cm-1)＝3433,3266,3166,2972,2937,1741,1653,1602,1581,1500,1439,1368,1349,1234,1197,1158,1115,1043,1006,917,772,725.
实施例3.溶解度实验
选择合成得到的化合物Ia以及母体化合物喜树碱CPT，溶于25℃的氯仿，溶解度结果列于表1.
表1.化合物Ia及CPT在25℃氯仿中的溶解度
化合物Ia在氯仿中的溶解度是CPT的多倍。正如我们预期的那样，合成产物Ia在有机溶剂中的溶解度要比CPT好很多。
实施例4.生物活性测试实验
细胞株和溶剂
肿瘤细胞株：
人肝癌细胞HEPG2，人胃癌细胞BGC803，人结肠癌细胞SW480，人胰腺癌细胞PANC-1
细胞培养于含10％胎牛血清的RPMI1640中培养基
溶剂：二甲亚砜(简称为DMSO)。
MTT法检测细胞抗肿瘤活性实施方案
本试验以斑蝥素为阳性对照，DMSO溶剂为空白对照，进行了浓度为50μmol/mL喜树碱-甘氨酸-5,6-二溴去甲斑蝥素结合物对肝癌细胞HEPG2、人胃癌细胞BGC803、结肠癌细胞SW480和胰腺癌PANC-1四种肿瘤细胞的抑制活性测试。在药物处理72h后，用标准MTT测定法评估使用喜树碱-甘氨酸-5,6-二溴去甲斑蝥素结合物I的抑制率。
表2、喜树碱-甘氨酸-5,6-二溴去甲斑蝥素结合物I对于四种肿瘤细胞的抑制活性
atest solvent is DMSO.
通过两次偶联反应，将喜树碱、甘氨酸和功能化的去甲斑蝥素构建成结合物，并以较好的收率得到一系列新型喜树碱-甘氨酸-5,6-二溴去甲斑蝥素结合物I。测试了合成得到的结合物I对于癌细胞体外抑制活性，尤其是，对于人肝癌细胞HEPG2、胃癌细胞BGC803、结肠癌细胞SW480和胰腺癌PANC-1四种癌细胞系有较强的抑制活性；可将其用于制备相应抗肿瘤候选药物。
Claims (9)
1.喜树碱-甘氨酸-5,6-二溴去甲斑蝥素结合物I：
其中，式I的R选自C1-C6的烷基、取代烷基、环烷基、苄基或取代苄基。
2.根据权利要求1所述的喜树碱-甘氨酸-5,6-二溴去甲斑蝥素结合物I，其中，式I的R选自C1-C4的烷基、环烷基或苄基。
3.根据权利要求2所述的喜树碱-甘氨酸-5,6-二溴去甲斑蝥素结合物I，其中，式I的R选自甲基、乙基、丙基、丁基、环丙基或苄基。
4.根据权利要求1-3任意一项所述的喜树碱-甘氨酸-5,6-二溴去甲斑蝥素结合物I的合成方法，包括以下步骤：
1)喜树碱与N-Boc-甘氨酸1在偶联剂及有机碱存在下在偶联剂及有机碱存在下通过酯化反应得到化合物2；2)化合物2在三氟乙酸催化下脱除Boc保护基团得到化合物3；3)与5,6-二溴去甲斑蝥素单酸酯II在偶联剂及有机碱存在下通过酯化反应得到喜树碱-甘氨酸-5,6-二溴去甲斑蝥素结合物I，合成路线见以下：
其中，合成路线中式II和式I的R保持一致，选自C1-C6的烷基、取代烷基、环烷基。
5.根据权利要求4所述的喜树碱-甘氨酸-5,6-二溴去甲斑蝥素结合物I的合成方法，其中，步骤1)中所述偶联剂选自EDCI、DCC或DIC；步骤1)中所述有机碱选自三乙胺、二异丙基胺、DMAP或DABCO；所述溶剂选自二氯甲烷或氯仿。
6.根据权利要求4所述的喜树碱-甘氨酸-5,6-二溴去甲斑蝥素结合物I的合成方法，其中，步骤2)中采用的溶剂选自二氯甲烷或氯仿。
7.根据权利要求4所述的喜树碱-甘氨酸-5,6-二溴去甲斑蝥素结合物I的合成方法，其中，步骤3)中所述偶联剂选自EDCI、DCC或DIC；步骤1)中所述有机碱选自三乙胺、二异丙基胺、DMAP或DABCO；所述溶剂选自二氯甲烷或氯仿。
8.根据权利要求1-3任意所述的喜树碱-甘氨酸-5,6-二溴去甲斑蝥素结合物I用于制备抗肿瘤药物的用途。
9.根据权利要求7所述的用途，其中，所述肿瘤选自肝癌、胃癌、结肠癌或胰腺癌。
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EA200000376A1 (ru) * | 1997-10-03 | 2000-10-30 | Фармация Энд Апджон С.П.А. | Полимерные производные камптотецинов |
| DE10047529A1 (de) * | 2000-09-22 | 2002-04-11 | Biotechnolog Forschung Gmbh | Triazolo-Epothilone |
| CN1656101A (zh) * | 2002-05-31 | 2005-08-17 | 希格马托制药工业公司 | 喜树碱20位酯 |
| CN102516347A (zh) * | 2011-12-15 | 2012-06-27 | 东北林业大学 | 喜树碱20位胆酸衍生物及其制备方法 |
| CN105399757A (zh) * | 2015-12-29 | 2016-03-16 | 遵义医学院 | 酸敏感型喜树碱-20位去甲斑蝥酸酯衍生物及其抗肿瘤应用 |
| CN105566338A (zh) * | 2014-10-08 | 2016-05-11 | 兰州大学 | 一种喜树碱类化合物及其制备方法和用途 |
-
2018
- 2018-06-08 CN CN201810589833.4A patent/CN110577551A/zh active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EA200000376A1 (ru) * | 1997-10-03 | 2000-10-30 | Фармация Энд Апджон С.П.А. | Полимерные производные камптотецинов |
| DE10047529A1 (de) * | 2000-09-22 | 2002-04-11 | Biotechnolog Forschung Gmbh | Triazolo-Epothilone |
| CN1656101A (zh) * | 2002-05-31 | 2005-08-17 | 希格马托制药工业公司 | 喜树碱20位酯 |
| CN102516347A (zh) * | 2011-12-15 | 2012-06-27 | 东北林业大学 | 喜树碱20位胆酸衍生物及其制备方法 |
| CN105566338A (zh) * | 2014-10-08 | 2016-05-11 | 兰州大学 | 一种喜树碱类化合物及其制备方法和用途 |
| CN105399757A (zh) * | 2015-12-29 | 2016-03-16 | 遵义医学院 | 酸敏感型喜树碱-20位去甲斑蝥酸酯衍生物及其抗肿瘤应用 |
Non-Patent Citations (1)
| Title |
|---|
| 严晓莺: "几种抗癌活性成分对人正常肝细胞LO2毒性的体外实验研究", 《中国优秀博硕士学位论文全文数据库（硕士） 医药卫生科技辑》 * |
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