CN109796468A - 大环nannocystin衍生物、及其制备方法和用途 - Google Patents

大环nannocystin衍生物、及其制备方法和用途 Download PDF

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CN109796468A
CN109796468A CN201910234635.0A CN201910234635A CN109796468A CN 109796468 A CN109796468 A CN 109796468A CN 201910234635 A CN201910234635 A CN 201910234635A CN 109796468 A CN109796468 A CN 109796468A
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nannocystin
cancer
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big ring
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CN109796468B (zh
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张炜程
陈悦
田云锋
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Nankai University
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Abstract

本发明创造的目的在于提供大环nannocystin衍生物、及其制备方法和用途，这些衍生物在体外抗癌活性测试中表现了很高的抗癌活性，可作为治疗癌症的药物以及癌症辅助治疗的药物使用。

Description

大环nannocystin衍生物、及其制备方法和用途
技术领域
本发明属于药物化学领域，具体涉及大环nannocystins的结构衍生物、制备方法以及这些衍生物在制备治疗癌症药物或治疗癌症的辅助药物中的用途。
背景技术
微生物产生的次级代谢物是发现新药的重要源泉。最近粘细菌(myxobacteria)作为一类重要的药源性微生物受到广泛关注。2015年分别由和Hoepfner领导的两个独立研究组先后发表文章，报道从一种粘细菌Nannocyctis的两个不同菌株ST201196和MB1016的发酵培养液中发现了一类具有新颖结构的化合物，命名为nannocystin(Angew.Chem.Int.Ed.2015,54,10145-10148；Angew.Chem.Int.Ed.2015,54,10149-10154)。其主要代表性化合物为nannocystin A。该分子具有21元大环结构，其骨架由聚酮和三肽两个片段首尾相接组成，含有9个手性中心和两个共轭反式烯烃双键。值得注意的是，该分子中的α，β-环氧酰胺为nannocystin类化合物独有，迄今尚未在其它已知天然产物中发现。
生物测试表明，nannocystin A具有良好的抗癌活性。例如，等发现nannocystin A对于14种癌细胞系具有很高的抗癌活性，IC50值可达较低纳摩尔浓度范围。特别是该分子对于普通人乳腺癌细胞MDA-MB231和耐药乳腺癌细胞MDA-A1均显示良好的抑制效果，其IC50值分别为6.5nM和12nM；相比之下，紫杉醇类抗癌药多西他赛(docetaxel)对于耐药癌细胞MDA-A1的抑制效果(IC50＝570nM)与MDA-MB231(IC50＝0.3nM)相比则下降很多。这显示了nannocystin A作为先导化合物在发展新型抗癌药物中的重要价值。
此外，由Hoepfner带领的另一个研究团队也发现nannocystin A对于472种癌细胞显示不同程度的抑制作用，其IC50值范围在0.5μM～5nM之间。进一步研究发现该分子的主要作用靶标为真核延长因子1A(eukaryotic elongation factor 1A)。值得注意的是，这一靶标与其他常见抗癌药物(例如紫杉醇，埃博霉素，顺铂等)的靶标不同。
鉴于(1)nannocystin A具有新颖的大环结构、(2)该分子在体外抗癌活性测试中表现较高的抗癌活性、以及(3)该分子具有独特的体内作用靶标，从nannocystin A的结构出发设计合成其结构衍生物，有望发展得到具有新颖抗癌作用机制的靶向抗癌药物。目前世界上包括本课题组在内的很多研究组都开展了该分子的全合成研究，并且已经各自独立地建立了合成nannocystin A或者其天然结构类似物的多条不同路线(Angew.Chem.Int.Ed.2016,55,13263-13266；Org.Lett.2016,18,4702–4705；Org.Lett.2016,18,5768-5770；Chem.Commun.2017,53,5549-5552；Org.Lett.2017,19,4536-4539；J.Org.Chem.2017,82,9217-9222；J.Org.Chem.2018,83,6977–6994)。
我们在本课题组发表的nannocystin A的高效全合成(Org.Lett.2016,18,5768-5770)的基础上，对于该分子开展了系统的抗癌活性构效关系，设计合成了大量衍生物并对其进行了生物测试。目前已经发表3篇文章(Eur.J.Med.Chem.2018,150,626–632；Tetrahedron Lett.2018,59,3206–3209；J.Mol.Struct.2019,1181,568–578)，从而初步阐明了该分子的关键活性结构要素。在此基础上，我们经过进一步大量系统研究，在保持该天然产物抗癌活性的同时简化其结构，得到了具有新颖结构的nannocystin衍生物，其中部分衍生物的活性甚至优于天然产物的活性。
发明内容
本发明创造的目的在于提供大环nannocystin衍生物、及其制备方法和用途，这些衍生物在体外抗癌活性测试中表现了很高的抗癌活性，可作为治疗癌症的药物以及癌症辅助治疗的药物使用。
大环nannocystin衍生物，该衍生物涉及如下式结构的化合物1及其药学上可接受的盐：
其中，R1＝氢、、碳原子数为1至10的饱和或不饱和芳香酰基，或者碳原子数为1至10的碳环、碳链、或者杂环酰基。
进一步，该衍生物涉及如下式结构的化合物2及其药学上可接受的盐：
其中，R2＝碳原子数为1至9的饱和或不饱和芳香酰基，或者碳原子数为1至9的碳环、或者碳原子数为1至9的碳链、或者碳原子数为1至9的杂环酰基。
进一步，该衍生物涉及如下式结构的化合物3及其药学上可接受的盐：
本发明还在于公开大环nannocystin衍生物的制备方法，化合物3的制备方法如下：
进一步，化合物2的制备方法如下：
另外，本发明还在于公开大环nannocystin衍生物在制备抗癌药物以及作为抗癌辅助治疗药物中的应用，其中，化合物1及其在药学上可以接受的盐用于治疗的癌症为肝癌、结肠癌、胰腺癌中的一种。
进一步，化合物2及其在药学上可以接受的盐用于治疗的癌症为肝癌、结肠癌、胰腺癌中的一种。
进一步，化合物3及其在药学上可以接受的盐用于治疗的癌症为肝癌、结肠癌、胰腺癌中的一种。
具体实施方式
下面通过具体的实例对本发明进行详细说明，但这些实施方式的用途和目的仅用来举例说明本发明，并非对本发明的实际保护范围构成任何形式的任何限定，更非将本发明的保护范围局限于此。
实施例1
室温下向溶于3毫升CH2Cl2的化合物4(1.00g,2.70mmol)和化合物5(548.45mg,2.35mmol)的溶液中先后加入HATU(1.3g,3.4mmol)和DIPEA(584mg,4.5mmol)。反应搅拌8小时后用旋干挥发性物质，剩余物溶于EtOAc(25mL)，依次用1％HCl,饱和NaHCO3水溶液、饱和食盐水洗，无水Na2SO4干燥。将干燥后的溶液减压浓缩后，不需纯化直接用于下一步反应。
将上述得到的固体的CH2Cl2溶液中加入HNEt2，室温搅拌2小时。旋蒸除去挥发性物质后硅胶柱分离得到化合物6(657.94mg,67％)。1H NMR(400MHz,CDCl3)δ7.84(d,J＝8.1Hz,1H),4.65(d,J＝8.5Hz,1H),4.05(d,J＝9.8Hz,1H),3.78(dd,J＝9.9,2.4Hz,1H),3.69(s,3H),2.84(d,J＝4.4Hz,1H),2.35(s,3H),1.76(s,1H),1.58–1.46(m,1H),1.40–1.24(m,1H),1.18–1.05(m,1H),0.93(t,J＝7.5Hz,3H),0.88–0.80(m,12H),-0.02(t,J＝7.8Hz,6H).13C NMR(101MHz,CDCl3)δ173.26,170.93,70.07,63.72,53.74,52.23,38.55,36.21,25.67,25.14,18.14,15.88,11.92,-5.57,-5.65.HRMS–ESI(m/z):[M+H]+calcd forC17H36N2NaO4Si+:383.2337；found:383.2340.
实施例2
室温下向溶于2毫升CH2Cl2的化合物6(100.59mg,0.279mmol)和化合物7(100mg,0.306mmol)的溶液中加入HATU(159mg,0.418mmol)and DIPEA(72mg,0.558mmol)，搅拌过夜。反应结束后旋干挥发物，EtOAc(50mL)溶解后分别用1％HCl，饱和NaHCO3水溶液，饱和食盐水洗，无水Na2SO4干燥。旋蒸除去挥发性物质后硅胶柱分离得到化合物8(151.72mg,74％)。1H NMR(400MHz,CDCl3)δ6.76(d,J＝7.6Hz,1H),6.33(s,1H),4.65(d,J＝11.3Hz,1H),4.54(d,J＝6.7Hz,1H),4.07(d,J＝9.7Hz,1H),3.87(s,1H),3.78(d,J＝9.7Hz,1H),3.69(s,3H),3.22(s,3H),3.10(s,1H),2.98(s,3H),2.15(s,1H),1.87(s,1H),1.78(s,3H),1.67(s,1H),1.50(s,3H),1.30(d,J＝17.0Hz,1H),1.01(s,1H),0.93(s,3H),0.86(s,12H),0.03(d,J＝11.9Hz,6H).13C NMR(101MHz,CDCl3)δ171.37,170.62,169.55,146.90,83.89,80.29,63.26,60.72,60.62,59.17,56.64,54.26,52.38,32.97,30.88,30.33,25.86,24.44,18.98,18.27,15.88,15.28,10.58,-5.34,-5.56.HRMS–MALDI(m/z):[M+Na]+calcdfor C27H49IN2O7SiNa+,691.2246；found:691.2249.
实施例3
室温下向化合物8(65.53mg,0.098mmol)的THF(2mL)溶液中加入LiOH水溶液(2.5M，0.2mL)，搅拌2小时。反应结束后加入10％NaHSO4水溶液，EtOAc(20mL)稀释后用饱和食盐水洗，无水Na2SO4干燥。旋蒸除去挥发性物质后硅胶柱分离得到化合物9，直接用于下一步反应。
室温下向溶解有化合物9(188.54mg,0.288mmol)，化合物10(129.20mg,0.345mmol)，HOBT(77.77mg,0.576mmol)，和EDCI(66.97mg,0.432mmol)的THF(4mL)溶液中加入NaHCO3(36.24mg,0.432mmol)，搅拌过夜。反应结束后减压旋蒸，浓缩物以EtOAc(50mL)溶解后用饱和食盐水洗，再以无水Na2SO4干燥。旋蒸除去挥发性物质后硅胶柱分离得到化合物11(213.22mg,81％)。1H NMR(400MHz,CDCl3)δ7.19(dd,J＝8.9,5.3Hz,5H),7.08(d,J＝8.7Hz,1H),6.75(d,J＝7.0Hz,1H),6.24(s,1H),5.54–5.43(m,2H),4.89–4.81(m,2H),4.44(t,J＝9.4Hz,2H),4.36–4.29(m,1H),3.96(dd,J＝10.0,3.7Hz,1H),3.77(t,J＝6.6Hz,1H),3.62(dd,J＝9.9,6.1Hz,1H),3.14–3.07(m,2H),3.05(s,3H),2.97(s,3H),2.74(s,1H),2.66(dd,J＝13.9,6.9Hz,1H),2.05(s,1H),1.77(s,2H),1.68(s,4H),1.37(d,J＝10.1Hz,3H),1.03(s,3H),1.00–0.96(m,3H),0.95(s,3H),0.80(d,J＝8.5Hz,15H),0.00(d,J＝1.7Hz,6H).13C NMR(101MHz,CDCl3)δ171.53,170.59,169.97,169.75,146.97,138.63,138.10,128.25,127.67,116.29,83.75,80.76,80.37,71.95,62.79,61.73,60.64,59.87,59.44,56.57,54.75,42.81,33.08,31.75,31.03,27.00,26.76,25.99,24.80,18.96,18.37,16.00,15.93,15.21,10.76,-5.25,-5.39.HRMS–MALDI(m/z):[M+Na]+calcd forC42H68IN3O9SiNa+,936.3662；found:936.3665.
实施例4
室温无水无氧条件下向溶于化合物11(191.94mg,0.21mmol)的无水DMF(50mL)中依次加入Pd(OAc)2(86.00mg,0.38mmol)和Cs2CO3(136.0mg,0.42mmol)，再加入Et3N(3.2mg,0.31mmol)的DMF(4mL)溶液，避光搅拌2天。反应结束后加入H2O(100mL)，再以EtOAc萃取三次(200mL×3)。合并的有机萃取溶液用饱和食盐水洗，无水Na2SO4干燥。旋蒸除去挥发性物质后硅胶柱分离得到化合物12(115.54mg,70％)。1H NMR(400MHz,CDCl3)δ7.28–7.18(m,6H),6.92(dd,J＝12.0,7.5Hz,2H),6.28(dd,J＝14.7,11.2Hz,1H),6.09–6.01(m,1H),5.90(s,1H),5.83(dd,J＝15.2,4.4Hz,1H),4.63(t,J＝10.0Hz,1H),4.51(d,J＝11.5Hz,1H),4.21(dt,J＝16.0,5.9Hz,1H),3.81(dd,J＝9.8,3.9Hz,1H),3.64–3.55(m,1H),3.49(t,J＝9.1Hz,1H),3.09(s,3H),3.00(s,3H),2.92(d,J＝9.7Hz,1H),2.58(s,1H),2.23(s,1H),2.15–2.03(m,3H),1.67(d,J＝6.2Hz,3H),1.45(s,3H),1.16(s,4H),1.12(s,3H),1.01(d,J＝6.7Hz,3H),0.80(dd,J＝13.4,6.2Hz,15H),-0.01(d,J＝6.4Hz,6H).13C NMR(101MHz,CDCl3)δ170.69,170.43,169.19,169.07,138.72,136.14,133.98,129.46,128.21,127.79,126.49,126.05,84.66,80.03,72.51,63.07,61.74,60.39,59.63,58.69,55.70,54.66,41.86,31.85,31.04,29.83,27.30,26.20,25.82,24.28,18.23,15.65,15.45,14.12,10.88,10.51,10.33,-5.33,-5.51.HRMS–MALDI(m/z):[M+Na]+calcd for C42H67N3O9SiNa+,808.4539；found:808.4542.
实施例5
室温下向化合物12(86.46mg,0.11mmol)的THF(4mL)溶液中加入TBAF(0.16ml,0.17mmol)，搅拌3小时。反应结束后加入NH4Cl(2mL)水溶液，EtOAc萃取5遍(15mL×5)。合并的有机相用饱和食盐水洗，再以无水Na2SO4干燥。旋蒸除去挥发性物质后硅胶柱分离得到化合物3(73.81mg,90％)。1H NMR(400MHz,DMSO)δ8.18(t,J＝14.7Hz,1H),7.48(d,J＝7.6Hz,2H),7.42(s,1H),7.29–7.24(m,3H),7.20(t,J＝7.0Hz,1H),6.33(dd,J＝14.6,11.6Hz,1H),6.04(td,J＝11.3,7.1Hz,2H),5.86(s,1H),5.01(s,1H),4.69–4.64(m,1H),4.56(t,J＝11.1Hz,2H),4.48–4.39(m,1H),3.59(dd,J＝10.5,2.8Hz,1H),3.51(dd,J＝10.9,5.3Hz,1H),3.45–3.39(m,1H),3.03(d,J＝7.8Hz,3H),2.93(s,3H),2.67–2.57(m,2H),2.09(d,J＝11.8Hz,1H),2.04(s,1H),1.95(d,J＝3.6Hz,1H),1.64(s,3H),1.41(s,3H),1.11(s,3H),1.04(d,J＝3.7Hz,1H),0.97(s,3H),0.90(d,J＝6.8Hz,3H),0.79(t,J＝6.1Hz,6H).13C NMR(101MHz,DMSO)δ170.46,169.62,168.88,168.25,139.82,137.94,133.40,129.12,127.83,127.01,126.04,124.95,83.93,78.59,71.77,62.75,61.21,59.43,59.16,58.10,55.14,53.34,41.71,30.89,30.81,29.64,28.19,24.59,23.98,15.16,14.83,10.72,10.05,9.85.HRMS–MALDI(m/z):[M+Na]+calcd for C36H53N3O9Na+,694.3674；found:694.3678.
实施例6
零摄氏度下向化合物3(33.59mg,0.05mmol)的CH2Cl2(4mL)溶液依次加入DMAP(0.61mg,0.005mmol)、NEt3(12.14mg,0.12mmol)、acetic anhydride(6.12mg,0.06mmol)，室温搅拌8小时。反应结束后加入饱和NH4Cl(2mL)水溶液，EtOAc萃取5遍(15mL×5)。合并的有机相用饱和食盐水洗，再以无水Na2SO4干燥。旋蒸除去挥发性物质后硅胶柱分离得到化合物2a(24.98mg,70％)。1H NMR(400MHz,DMSO)δ8.62(d,J＝9.9Hz,1H),7.92(d,J＝8.5Hz,1H),7.53(d,J＝7.5Hz,2H),7.32(t,J＝7.4Hz,2H),7.28–7.23(m,1H),6.43–6.31(m,1H),6.16–6.06(m,2H),5.93(s,1H),5.12(s,1H),4.77(dd,J＝13.5,5.7Hz,1H),4.63(d,J＝9.8Hz,2H),4.13–4.01(m,2H),3.64(d,J＝10.0Hz,1H),3.09(s,3H),3.01(s,3H),2.67(d,J＝8.6Hz,2H),2.12(t,J＝12.4Hz,1H),1.97(s,1H),1.92(s,3H),1.68(s,3H),1.45(s,3H),1.30(s,1H),1.12(s,3H),1.00(s,3H),0.95(d,J＝6.7Hz,4H),0.83(t,J＝7.2Hz,7H).13CNMR(101MHz,DMSO)δ170.29,169.90,169.65,168.79,167.84,139.84,138.10,133.47,129.04,127.82,127.03,126.06,124.94,83.93,78.72,71.82,63.90,61.22,59.52,58.90,58.18,55.17,50.19,41.86,31.05,30.79,29.70,28.05,24.46,24.07,20.57,14.89,14.80,10.74,10.09,9.77.HRMS–ESI(m/z):[M+H]+calcd for C38H56N3O10 +:714.3960；found:714.3949.
实施例7
零摄氏度下向化合物3(33.59mg,0.05mmol)的CH2Cl2(4mL)溶液依次加入NEt3(16.19mg,0.16mmol)和正戊酰氯(19.2mg,0.16mmol)，室温搅拌8小时。反应结束后加入饱和NH4Cl(2mL)水溶液，EtOAc萃取5遍(15mL×5)。合并的有机相用饱和食盐水洗，再以无水Na2SO4干燥。旋蒸除去挥发性物质后硅胶柱分离得到化合物2b(22.68mg,60％)。1H NMR(400MHz,DMSO)δ8.63(d,J＝9.8Hz,1H),7.83(d,J＝8.3Hz,1H),7.53(d,J＝7.4Hz,2H),7.32(t,J＝7.4Hz,2H),7.25(t,J＝6.9Hz,1H),6.37(dd,J＝14.5,11.7Hz,1H),6.15–6.06(m,2H),5.93(s,1H),5.13(s,1H),4.78–4.71(m,1H),4.62(dd,J＝10.5,8.8Hz,2H),4.11(qd,J＝11.1,5.2Hz,2H),3.64(dd,J＝10.5,3.0Hz,1H),3.09(s,3H),3.00(s,3H),2.68(dd,J＝9.9,1.9Hz,2H),2.24–2.17(m,2H),2.12(t,J＝9.3Hz,1H),2.03–1.94(m,1H),1.68(s,3H),1.45(s,4H),1.30–1.19(m,3H),1.12(s,3H),1.00(s,3H),0.95(d,J＝6.8Hz,4H),0.86–0.79(m,11H).13C NMR(101MHz,DMSO)δ172.47,170.30,169.66,168.67,167.76,139.83,138.07,133.43,129.07,127.83,127.03,126.05,124.92,83.93,78.70,71.78,63.83,61.20,59.50,58.92,58.16,55.16,50.34,41.84,33.08,30.94,30.82,29.67,28.08,26.38,24.46,24.02,21.59,14.92,14.80,13.58,10.72,10.04,9.75.HRMS–MALDI(m/z):[M+Na]+calcd for C41H61N3O10Na+,778.4249；found:778.4252.
实施例8
零摄氏度下向化合物3(33.59mg,0.05mmol)的CH2Cl2(4mL)溶液依次加入NEt3(16.19mg,0.16mmol)和化合物13(14.03mg,0.075mmol)，室温搅拌8小时。反应结束后加入饱和NH4Cl(2mL)水溶液，EtOAc萃取5遍(15mL×5)。合并的有机相用饱和食盐水洗，再以无水Na2SO4干燥。旋蒸除去挥发性物质后硅胶柱分离得到化合物2c(30.98mg,75％)。1H NMR(400MHz,DMSO)δ8.56(d,J＝9.8Hz,1H),7.77(d,J＝8.3Hz,1H),7.47(d,J＝7.4Hz,2H),7.25(t,J＝7.7Hz,2H),7.18(t,J＝7.2Hz,1H),6.31(dd,J＝15.2,10.9Hz,1H),6.09–6.00(m,2H),5.87(s,1H),5.06(s,1H),4.71–4.65(m,1H),4.56(dd,J＝10.4,8.9Hz,2H),4.04(ddd,J＝16.9,11.0,5.1Hz,2H),3.57(dd,J＝10.5,2.9Hz,1H),3.02(s,4H),2.93(s,3H),2.61(dd,J＝9.9,1.8Hz,2H),2.16–2.08(m,2H),2.04(d,J＝11.4Hz,1H),1.97–1.88(m,1H),1.62(s,3H),1.40(d,J＝8.1Hz,6H),1.16(s,10H),1.05(s,3H),0.93(s,3H),0.89(d,J＝6.8Hz,4H),0.80–0.74(m,11H).13C NMR(101MHz,DMSO)δ172.47,170.29,169.65,168.67,167.76,139.83,138.08,133.43,129.09,127.83,127.02,126.05,124.92,83.95,78.70,71.79,63.83,61.20,59.49,58.94,58.16,55.15,50.35,41.85,33.36,31.32,30.96,30.83,29.66,28.87,28.70,28.44,28.10,24.47,24.28,24.04,22.14,14.93,14.80,13.99,10.71,10.05,9.75.HRMS–MALDI(m/z):[M+Na]+calcd for C46H71N3O10Na+,848.5032；found:848.5035.
实施例9
零摄氏度下向化合物3(33.59mg,0.05mmol)的CH2Cl2(4mL)溶液依次加入DMAP(0.61mg,0.005mmol)，NEt3(12.14mg,0.12mmol)，和丁二酸酐(6.00mg,0.06mmol)，室温搅拌8小时。反应结束后加入饱和NH4Cl(2mL)水溶液，EtOAc萃取5遍(15mL×5)。合并的有机相用饱和食盐水洗，再以无水Na2SO4干燥。旋蒸除去挥发性物质后硅胶柱分离得到化合物2d(19.30mg,50％)。1H NMR(400MHz,DMSO)δ12.23(s,1H),8.61(d,J＝9.8Hz,1H),7.90(d,J＝8.6Hz,1H),7.52(d,J＝7.5Hz,2H),7.30(t,J＝7.4Hz,2H),7.23(t,J＝7.2Hz,1H),6.35(dd,J＝14.4,11.5Hz,1H),6.13–6.04(m,2H),5.92(s,1H),5.10(s,1H),4.77–4.71(m,1H),4.64–4.58(m,2H),4.07(td,J＝10.8,6.0Hz,2H),3.62(dd,J＝10.4,2.9Hz,1H),3.07(s,4H),2.99(s,3H),2.65(d,J＝8.0Hz,2H),2.42–2.39(m,4H),2.10(s,1H),1.96(s,1H),1.66(s,3H),1.44(s,3H),1.12(s,1H),1.10(s,2H),0.98(s,3H),0.94(d,J＝6.8Hz,3H),0.81(dd,J＝10.5,6.9Hz,8H).13C NMR(101MHz,DMSO)δ173.27,171.72,170.29,169.64,168.78,167.78,139.84,138.09,133.46,129.05,127.83,127.03,126.06,124.94,83.93,78.71,71.81,64.08,61.21,59.52,58.93,58.19,55.17,50.22,41.86,31.08,29.70,29.62,28.56,28.50,28.09,24.47,24.06,14.87,14.79,10.73,10.14,9.77.HRMS–ESI(m/z):[M+H]+calcd for C40H57N3O12 +,771.3937；found:848.3098.
实施例10
零摄氏度下向化合物3(33.59mg,0.05mmol)的CH2Cl2(4mL)溶液依次加入DMAP(0.61mg,0.005mmol)，NEt3(12.14mg,0.12mmol)，EDCI(13.38mg,0.07mmol)和丙烯酸(4.32mg,0.06mmol)，室温搅拌8小时。反应结束后加入饱和NH4Cl(2mL)水溶液，EtOAc萃取5遍(15mL×5)。合并的有机相用饱和食盐水洗，再以无水Na2SO4干燥。旋蒸除去挥发性物质后硅胶柱分离得到化合物2e(24.68mg,68％)。1H NMR(400MHz,CDCl3)δ7.35(d,J＝13.0Hz,4H),7.29(d,J＝4.7Hz,1H),7.03(d,J＝6.4Hz,1H),6.87(d,J＝8.8Hz,1H),6.35(dd,J＝10.6,6.7Hz,2H),6.14(d,J＝10.7Hz,1H),6.02–5.84(m,3H),5.79(d,J＝10.5Hz,1H),4.74(dd,J＝23.5,7.4Hz,2H),4.53(d,J＝11.5Hz,1H),4.29(ddd,J＝28.7,11.2,5.2Hz,2H),3.68(d,J＝7.6Hz,1H),3.21(d,J＝4.8Hz,1H),3.18(s,3H),3.10(s,3H),3.01(d,J＝9.7Hz,1H),2.68(s,1H),2.19–2.08(m,2H),1.79(s,1H),1.74(s,3H),,1.53(s,3H),1.24(s,3H),1.15(s,3H),1.09(d,J＝6.8Hz,3H),0.99–0.93(m,2H),0.87(dd,J＝17.1,6.7Hz,6H)13C NMR(101MHz,CDCl3)δ170.98,170.23,169.22,168.06,165.60,138.62,136.38,134.15,132.12,129.22,128.37,128.02,127.63,126.76,126.21,84.57,80.36,72.58,64.12,61.94,60.79,60.13,58.81,55.98,51.92,42.03,31.79,31.47,30.14,27.41,26.48,24.51,15.65,15.51,11.28,10.81,10.65.HRMS–MALDI(m/z):[M+Na]+calcd forC39H55N3O10Na+,748.3780；found:748.3782.
实施例11
零摄氏度下向化合物3(33.59mg,0.05mmol)的CH2Cl2(4mL)溶液依次加入DMAP(0.61mg,0.005mmol)，NEt3(12.14mg,0.12mmol)，EDCI(13.38mg,0.07mmol)和化合物14(8.89mg,0.06mmol)，室温搅拌8小时。反应结束后加入饱和NH4Cl(2mL)水溶液，EtOAc萃取5遍(15mL×5)。合并的有机相用饱和食盐水洗，再以无水Na2SO4干燥。旋蒸除去挥发性物质后硅胶柱分离得到化合物2f(30.07mg,78％)。1H NMR(400MHz,DMSO)δ8.71(d,J＝9.6Hz,1H),7.96(d,J＝8.4Hz,1H),7.68(d,J＝16.9Hz,3H),7.59(d,J＝7.0Hz,2H),7.50(s,3H),7.37(d,J＝6.4Hz,2H),7.32(d,J＝6.5Hz,1H),6.54(d,J＝15.6Hz,1H),6.49–6.38(m,1H),6.16(t,J＝12.4Hz,2H),5.99(s,1H),5.17(s,1H),4.93(s,1H),4.70(d,J＝9.6Hz,2H),4.31(s,2H),3.71(d,J＝9.9Hz,2H),3.15(s,3H),3.07(s,3H),2.76(d,J＝9.9Hz,3H),2.17(s,1H),2.07(s,1H),1.74(s,3H),1.51(s,3H),1.35(s,1H),1.19(s,3H),1.06(s,3H),1.02(d,J＝5.7Hz,3H),0.88(d,J＝5.4Hz,6H).13C NMR(101MHz,DMSO)δ170.26,169.73,168.74,167.76,165.58,144.86,139.78,137.94,133.84,133.45,130.63,129.35,129.04,128.21,127.80,127.00,126.03,124.95,117.47,83.82,78.69,71.71,64.27,61.14,59.60,58.98,58.13,55.14,50.45,41.80,30.95,30.82,29.68,28.07,24.61,23.98,14.97,14.78,10.77,10.03,9.83.HRMS–MALDI(m/z):[M+Na]+calcd for C45H59N3O10Na+,824.4093；found:824.4098.
实施例12
零摄氏度下向化合物3(33.59mg,0.05mmol)的CH2Cl2(4mL)溶液依次加入DMAP(0.61mg,0.005mmol)，NEt3(12.14mg,0.12mmol)，EDCI(13.38mg,0.07mmol)和化合物15(11.04mg,0.06mmol)，室温搅拌8小时。反应结束后加入饱和NH4Cl(2mL)水溶液，EtOAc萃取5遍(15mL×5)。合并的有机相用饱和食盐水洗，再以无水Na2SO4干燥。旋蒸除去挥发性物质后硅胶柱分离得到化合物2g(31.39mg,75％)。1H NMR(400MHz,DMSO)δ8.66(d,J＝9.6Hz,1H),7.97(d,J＝8.7Hz,1H),7.60–7.50(m,3H),7.31(t,J＝7.3Hz,2H),7.24(t,J＝8.5Hz,3H),6.54(d,J＝16.5Hz,1H),6.41–6.32(m,1H),6.10(t,J＝12.8Hz,2H),5.93(s,1H),5.10(s,1H),4.87(s,1H),4.64(dd,J＝10.5,4.2Hz,2H),4.25(d,J＝6.6Hz,2H),3.64(d,J＝8.7Hz,1H),3.08(s,3H),3.00(s,3H),2.67(d,J＝8.8Hz,2H),2.11(t,J＝12.0Hz,1H),1.98(s,1H),1.68(s,3H),1.44(s,3H),1.29(s,3H),1.25(s,1H),1.13(s,3H),0.99(s,3H),0.95(d,J＝6.7Hz,3H),0.83–0.79(m,6H).13C NMR(101MHz,DMSO)δ170.21,169.63,168.77,167.65,165.19,163.11(d,J＝6.6Hz),160.56(d,J＝6.6Hz),139.77,137.98,133.43,131.70(t,J＝11.0Hz),130.39,128.93,127.77,126.97,126.01,124.92,123.34(t,J＝9.0Hz),112.43(d,J＝24.8Hz),83.86,78.69,71.74,64.48,61.14,59.53,58.92,58.11,55.13,50.28,41.81,31.13,30.75,29.81,28.98,28.01,24.46,23.99,22.07,14.83,14.77,10.73,10.01,9.77.19F NMR(376MHz,DMSO)δ-111.25.HRMS–MALDI(m/z):[M+Na]+calcd for C45H57N3O10Na+,860.3904；found:860.3910.
实施例13
零摄氏度下向化合物3(33.59mg,0.05mmol)的CH2Cl2(4mL)溶液依次加入DMAP(0.61mg,0.005mmol)，NEt3(12.14mg,0.12mmol)，EDCI(13.38mg,0.07mmol)和苯甲酸(7.32mg,0.06mmol)，室温搅拌8小时。反应结束后加入饱和NH4Cl(2mL)水溶液，EtOAc萃取5遍(15mL×5)。合并的有机相用饱和食盐水洗，再以无水Na2SO4干燥。旋蒸除去挥发性物质后硅胶柱分离得到化合物2h(28.32mg,73％)。1H NMR(400MHz,DMSO)δ8.72(d,J＝10.0Hz,1H),8.01(d,J＝8.0Hz,1H),7.94(d,J＝7.3Hz,2H),7.66(d,J＝7.3Hz,1H),7.53(dd,J＝12.9,7.6Hz,4H),7.32(t,J＝7.3Hz,2H),7.26(d,J＝7.0Hz,1H),6.43–6.33(m,1H),6.12(t,J＝13.0Hz,2H),5.95(s,1H),5.12(s,1H),4.94(s,1H),4.65(dd,J＝10.4,6.2Hz,2H),4.38(d,J＝13.5Hz,2H),3.65(d,J＝8.0Hz,1H),3.10(s,4H),3.02(s,3H),2.70(d,J＝10.6Hz,2H),2.18–2.09(m,1H),2.00(s,2H),1.69(s,3H),1.45(d,J＝8.6Hz,3H),1.27(s,2H),1.07(s,3H),0.96(d,J＝7.2Hz,5H),0.81(s,3H),0.76(d,J＝6.4Hz,3H).13C NMR(101MHz,DMSO)δ170.35,169.69,168.81,167.68,165.34,139.85,138.13,133.52,133.42,129.34,129.31,129.12,128.62,127.83,127.03,126.04,124.89,83.95,78.70,71.71,65.24,61.24,59.54,58.94,58.18,55.15,50.44,41.86,31.01,30.82,29.71,28.05,24.50,24.02,14.93,14.81,10.71,10.11,9.71.HRMS–MALDI(m/z):[M+Na]+calcd forC36H53N3O9Na+,798.3936；found:798.3940.
实施例14
零摄氏度下向化合物3(33.59mg,0.05mmol)的CH2Cl2(4mL)溶液依次加入DMAP(0.61mg,0.005mmol)，NEt3(12.14mg,0.12mmol)，EDCI(13.38mg,0.07mmol)和化合物16(7.68mg,0.06mmol)，室温搅拌8小时。反应结束后加入饱和NH4Cl(2mL)水溶液，EtOAc萃取5遍(15mL×5)。合并的有机相用饱和食盐水洗，再以无水Na2SO4干燥。旋蒸除去挥发性物质后硅胶柱分离得到化合物2i(28.12mg,72％)。1H NMR(400MHz,CDCl3)δ7.38–7.33(m,4H),7.31–7.27(m,1H),7.03(d,J＝6.7Hz,1H),6.81(d,J＝9.0Hz,1H),6.35(dd,J＝14.7,11.5Hz,1H),6.14(d,J＝10.7Hz,1H),5.99(s,1H),5.92(dd,J＝15.3,4.6Hz,1H),4.76–4.65(m,2H),4.52(d,J＝11.5Hz,1H),4.29(dd,J＝11.3,5.4Hz,1H),4.14(dd,J＝11.3,4.4Hz,1H),3.67(dd,J＝10.5,2.6Hz,1H),3.17(s,3H),3.09(s,3H),2.98(d,J＝8.2Hz,1H),2.64(d,J＝11.8Hz,1H),2.21(ddd,J＝33.6,16.7,7.8Hz,3H),1.83(d,J＝12.5Hz,2H),1.73(d,J＝7.9Hz,3H),1.73–1.66(m,2H),1.61(s,2H),1.55–1.51(m,3H),1.42–1.30(m,4H),1.25(s,4H),1.20(d,J＝4.9Hz,1H),1.17(s,3H),1.10(d,J＝6.8Hz,3H),1.02–0.93(m,2H),0.87(dd,J＝11.9,6.7Hz,6H).13C NMR(101MHz,CDCl3)δ175.73,170.92,170.38,169.01,168.16,138.79,136.54,134.12,129.49,128.37,127.97,126.68,126.08,84.70,80.39,72.65,63.78,61.91,60.75,60.04,58.80,55.90,52.11,43.03,42.04,31.83,31.40,30.11,29.04,28.90,27.28,26.45,25.74,25.45,25.40,24.47,15.63,15.52,11.08,10.70,10.42.HRMS–MALDI(m/z):[M+Na]+calcd for C43H63N3O10Na+,804.4406；found:804.4410.
实施例15
零摄氏度下向化合物3(33.59mg,0.05mmol)的CH2Cl2(4mL)溶液依次加入DMAP(0.61mg,0.005mmol)，NEt3(12.14mg,0.12mmol)，EDCI(13.38mg,0.07mmol)和化合物17(7.38mg,0.06mmol)，室温搅拌8小时。反应结束后加入饱和NH4Cl(2mL)水溶液，EtOAc萃取5遍(15mL×5)。合并的有机相用饱和食盐水洗，再以无水Na2SO4干燥。旋蒸除去挥发性物质后硅胶柱分离得到化合物2j(21.36mg,55％)。1H NMR(400MHz,DMSO)δ8.80(d,J＝4.3Hz,2H),8.72(d,J＝9.7Hz,1H),8.07(d,J＝8.4Hz,1H),7.78(d,J＝4.7Hz,2H),7.52(d,J＝7.4Hz,1H),7.35–7.27(m,3H),7.24(d,J＝6.6Hz,1H),6.42–6.30(m,1H),6.09(dd,J＝18.1,6.9Hz,2H),5.93(s,1H),5.10(s,1H),4.91(d,J＝16.6Hz,1H),4.64(d,J＝10.5Hz,2H),4.42(s,2H),3.63(d,J＝10.6Hz,1H),3.09(d,J＝14.8Hz,4H),3.00(s,3H),2.67(d,J＝9.7Hz,2H),2.10(t,J＝12.0Hz,1H),1.98(s,1H),1.67(s,3H),1.48–1.41(m,4H),1.28(s,1H),1.04(d,J＝7.8Hz,3H),0.94(d,J＝6.0Hz,5H),0.82–0.77(m,4H),0.73(d,J＝6.3Hz,3H).13C NMR(101MHz,DMSO)δ170.32,169.69,168.86,167.53,164.20,150.70,139.82,138.10,136.53,133.44,129.07,127.83,127.04,126.04,124.90,122.63,83.91,78.72,71.68,65.78,61.22,59.56,58.90,58.19,55.16,50.30,41.86,31.06,29.71,29.04,27.99,24.56,24.02,14.91,14.80,10.73,10.12,9.74.HRMS–MALDI(m/z):[M+Na]+calcdfor C42H56N4O10Na+,799.3889；found:799.3893.
实施例16
零摄氏度下向化合物3(33.59mg,0.05mmol)的CH2Cl2(4mL)溶液依次加入DMAP(0.61mg,0.005mmol)，NEt3(12.14mg,0.12mmol)，EDCI(13.38mg,0.07mmol)和化合物18(9.42mg,0.06mmol)，室温搅拌8小时。反应结束后加入饱和NH4Cl(2mL)水溶液，EtOAc萃取5遍(15mL×5)。合并的有机相用饱和食盐水洗，再以无水Na2SO4干燥。旋蒸除去挥发性物质后硅胶柱分离得到化合物2k(18.25mg,45％)。1H NMR(400MHz,MeOD)δ7.47(d,J＝7.3Hz,2H),7.32(t,J＝6.9Hz,3H),7.25(d,J＝6.9Hz,1H),6.48–6.39(m,1H),6.15(d,J＝10.6Hz,1H),6.04(d,J＝23.1Hz,2H),4.71–4.62(m,3H),4.39(d,J＝9.9Hz,1H),3.70(d,J＝10.5Hz,1H),3.18(d,J＝9.7Hz,4H),3.08(s,3H),2.90(d,J＝10.1Hz,1H),2.69(d,J＝6.4Hz,1H),2.66(s,3H),2.61(s,3H),2.18(dd,J＝23.6,14.9Hz,3H),1.73(s,3H),1.52(s,3H),1.29(m,1H),1.24(s,3H),1.10(s,3H),1.07(d,J＝6.4Hz,3H),0.92–0.85(m,8H).13C NMR(101MHz,MeOD)δ172.88,172.18,171.55,170.66,169.18,162.57,161.30,140.92,138.66,134.45,131.33,129.05,128.38,127.48,126.59,122.17,85.91,80.93,73.39,65.99,62.71,61.55,61.19,59.92,55.95,52.95,43.45,32.44,32.31,30.73,28.56,25.47,25.30,19.02,17.24,15.83,15.52,10.80,10.49,10.37.HRMS–MALDI(m/z):[M+Na]+calcdfor C42H58N4O10Na+,833.3766；found:833.3770.
实施例17
零摄氏度下向化合物3(33.59mg,0.05mmol)的CH2Cl2(4mL)溶液依次加入DMAP(0.61mg,0.005mmol)，NEt3(12.14mg,0.12mmol)，EDCI(13.38mg,0.07mmol)和化合物19(5.88mg,0.06mmol)，室温搅拌8小时。反应结束后加入饱和NH4Cl(2mL)水溶液，EtOAc萃取5遍(15mL×5)。合并的有机相用饱和食盐水洗，再以无水Na2SO4干燥。旋蒸除去挥发性物质后硅胶柱分离得到化合物2l(18.42mg,49％)。1H NMR(400MHz,DMSO)δ8.60(d,J＝9.8Hz,1H),7.82(d,J＝8.3Hz,1H),7.53(d,J＝7.5Hz,2H),7.32(t,J＝7.5Hz,3H),7.26(d,J＝7.3Hz,1H),6.37(dd,J＝14.6,11.7Hz,1H),6.09(dd,J＝19.9,8.0Hz,2H),5.93(s,1H),5.12(s,1H),4.78–4.72(m,1H),4.61(dd,J＝10.5,8.0Hz,2H),4.12(ddd,J＝17.1,11.0,5.2Hz,2H),3.64(dd,J＝10.4,2.9Hz,1H),3.09(s,3H),2.99(s,3H),2.70–2.65(m,2H),2.41(s,1H),2.12–2.05(m,3H),2.01–1.95(m,1H),1.81–1.75(m,1H),1.68(s,3H),1.45(s,3H),1.24(s,3H),1.11(s,3H),0.99(s,3H),0.95(d,J＝6.8Hz,3H),0.83(dd,J＝8.7,6.9Hz,6H).13C NMR(101MHz,DMSO)δ174.58,170.72,170.15,169.16,168.17,148.00,140.24,138.44,133.90,129.46,128.27,127.49,126.51,125.40,84.33,79.15,72.18,61.63,59.97,59.43,58.60,55.61,50.94,42.24,37.58,31.40,31.27,30.13,29.47,28.54,25.08,24.94,24.46,18.27,15.40,15.25,11.20,10.53,10.26.HRMS–MALDI(m/z):[M+Na]+calcd for C41H57N3O10Na+,774.3936；found:774.3940.
实施例18
零摄氏度下向化合物3(33.59mg,0.05mmol)的CH2Cl2(4mL)溶液依次加入DMAP(0.61mg,0.005mmol)，NEt3(12.14mg,0.12mmol)，EDCI(13.38mg,0.07mmol)和化合物20(5.88mg,0.06mmol)，室温搅拌8小时。反应结束后加入饱和NH4Cl(2mL)水溶液，EtOAc萃取5遍(15mL×5)。合并的有机相用饱和食盐水洗，再以无水Na2SO4干燥。旋蒸除去挥发性物质后硅胶柱分离得到化合物2m(22.20mg,60％)。1H NMR(400MHz,CDCl3)δ7.34(d,J＝12.9Hz,4H),7.28(s,1H),6.99(d,J＝6.6Hz,1H),6.84(d,J＝9.0Hz,1H),6.39–6.30(m,1H),6.14(d,J＝10.6Hz,1H),5.99(s,1H),5.91(dd,J＝15.3,4.4Hz,1H),4.71(d,J＝8.8Hz,2H),4.54(d,J＝11.4Hz,1H),4.22(d,J＝5.4Hz,1H),3.68(d,J＝9.7Hz,1H),3.18(s,3H),3.11(s,3H),3.00(d,J＝9.9Hz,1H),2.68(s,1H),2.60(s,1H),2.18–2.08(m,2H),1.75(s,3H),1.60(d,J＝9.1Hz,1H)1.53(s,3H),1.25(s,6H),1.18(s,3H),1.09(d,J＝6.7Hz,3H),0.95(s,2H),0.86(dd,J＝18.6,12.8Hz,9H).13C NMR(101MHz,CDCl3)δ174.51,170.95,170.25,169.16,168.14,138.65,136.39,134.13,129.27,128.35,127.97,126.74,126.20,84.60,80.33,72.58,63.96,61.93,60.75,60.14,58.80,55.96,52.03,42.00,31.81,31.46,30.12,29.83,27.35,26.43,24.50,15.65,15.52,12.75,11.24,10.77,10.67,9.02.HRMS–MALDI(m/z):[M+Na]+calcd for C40H57N3O10Na+,762.3936；found:762.3940.
实施例19：生物活性测试
将各种癌细胞配成2×105/mL细胞悬液，加入24孔板圆底细胞培养板内，分别加入从实施例1至实施例18所合成的化合物2a-2m和3、以及用于活性对照的天然nannocystinA,每一测试浓度5孔，置37℃、5％CO2饱和湿度条件下培养18小时，用MTT法在酶联检测仪570nm波长测得吸光度(A)值，计算出本发明化合物对测试癌细胞的抑制作用。
表1化合物2a-2m、化合物3对各种癌细胞的抑制活性(IC50,nM)
比较以上抑制活性结果可以发现，本发明合成的nannocystin衍生物的活性已经达到甚至超过天然产物nannocystin A。例如，化合物2a,2k,3对于HepG2癌细胞的抑制效果要优于nannocystin A，化合物2a,2e,2i-2k,2m,3对于PNAC1癌细胞的抑制效果要优于nannocystin A，化合物2a对于HCT116癌细胞的抑制效果要优于nannocystin A。这些结果表明，本发明的具有简化结构的类似物具有与对应天然产物相当甚至更优的抗癌活性。由于天然nannocystin A以及本发明合成的衍生物的作用靶标均为真核延长因子1A，这些抗癌抑制活性结果表明通过优化母体化合物nannocystin A的结构，可以获得与靶标结合更强的化合物，同时通过简化结构，也能优化其他方面的成药性质。
以上所述仅为本发明创造的较佳实施例而已，并不用以限制本发明创造，凡在本发明创造的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明创造的保护范围之内。

Claims (8)

1.大环nannocystin衍生物，其特征在于，该衍生物涉及如下式结构的化合物1及其药学上可接受的盐：
其中，R1＝氢、碳原子数为1至10的饱和或不饱和芳香酰基，或者碳原子数为1至10的碳环、碳链、或者杂环酰基。
2.根据权利要求1所述的大环nannocystin衍生物，其特征在于，该衍生物涉及如下式结构的化合物2及其药学上可接受的盐：
其中，R2＝碳原子数为1至9的饱和或不饱和芳香酰基，或者碳原子数为1至9的碳环、或者碳原子数为1至9的碳链、或者碳原子数为1至9的杂环酰基。
3.根据权利要求1或2所述的大环nannocystin衍生物，其特征在于，该衍生物涉及如下式结构的化合物3及其药学上可接受的盐：
4.根据权利要求3所述的大环nannocystin衍生物的制备方法，其特征在于，化合物3的制备方法如下：
5.根据权利要求4所述的大环nannocystin衍生物的制备方法，其特征在于，化合物2的制备方法如下：
6.根据权利要求1所述的大环nannocystin衍生物在制备抗癌药物以及作为抗癌辅助治疗药物中的应用，其特征在于，化合物1及其在药学上可以接受的盐用于治疗的癌症为肝癌、结肠癌、胰腺癌中的一种。
7.根据权利要求2所述的大环nannocystin衍生物在制备抗癌药物以及作为抗癌辅助治疗药物中的应用，其特征在于，化合物2及其在药学上可以接受的盐用于治疗的癌症为肝癌、结肠癌、胰腺癌中的一种。
8.根据权利要求3所述的大环nannocystin衍生物在制备抗癌药物以及作为抗癌辅助治疗药物中的应用，其特征在于，化合物3及其在药学上可以接受的盐用于治疗的癌症为肝癌、结肠癌、胰腺癌中的一种。
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