CN109575051B - 一种天然药物成分修饰衍生物及其抗肿瘤应用 - Google Patents
一种天然药物成分修饰衍生物及其抗肿瘤应用 Download PDFInfo
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Abstract
本方案公开了新药设计与合成领域的一类喜树碱衍生物I及其合成方法,喜树碱衍生物I的结构式为:
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通过天然药物成分-喜树碱修饰后得到的系列衍生物及其抗肿瘤方面的应用。
背景技术
喜树碱(CPT)是一种细胞毒性喹啉生物碱和一类有前途的抗肿瘤药物,最初是在20世纪60年代初被Wall及其同事发现的。它抑制DNA拓扑酶I(DNA Top-I),除了低溶解度和(高)药物不良反应外,它还显示出显著的抗小鼠白血病的抗癌活性。已经尝试了一些方法来合成喜树碱的衍生物,使其具有更大的生物活性和增强稳定性。其中许多化合物是分子A、B和C环修饰的产物,但这些修饰很少有增强内酯环在生理条件下的稳定性。近年来,20-羟基的酯化问题受到了越来越多的关注。由于20s-羟基被认为有增强内酯水解速度的作用--CPT(喜树碱)在中性pH值通过改变内酯-羧酸平衡而有利于形成羧酸的形式。20-羟基的酯化阻断了这一过程。这种酯化改性可提高其稳定性和水溶性。不幸的是,由于人类的生理状况可能会分解所有已知的CPT衍生物,仍然需要提供新的CPT衍生物。
在不降低生物活性的情况下,开发新型功能化的20-位酯,提高其水解稳定性是可取的。丙氨酸(Ala)含有活性的–NH2和-OH基团,因此选择了丙氨酸(Ala)作为链接剂,结合两种抗癌药物,即通过酯化CPT的20-OH基团。选择喜树碱(CPT)和去甲斑蝥素衍生物来构建双抗癌药物结合物,这是因为一方面喜树碱是DNA-拓扑酶I抑制剂,能抑制DNA合成;另一方面去甲斑蝥素素具有刺激白细胞骨髓产生的独特特征,与大多数其他容易诱发骨髓抑制的抗癌药物形成鲜明对比。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-羟基和去甲斑蝥素类衍生物通过丙氨酸作为连接链连接在一起的结构独特的天然药物成分修饰后得到的系列衍生物I,并设计合成方法高收率制备了该目标衍生物。
发明内容
本发明提供了一种结构修饰的喜树碱衍生物;其结构式如式I所示:
其中,式I的R选自H、Br或脱氢;R1选自C1-C3的烷基、环烷基、苄基、取代苄基。
一种优选的实施方式,式I的R选自H、Br或脱氢;R1选自C1-C3的烷基、环烷基、苄基。按照化学结构的书写规则,结构式中的虚线代表该化合键可以是不饱和双键或者是饱和键。
另一方面,本发明提供了喜树碱衍生物I的合成方法,包括以下步骤:1)喜树碱与N-Boc-丙氨酸1在偶联剂、有机碱催化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)化合物3与去甲斑蝥素衍生物单酸酯II在偶联剂、有机碱催化下通过酯化反应得到喜树碱衍生物I,步骤1)~步骤3)均在有溶剂的条件下进行,合成路线见以下:
其中,合成路线中式II的R和R1和式I的R和R1保持一致,R选自H、Br或脱氢为双键;R1选自C1-C3的烷基、环烷基、苄基、取代苄基。
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衍生物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衍生物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衍生物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衍生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,本发明制备喜树碱衍生物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。
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去甲斑蝥素衍生物4,化合物4中的双键可还原得到化合物5或者溴代得到化合物6、将上述化合物4、5或6分别与相应的ROH试剂反应得到去甲斑蝥单酸酯衍生物IIa-i。
(1)、制备去甲斑蝥素衍生物4
顺丁烯二酸酐12.021g,置于干燥的研体中研细溶解于乙醚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4(17.459g,85.75%),为白色固体。熔点122~123℃,比移值Rf0.52(展开剂为石油醚∶乙酸乙酯=3∶1);1HNMR(400MHz,CDCl3):δ3.18(s,2H),5.47(s,2H),6.58(s,2H)。
(2)、制备去甲斑蝥素5
取5,6-双脱氢去甲斑蝥素4(1.09g)于施兰克瓶中,加入20ml四氢呋喃使其溶解,加入110mg钯碳Pd/C,真空除去烧瓶中空气后通入氢气,25℃下搅拌使其反应,反应结束后抽滤除去钯碳,将所得滤液旋蒸,干燥,即得去甲斑蝥素5 794.3mg,收率72.2%,为白色固体。1HNMR(400MHz,DMSO-d6):δ:4.85(s,2H),3.34(d,J=20Hz,2H),1.65(d,J=8Hz,4H)。13CNMR(100MHz,DMSO-d6):δ:173.35,80.08,51.14,40.35,40.14,39.93,39.72,27.90.
(3)、制备反式-5,6-二溴去甲斑蝥素6
室温下,取5-烯-去甲斑蝥素4 5.00g,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6,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。
(2)、制备去甲斑蝥素衍生物单酸酯IIa-IIc
去甲斑蝥素衍生物单酸甲酯IIa(R=Me):称取4.15g去甲斑蝥素衍生物4溶于25ml无水甲醇中,形成悬浮液。然后向悬浮液中逐滴加入0.73ml(0.51g)三乙胺,室温下搅拌24h,旋蒸除去甲醇,得到目标粗产品。将得到的粗产品溶解于25ml二氯甲烷中,用7ml的1mol/L盐酸萃取一次,留下有机相,用10ml饱和食盐水萃取一次,留下有机相,加入适量无水MgSO4干燥15-30min,抽滤,滤饼用二氯甲烷冲洗2-3次,留下滤液,将滤液旋蒸,得到化合物IIa(4.50g,91%),为白色固体。1HNMR(400MHz,DMSO-d6):δ12.45(br,1H),6.41-6.45(m,2H),5.06(s,2H),3.64(s,3H),2.71(s,2H).13CNMR(100MHz,DMSO-d6):δ172.64,172.09,136.71,136.59,80.00,79.67,51.48,46.65,45.94。
去甲斑蝥素衍生物单酸乙酯IIb(R=Et):取去甲斑蝥素衍生物4 4.16g于烧瓶中,加入无水乙醇25ml,三乙胺0.73ml,25℃下搅拌24h,旋蒸除去乙醇,将得到的剩余物溶于25ml二氯甲烷中,使其溶解,用1equ.7ml盐酸萃取,留下有机相,再用10ml饱和食盐水萃取,留下有机相,加入适量无水硫酸镁干燥15-30分钟,抽滤,将滤液旋蒸,干燥,即得目标化合物IIb 3.95g(74.3%),为白色固体。1HNMR(400MHz,DMSO):δ:6.47(d,J=8Hz,1H),6.44(d,J=8Hz,1H),5.28(d,J=28Hz,2H),4.15(t,J=4Hz,2H),2.86(d,J=8Hz,1H),2.82(d,J=8Hz,1H),1.25(t,J=4Hz,3H).13CNMR(100MHz,DMSO):δ:177.42,171.42,136.85,136.30,80.61,80.32,61.40,47.27,46.77,13.99。
去甲斑蝥素衍生物单酸苄酯IIc(R=Bn):取去甲斑蝥素衍生物4 5.00g于烧瓶中,加入二氯甲烷40ml,苯甲醇4.7ml,4-二甲氨基吡啶0.367g,25℃下搅拌三天,抽滤,收集滤饼上的白色固体,干燥,即得化合物IIc 4.067g(50%),为白色固体。1HNMR(DMSO):δ:7.32-7.35(m,5H),6.44(d,J=36Hz,2H),4.95-5.10(m,4H),2.76(t,J=8Hz,2H).13CNMR(100MHz,DMSO):δ:173.07,171.93,137.15,136.97,128.79,128.40,80.49,80.16,66.31,47.14,46.41,40.57,40.36,39.52,39.31.
(3)、制备去甲斑蝥素单酸酯IId-IIf
去甲斑蝥素单酸甲酯IId(R=Me):称取去甲斑蝥素5 503.6mg(3mmol),溶于5ml甲醇中,加热到80℃~85℃,冷却回流,反应3.5h后放置冰箱中冷却12h,析出无色固体,抽滤,得到去甲斑蝥素单酸甲酯IId 433mg(0.725mmol),产率72.2%.1HNMR(400MHz,DMSO-d6):δ:12.22(s,1H),4.66(s,2H),3.49(s,3H),2.98(s,2H),1.50(m,4H).13CNMR(100MHz,DMSO-d6):δ:172.72,172.04,78.26,77.93,52.38,51.63,51.30,28.96,28.89.
去甲斑蝥素单酸乙酯IIe(R=Et):称取去甲斑蝥素5 672mg于烧瓶中,加入30ml无水乙醇使其溶解,80℃加热回流,4.5小时后反应完全,旋蒸,以乙酸乙酯为洗脱液过硅胶柱,点板,收集显色的样品旋蒸,干燥,即得去甲斑蝥素单酸乙酯IIe 747.2mg(收率87%),白色固体。1HNMR(400MHz,CDCl3):δ:4.91(d,J=24Hz,2H),4.11(d,J=8Hz,2H),2.99(q,J=12Hz,3H),1.81(t,J=4Hz,2H),1.52(d,J=8Hz,2H),1.21(t,J=8Hz,3H).13CNMR(100MHz,CDCl3):δ:176.45,170.87,78.59,78.29,77.03,76.71,61.16,52.27,28.97,13.94.
去甲斑蝥素单酸苄酯IIf(R=Bn):取去甲斑蝥素5 200mg(1.19mmol),置于圆底烧瓶中,加入4ml二氯甲烷溶解,后加入0.17ml三乙胺和0.13ml苄醇(1.2mmol),反应1h后,在160℃加热回流5h,冷却后,减压除去溶剂,将剩余物经柱层析得到去甲斑蝥素单酸苄酯IIf234mg,产率71.2%,为白色固体。1HNMR(400MHz,DMSO-d6):δ:12.29(s,1H),7.29-7.34(m,5H),5.01(d,J=16Hz,1H),4.99(d,J=12Hz,1H),4.69(t,J=4Hz,2H),3.03(d,J=4Hz,2H),1.49-1.53(m,4H).13CNMR(100MHz,DMSO-d6):δ:172.76,171.49,136.17,128.79,128.37,128.35,127.46,127.31,78.35,78.01,66.06,52.41,51.34,28.95,28.93.
(4)、制备去甲斑蝥素单酸酯IIg-IIi
制备5,6-二溴去甲斑蝥素单酸甲酯IIg(R=Me):
取反式-5,6-二溴去甲斑蝥素6 0.50g,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.
制备5,6-二溴去甲斑蝥素单酸乙酯IIh(R=Et):
取反式-5,6-二溴去甲斑蝥素6 0.5g,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.
制备5,6-二溴去甲斑蝥素单酸苄酯IIi(R=Bn):
在0℃下,取反式-5,6-二溴去甲斑蝥素6 0.2g,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:制备喜树碱衍生物I
喜树碱衍生物I可以通过以下步骤制备得到:1)、喜树碱与N-Boc-丙氨酸1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)、与去甲斑蝥素衍生物单酸酯II通过酯化反应得到喜树碱衍生物I。
化合物3的制备
化合物3的制备通过两步反应得到:1)、喜树碱与N-Boc-丙氨酸1DIC作为偶联催化剂通过酯化反应得到化合物2;2)、化合物2在30%的三氟乙酸水溶液催化下在二氯甲烷反应溶剂中脱除Boc保护基团得到化合物3。
化合物2(BOC-Ala-CPT)的制备
将CPT(160mg,0.45mmol),N-Boc-丙氨酸(1,160mg,0.93mmol,1.2equ.)和DMAP(0.053g,0.45mmol,1.0equ.)溶于CH2Cl2(20mL)中。将反应混合物冷却至0℃。将DIPC(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,分离有机相并用无水MgSO4干燥。减压除去溶剂,以MeOH/CHCl3=1/9作为洗脱剂,通过快速柱色谱纯化粗产物,得到目标化合物2BOC-Ala-CPT(196.2mg,86.2%),为黄色固体。Rf=0.68(DCM:CH3OH=20:1).1H NMR(400MHz,CDCl3)δ=8.38(s,1H),8.20(d,J=8.4Hz,1H),7.92(d,J=8.2Hz,1H),7.81(t,J=8.2Hz,1H),7.65(t,J=7.4Hz,1H),7.31(s,1H),5.69(d,J=17.2Hz,1H),5.40(d,J=17.2Hz,1H),5.03(d,J=9.4Hz,1H),4.52–4.40(m,1H),4.05(d,J=8.5Hz,1H),3.87–3.80(m,1H),2.27(dt,J=14.1,7.0Hz,1H),2.17(dd,J=14.2,7.2Hz,1H),1.50(d,J=7.2Hz,3H),1.13(d,J=6.5Hz,9H),0.99(t,J=7.5Hz,3H).13C NMR(100MHz,CDCl3)δ=171.91,156.83,156.08,148.94,146.40,131.02,130.52,129.79,129.32,127.97,96.29,67.07,49.97,42.17,31.67,28.43,23.51,7.59.
化合物3(Ala-CPT)的制备
将上述步骤制备得到化合物2(150mg,0.31mmol)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(64.7mg,53.4%),为淡黄色固体。Rf=0.32(DCM:CH3OH=20:1).1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),8.54(d,J=38.1Hz,2H),8.23–8.03(m,2H),7.86(t,J=7.6Hz,1H),7.71(t,J=7.5Hz,1H),7.25(d,J=12.3Hz,1H),5.54(s,2H),5.30(s,2H),4.50(d,J=65.5Hz,1H),2.20(dq,J=23.3,7.0Hz,2H),1.56(dd,J=17.4,7.1Hz,3H),1.00–0.94(m,3H).13C NMR(100MHz,DMSO-d6)δ=169.88,169.16,167.15,158.84,158.51,156.89,152.69,148.32,146.60,145.49,144.74,132.17,130.99,130.21,129.30,129.05,128.46,128.26,119.52,119.03,95.82,77.94,66.87,50.72,48.25,41.10,30.51,23.72,16.26,7.99.
喜树碱衍生物I的制备
化合物3与去甲斑蝥素衍生物单酸酯II通过酯化反应得到喜树碱衍生物I。
喜树碱衍生物Ia-Ii的制备
表1.制备喜树碱衍生物Ia-i
喜树碱衍生物Ia的制备
将化合物3(100mg,0.24mmol),化合物IIa(107mg,0.54mmol)),EDCI盐酸盐(124.0mg,0.65mmol)和DMAP(27.40mg,0.22mmol)悬浮于CH2Cl2(15ml)中,所得反应液在室温下搅拌48h,并使用薄层色谱板(DCM:CH3OH=20:1)监测反应的进展。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,有机层用无水MgSO4干燥。减压蒸馏除去溶剂,残余物通过快速柱色谱纯化,用CH2Cl2:CH3OH=97:3进行洗脱,得到淡黄色固体目标化合物Ia(98mg,69%);Rf=0.22(CH2Cl2:CH3OH=95:5).M.p.120-121℃,1H NMR(400MHz,CDCl3)δ=8.37(s,1H),8.17(dd,J=16.7,8.4Hz,1H),7.91(d,J=8.1Hz,1H),7.79(t,J=7.6Hz,1H),7.63(t,J=7.5Hz,1H),7.21(d,J=24.7Hz,1H),6.86(dd,J=39.4,7.4Hz,1H),6.50–6.29(m,2H),5.65(dd,J=17.2,6.2Hz,1H),5.40(s,1H),5.31(d,J=7.9Hz,1H),5.27(s,1H),5.09(d,J=66.0Hz,1H),4.76–4.67(m,1H),3.66(d,J=33.5Hz,3H),2.82(dd,J=14.2,4.3Hz,1H),2.29(dt,J=14.6,7.3Hz,1H),2.18(dt,J=14.2,7.7Hz,1H),2.05(s,2H),1.55(d,J=7.0Hz,1H),1.44(d,J=7.2Hz,1H),1.11(d,J=6.5Hz,1H),0.98(dt,J=15.1,7.4Hz,3H).13C NMR(100MHz,CDCl3)δ=172.02,171.59,171.54,171.12,171.05,170.98,170.70,166.92,166.67,157.25,152.19,148.79,146.43,146.38,145.36,145.11,136.84,136.78,136.74,135.59,135.54,135.45,131.20,131.14,130.61,130.57,129.67,128.39,128.36,128.15,128.00,120.37,120.04,109.99,95.91,95.90,81.25,79.23,67.05,53.44,52.90,52.29,49.95,48.14,48.09,48.01,47.94,47.61,42.14,31.75,31.66,23.47,18.87,17.68,7.54.IR(KBr)ν(cm-1)=3426,3062,2970,1749,1664,1617,1454,1402,1232,1157,1057,762.HRMS(ESI-TOF):600.1997[M+1].
喜树碱衍生物Ib的制备
将化合物3(120mg,0.29mmol),化合物IIb(130mg,0.61mmol)),EDCI盐酸盐(150.0mg,0.78mmol)和DMAP(37.0mg,0.30mmol)悬浮于CH2Cl2(15ml)中,所得反应液在室温下搅拌48h,并使用薄层色谱板(DCM:CH3OH=20:1)监测反应的进展。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,有机层用无水MgSO4干燥。减压蒸馏除去溶剂,残余物通过快速柱色谱纯化,用CH2Cl2:CH3OH=20:1进行洗脱,得到淡黄色固体目标化合物Ib(146mg,83%);M.p.111-112℃,Rf=0.26(DCM:CH3OH=95:5).1H NMR(400MHz,CDCl3)δ=8.35(s,1H),8.15(dd,J=15.6,8.6Hz,1H),7.89(d,J=7.9Hz,1H),7.77(t,J=7.6Hz,1H),7.61(t,J=7.5Hz,1H),7.28(s,1H),6.88(dd,J=68.5,7.5Hz,1H),6.43–6.31(m,1H),5.63(dd,J=17.2,3.9Hz,1H),5.37(t,J=5.1Hz,1H),5.32(dd,J=12.1,5.7Hz,1H),5.21(d,J=11.3Hz,2H),5.08(d,J=66.5Hz,1H),4.73–4.63(m,1H),4.20(ddd,J=14.2,7.1,3.2Hz,1H),2.86–2.76(m,1H),2.32–2.10(m,2H),1.58–1.40(m,3H),1.23–1.13(m,3H),1.02–0.91(m,3H).13C NMR(100MHz,CDCl3)δ=171.60,171.18,171.16,171.11,171.05,170.92,170.63,166.92,166.89,157.26,157.22,152.23,152.15,148.80,148.74,146.41,146.36,145.31,145.11,136.91,136.80,135.46,135.37,131.22,131.16,130.65,130.54,129.62,129.58,128.38,128.36,128.17,128.13,128.10,128.07,127.97,120.34,120.03,95.93,95.81,81.28,79.20,67.11,61.87,61.31,53.47,49.94,48.17,48.00,47.88,47.60,42.04,31.73,23.48,18.89,17.49,14.08,7.52.IR(KBr)ν(cm-1)=3409,3059,2981,2933,1751,1664,1618,1559,1501,1453,1403,1232,1152,1056,762.HRMS(ESI-TOF):614.2086[M+1].
喜树碱衍生物Ic的制备
将化合物3(110mg,0.26mmol),化合物IIc(130mg,0.61mmol)),EDCI盐酸盐(150.0mg,0.78mmol)和DMAP(40.0mg,0.33mmol)悬浮于CH2Cl2(15ml)中,所得反应液在室温下搅拌48h,并使用薄层色谱板(DCM:CH3OH=20:1)监测反应的进展。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,有机层用无水MgSO4干燥。减压蒸馏除去溶剂,残余物通过快速柱色谱纯化,用CH2Cl2:CH3OH=20:1进行洗脱,得到淡黄色固体目标化合物Ic(147mg,83%);M.p.121-122℃,Rf=0.22(DCM:CH3OH=95:5).1H NMR(400MHz,CDCl3)δ=8.37(s,1H),8.16(dd,J=26.1,8.4Hz,1H),7.91(d,J=8.2Hz,1H),7.83–7.76(m,1H),7.64(td,J=7.9,3.7Hz,1H),7.38–7.26(m,5H),7.21(d,J=21.3Hz,1H),6.92(d,J=7.5Hz,1H),6.78(d,J=9.3Hz,1H),6.42(ddd,J=9.9,4.9,1.5Hz,1H),6.38–6.30(m,1H),5.65(dd,J=17.2,4.0Hz,1H),5.42–5.38(m,1H),5.37–5.29(m,1H),5.28(d,J=3.8Hz,1H),5.24–5.21(m,1H),5.18(d,J=6.9Hz,1H),5.11–5.04(m,1H),5.04–4.97(m,1H),4.61–4.49(m,1H),2.95–2.78(m,2H),2.34–2.25(m,1H),2.19(td,J=13.7,7.4Hz,1H),1.54(dd,J=17.3,7.1Hz,2H),1.34(d,J=7.2Hz,2H),0.97(q,J=7.5Hz,3H).13C NMR(100MHz,CDCl3)δ=184.22,171.13,170.93,170.77,166.85,166.17,164.76,164.16,157.29,155.12,152.20,148.69,146.01,145.20,136.82,135.56,135.51,131.16,129.71,128.65,128.62,128.58,128.54,128.45,128.42,128.40,128.38,128.36,128.24,128.18,128.14,128.10,128.01,127.96,95.85,81.29,79.30,67.13,49.97,47.98,31.74,7.53.IR(KBr)ν(cm-1)=3425,3062,2970,2934,1749,1664,1617,1562,1500,1454,1402,1232,1168,1057,760.HRMS(ESI-TOF):676.2311[M+1].
喜树碱衍生物Id的制备
将化合物3(160mg,0.38mmol),化合物IId(160mg,0.80mmol)),EDCI盐酸盐(150.0mg,0.74mmol)和DMAP(53.0mg,0.43mmol)悬浮于CH2Cl2(15ml)中,所得反应液在室温下搅拌48h,并使用薄层色谱板(DCM:CH3OH=20:1)监测反应的进展。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,有机层用无水MgSO4干燥。减压蒸馏除去溶剂,残余物通过快速柱色谱纯化,用CH2Cl2:CH3OH=20:1进行洗脱,得到淡黄色固体目标化合物Id(204mg,89%);M.p.118-119℃,Rf=0.11(DCM:CH3OH=95:5).1H NMR(400MHz,CDCl3)δ=8.39(s,1H),8.18(dd,J=19.0,8.5Hz,1H),7.92(d,J=8.0Hz,1H),7.81(t,J=7.5Hz,1H),7.65(t,J=7.4Hz,1H),7.31(s,0H),7.19(s,1H),6.90(dd,J=14.3,7.6Hz,1H),5.65(d,J=17.3Hz,1H),5.39(d,J=17.2Hz,1H),5.00(d,J=4.5Hz,1H),4.89–4.83(m,1H),4.80(d,J=5.1Hz,0H),4.75–4.60(m,2H),3.74–3.61(m,3H),3.58–3.52(m,1H),3.03(dd,J=12.6,6.7Hz,2H),2.31(dd,J=13.8,7.2Hz,1H),2.18(dd,J=15.8,9.3Hz,1H),1.81–1.76(m,1H),1.69–1.63(m,1H),1.53(t,J=7.7Hz,2H),1.43(d,J=7.1Hz,2H),1.14(d,J=6.4Hz,1H),0.97(q,J=7.5Hz,3H).13C NMR(100MHz,CDCl3)δ=181.91,174.13,173.24,171.12,169.19,168.36,168.35,166.90,139.22,133.35,133.11,131.34,131.32,131.20,131.15,130.60,130.55,129.73,129.68,128.16,128.03,95.92,84.60,80.59,79.62,77.80,67.03,54.88,52.40,52.05,50.78,47.41,29.18,28.28,25.74,23.33,7.52.IR(KBr)ν(cm-1)=3440,3060,2962,1745,1664,1617,1565,1453,1402,1232,1201,1152,1057,996,815,783,724.HRMS(ESI-TOF):602.2207[M+1].
喜树碱衍生物Ie的制备
将化合物3(120mg,0.29mmol),化合物IIe(130mg,0.61mmol),EDCI盐酸盐(150.0mg,0.74mmol)和DMAP(53.0mg,0.43mmol)悬浮于CH2Cl2(15ml)中,所得反应液在室温下搅拌48h,并使用薄层色谱板(DCM:CH3OH=20:1)监测反应的进展。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,有机层用无水MgSO4干燥。减压蒸馏除去溶剂,残余物通过快速柱色谱纯化,用CH2Cl2:CH3OH=20:1进行洗脱,得到淡黄色固体目标化合物Ie(148mg,84%);M.p.92-93℃,Rf=0.28(DCM:CH3OH=95:5).1H NMR(400MHz,CDCl3)δ=8.37(s,1H),8.25(d,J=8.6Hz,1H),7.92(d,J=8.1Hz,1H),7.85–7.79(m,1H),7.65(t,J=7.4Hz,1H),7.30(s,1H),5.66(s,1H),5.38(d,J=17.3Hz,1H),5.27(s,2H),4.95(d,J=6.4Hz,1H),4.91(d,J=6.8Hz,1H),3.47(s,1H),2.90–2.82(m,2H),2.28(dd,J=14.0,7.4Hz,1H),2.15(dd,J=14.1,7.3Hz,1H),1.86–1.80(m,2H),1.69(d,J=7.3Hz,3H),1.55(s,1H),1.45(d,J=7.2Hz,1H),1.23(s,2H),0.94(t,J=7.4Hz,3H),0.89–0.81(m,3H).13C NMR(100MHz,CDCl3)δ=175.91,175.61,168.01,166.57,157.29,152.37,148.91,146.29,145.06,131.04,130.53,130.41,129.81,128.51,128.41,128.25,128.14,128.11,127.97,120.40,110.01,96.25,79.19,67.09,49.91,49.89,49.73,48.33,31.85,29.69,28.63,28.50,14.09,7.51.IR(KBr)ν(cm-1)=3441,2992,2958,2927,1731,1664,1617,1567,1455,1402,1372,1237,1203,1054,1008,929,866,817,764.HRMS(ESI-TOF):570.1889[M-OEt+1].
喜树碱衍生物If的制备
将化合物3(110mg,0.26mmol),化合物IIf(150mg,0.54mmol),EDCI盐酸盐(150.0mg,0.74mmol)和DMAP(53.0mg,0.43mmol)悬浮于CH2Cl2(15ml)中,所得反应液在室温下搅拌48h,并使用薄层色谱板(DCM:CH3OH=20:1)监测反应的进展。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,有机层用无水MgSO4干燥。减压蒸馏除去溶剂,残余物通过快速柱色谱纯化,用CH2Cl2:CH3OH=20:1进行洗脱,得到淡黄色固体目标化合物If(163mg,92%);M.p.108-109℃,Rf=0.21(DCM:CH3OH=95:5).1H NMR(400MHz,CDCl3)δ=8.36(s,1H),8.15(dd,J=30.8,7.7Hz,1H),7.91(d,J=7.6Hz,1H),7.84–7.72(m,1H),7.68–7.59(m,1H),7.30(d,J=21.7Hz,5H),7.05(dd,J=104.4,4.2Hz,2H),5.64(d,J=17.1Hz,1H),5.37(d,J=17.2Hz,1H),5.21(d,J=12.6Hz,1H),5.10(d,J=18.4Hz,1H),5.04–4.96(m,1H),4.83(d,J=19.6Hz,1H),4.66(s,1H),4.60–4.50(m,1H),3.07(d,J=23.6Hz,1H),2.31(dt,J=13.3,7.0Hz,1H),2.25–2.11(m,1H),1.76(s,2H),1.50(d,J=6.5Hz,3H),1.43–1.22(m,2H),1.13(d,J=6.1Hz,2H),0.90–1.06(m,3H).13CNMR(100MHz,CDCl3)δ=170.80,170.60,170.29,169.85,169.63,157.36,157.32,152.25,148.83,146.40,145.36,135.63,135.55,131.12,130.60,130.57,130.52,129.71,128.64,128.58,128.55,128.51,128.39,128.34,128.29,128.22,128.18,128.13,128.09,127.99,127.95,120.19,96.06,80.69,79.66,77.91,67.28,66.96,55.00,52.62,50.95,50.03,47.99,42.34,31.73,29.22,29.06,28.43,25.78,23.37,18.72,17.62,7.60,7.54.IR(KBr)ν(cm-1)=3445,3063,2962,2951,1748,1708,1664,1617,1455,1401,1232,1185,1056,997,825,761.HRMS(ESI-TOF):678.2473[M+1].
喜树碱衍生物Ig的制备
将化合物3(110mg,0.26mmol),化合物IIg(240mg,0.67mmol),EDCI盐酸盐(130.0mg,0.68mmol)和DMAP(60.0mg,0.49mmol)悬浮于CH2Cl2(15ml)中,所得反应液在室温下搅拌48h,并使用薄层色谱板(DCM:CH3OH=20:1)监测反应的进展。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,有机层用无水MgSO4干燥。减压蒸馏除去溶剂,残余物通过快速柱色谱纯化,用CH2Cl2:CH3OH=20:1进行洗脱,得到淡黄色固体目标化合物Ig(169mg,85%);M.p.126-127℃,Rf=0.28(DCM:CH3OH=95:5).1H NMR(400MHz,CDCl3)δ=8.36(d,J=11.1Hz,1H),8.21(dd,J=16.9,8.8Hz,1H),7.90(t,J=7.3Hz,1H),7.83–7.75(m,1H),7.64(d,J=7.5Hz,1H),7.19(dd,J=18.8,8.3Hz,1H),5.64(d,J=17.2Hz,1H),5.37(d,J=17.2Hz,1H),5.22(d,J=11.8Hz,2H),5.07–4.91(m,1H),4.89–4.71(m,2H),4.70(s,1H),4.40–4.22(m,1H),3.93–3.79(m,1H),3.73(s,1H),3.68(d,J=12.7Hz,1H),3.60(d,J=19.5Hz,1H),3.45–3.29(m,1H),2.29(dd,J=13.8,7.2Hz,1H),2.23(s,1H),2.16(ddd,J=15.2,8.5,6.2Hz,1H),1.61–1.41(m,3H),0.98(tt,J=15.1,5.7Hz,3H).13C NMR(100MHz,CDCl3)δ=172.76,171.12,171.06,169.32,168.93,168.02,167.20,166.96,157.24,152.08,148.78,146.52,145.07,131.26,131.20,131.13,130.65,130.56,129.85,129.64,128.39,128.33,128.17,128.12,128.07,128.01,96.63,95.99,95.58,86.68,86.52,86.34,85.35,83.98,83.64,82.91,67.16,54.05,54.00,53.82,53.68,53.47,53.04,52.64,52.30,51.61,51.53,48.87,48.18,47.57,45.60,31.65,17.84,17.67,7.66,7.55.IR(KBr)ν(cm-1)=3387,3057,2981,2941,1746,1664,1617,1561,1453,1351,1297,1232,1166,1057,948,765,761,723.HRMS(ESI-TOF):760.0343[M+1].
喜树碱衍生物Ih的制备
将化合物3(150mg,0.36mmol),化合物IIh(238mg,0.64mmol),EDCI盐酸盐(150.0mg,0.74mmol)和DMAP(60.0mg,0.49mmol)悬浮于CH2Cl2(15ml)中,所得反应液在室温下搅拌48h,并使用薄层色谱板(DCM:CH3OH=20:1)监测反应的进展。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,有机层用无水MgSO4干燥。减压蒸馏除去溶剂,残余物通过快速柱色谱纯化,用CH2Cl2:CH3OH=20:1进行洗脱,得到淡黄色固体目标化合物Ih(235mg,85%);M.p.165-166℃,Rf=0.31(DCM:CH3OH=95:5).1H NMR(400MHz,CDCl3)δ=8.38(s,1H),8.23(dt,J=30.1,9.0Hz,1H),7.92(d,J=7.8Hz,1H),7.81(t,J=7.1Hz,1H),7.64(t,J=6.3Hz,1H),7.23–7.10(m,1H),7.03–6.91(m,1H),6.68(dd,J=23.9,7.4Hz,1H),5.71–5.61(m,1H),5.43–5.35(m,0H),5.34(d,J=0.9Hz,0H),5.14–4.97(m,1H),4.90–4.78(m,1H),4.77–4.66(m,1H),4.38–4.25(m,1H),4.14(dt,J=13.2,6.7Hz,1H),4.06–3.90(m,1H),3.87–3.75(m,1H),3.35–3.15(m,1H),3.12–2.87(m,1H),2.33–2.24(m,1H),2.23–2.11(m,1H),1.61–1.41(m,3H),1.34–1.21(m,2H),1.22–1.13(m,2H),1.08–0.93(m,4H).13C NMR(100MHz,CDCl3)δ=171.08,171.01,170.83,167.10,166.94,166.64,166.48,159.80,157.28,152.12,146.49,131.22,131.18,131.11,131.10,130.65,130.64,130.62,130.55,129.68,129.66,129.63,128.17,128.15,128.13,128.11,128.07,128.05,128.02,127.99,120.04,109.98,95.74,93.58,85.40,82.99,67.08,62.21,50.04,31.90,29.68,13.87,7.64.IR(KBr)ν(cm-1)=3396,3060,2980,2936,1747,1664,1617,1561,1502,1453,1402,1297,1232,1199,1166,1056,948,761.HRMS(ESI-TOF):774.0519[M+1].
喜树碱衍生物Ii的制备
将化合物3(200mg,0.48mmol),化合物IIi(386mg,0.89mmol),EDCI盐酸盐(150.0mg,0.74mmol)和DMAP(65.0mg,0.53mmol)悬浮于CH2Cl2(15ml)中,所得反应液在室温下搅拌48h,并使用薄层色谱板(DCM:CH3OH=20:1)监测反应的进展。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,有机层用无水MgSO4干燥。减压蒸馏除去溶剂,残余物通过快速柱色谱纯化,用CH2Cl2:CH3OH=20:1进行洗脱,得到淡黄色固体目标化合物Ii(334mg,84%);M.p.167-168℃,Rf=0.32(DCM:CH3OH=95:5).1H NMR(400MHz,CDCl3)δ=8.35(s,1H),8.21(dd,J=17.1,8.6Hz,1H),7.89(t,J=7.3Hz,1H),7.85–7.74(m,1H),7.68–7.56(m,1H),7.44–7.12(m,5H),7.11–6.95(m,1H),5.63(dd,J=17.1,9.7Hz,1H),5.36(dd,J=17.3,9.0Hz,1H),5.18–5.09(m,1H),5.09–5.00(m,1H),5.00–4.92(m,1H),4.87(dd,J=16.3,11.9Hz,1H),4.78(d,J=6.5Hz,1H),4.69–4.53(m,1H),4.39–4.24(m,1H),4.00–3.87(m,1H),3.87–3.70(m,1H),3.51–3.20(m,1H),3.08(td,J=17.1,13.6,8.5Hz,1H),2.34–2.22(m,1H),2.19(s,1H),2.11(dt,J=21.5,7.6Hz,1H),1.68(dd,J=7.3,2.7Hz,1H),1.52–1.44(m,1H),1.39(q,J=9.1,6.3Hz,1H),1.05–0.87(m,3H).13C NMR(100MHz,CDCl3)δ=171.16,168.72,168.12,167.58,166.60,157.24,152.08,148.83,146.49,145.01,131.21,130.60,129.68,128.67,128.63,128.60,128.56,128.48,128.43,128.42,128.34,128.26,128.15,128.14,128.13,128.12,128.10,128.05,128.04,128.00,127.99,127.60,127.54,126.96,120.20,96.18,86.51,82.98,67.58,67.05,65.24,49.89,48.80,47.90,31.68,17.66,14.13,7.53.IR(KBr)ν(cm-1)=3399,3061,2979,2938,1748,1664,1617,1561,1500,1454,1401,1384,1350,1298,1256,1232,1166,1057,949,889,780.HRMS(ESI-TOF):836.0629[M+1].
溶解度实验
选择合成得到的化合物I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2.
表2.化合物I及CPT在25℃氯仿中的溶解度
据文献报道,喜树碱本身的溶解度较差,这也阻碍了其在体内和临床上的研究。相比之下,本发明化合物I具有显着改善的亲水溶解度,范围为54mg-70mg/mL(表2),可见20-酯基团的引入导致亲水溶解度提高数倍以上。
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喜树碱衍生物对肝癌细胞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48或72h后,用标准MTT测定法评估使用喜树碱衍生物I的抑制率。
表3、喜树碱衍生物I对于四种肿瘤细胞的抑制率a
atest solvent is DMSO.,在c=50μM下测试肿瘤细胞抑制率(%),5个平行复孔测试,抑制率为平均值±SD(标准误差);b测试溶剂为DMSO。
通过两次偶联反应,将喜树碱、丙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衍生物I。测试了合成得到的结合物I对于癌细胞体外抑制活性,证实了对于人肝癌细胞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 (7)
3.根据权利要求2所述的喜树碱衍生物I的合成方法,其特征在于: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。
4.根据权利要求2所述的喜树碱衍生物I的合成方法,其特征在于:其中,步骤2)中采用的溶剂选自二氯甲烷或氯仿。
5.根据权利要求2所述的喜树碱衍生物I的合成方法,其特征在于: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。
6.根据权利要求1所述的喜树碱衍生物I用于制备抗肿瘤药物的用途。
7.根据权利要求6所述的喜树碱衍生物I用于制备抗肿瘤药物的用途,其特征在于:所述肿瘤选自肝癌、胃癌、结肠癌或胰腺癌。
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