CN114591297A - 含色氨酸多肽马来酰亚胺化衍生物及其制备方法与应用 - Google Patents
含色氨酸多肽马来酰亚胺化衍生物及其制备方法与应用 Download PDFInfo
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Abstract
本发明涉及一种含色氨酸多肽马来酰亚胺化衍生物及其制备方法和应用。本发明首次实现了在色氨酸七号位的马来酰亚胺化,操作过程简单,无导向基团,位点选择性高,反应高效,只需一步便可制得,并且该化合物能高效连接生物分子基团,具有较大的药物研发研究前景,为研发抗肿瘤药物提供了新的方案。
Description
(一)技术领域
本发明涉及一种含色氨酸多肽马来酰亚胺化衍生物及其制备方法和其在制备抗肿瘤药物中的应用。
(二)背景技术
马来酰亚胺及其衍生物在药物化学和化学生物学中发挥着重要作用。它们不仅是药物的重要组成部分,还可以通过迈克尔加成作为偶联生物活性分子的生物相容性手柄,为构建ADC提供了有力的工具,例如FDA批准的抗癌药物rentuximab vedotin和trastuzumab emtansine。另一方面,多肽是重要的生物活性分子,在药物化学、生物技术和化学生物学等领域有着广泛的应用。近年来,一些基于Trp残基的后期修饰的方法已被成功开发出来。而传统对于Trp残基的后期修饰的方法:通常需要先在Trp的吲哚杂环的1号上引入保护基团或导向基团,完成其他位点的修饰后,最后脱保护或导向基团,实现修饰。这类方法方法步骤繁多,反应收率低,这些存在的问题大大的降低了对于含Trp的多肽的后期修饰研究的进展。
(三)发明内容
本发明的目的是提供一种含色氨酸多肽马来酰亚胺化衍生物及其制备方法和其在制备抗肿瘤药物中的应用。
为了实现上述目的,本发明采用的技术方案是:
第一方面,本发明提供一种式(I)所示的含色氨酸多肽马来酰亚胺化衍生物,
式(I)中,AA为氨基酸残基,m为氨基酸残基的个数,取0~4的自然数,当m=0时,R2直接与色氨酸残基的氨基端连接;
R1为氨基酸羧基端保护基(包括但不限于:-OMe、-OEt);
R2为氨基酸氨基端保护基(包括但不限于:Boc-、Cbz-、Ac-);
优选的,所述含色氨酸多肽马来酰亚胺化衍生物为下式之一:
第二方面,本发明提供一种上述式(I)所示含色氨酸多肽马来酰亚胺化衍生物的制备方法,所述方法包括:以式(II)所示的含色氨酸多肽为底物,加入式(III)化合物,在催化剂、添加剂、氧化剂存在下,于溶剂中、在70-90℃(优选80℃)下搅拌反应6~24小时,所得反应混合物经后处理,制得式(I)所示含色氨酸多肽马来酰亚胺化衍生物;
所述催化剂为二氯(五甲基环戊二烯基)合铑(III)二聚体(CAS:12354-85-7);所述添加剂为双三氟甲烷磺酰亚胺银盐(CAS:189114-61-2);所述氧化剂为氧化银;所述溶剂为二氯甲烷;
所述式(II)所示的含色氨酸多肽、式(III)化合物、添加剂、催化剂、氧化剂的物质的量之比为1:2~3:0.1~0.25:0.4~1:1~1.5(优选1:3:0.2:0.5:1)。
由于一号位特戊酰基(Piv)的导向作用,可增加色氨酸吲哚七号位C-H活化的独特反应性和对后期肽功能化的官能团的耐受性。使马来酰亚胺实现在色氨酸吲哚七号位的碳氢活化反应。
进一步,所述溶剂的体积以所述底物的物质的量计为30-50mL/mmol(优选50mL/mmol)。
进一步,所述后处理为:将乙酸乙酯和水加入到反应液中进行萃取,取有机层依次用1N盐酸、饱和碳酸氢钠、饱和氯化钠溶液洗涤,取有机层经过无水硫酸钠干燥、过滤、取滤液真空浓缩,即得粗品;以体积比为4:1的乙酸乙酯与石油醚的混合溶剂作为洗脱剂对粗品进行硅胶柱层析,收集含目标化合物的洗脱液,减压除去溶剂,干燥,得到(I)所示含色氨酸多肽马来酰亚胺化衍生物。
本发明推荐所述乙酸乙酯和水的体积比为2:1。
第三方面,本发明还提供上述含色氨酸多肽马来酰亚胺化衍生物在制备抗肿瘤药物中的应用。
进一步,所述肿瘤为肺癌(A549细胞)。
与现有技术相比,本发明的有益效果主要体现在:本发明化合物通过钯催化色氨酸,首次实现了在色氨酸七号位的马来酰亚胺化,操作过程简单,无导向基团,位点选择性高,反应高效,只需一步便可制得;并且该化合物具有一定抗肿瘤活性,且能高效连接生物分子基团,具有较大的药物研发研究前景,为研发药物提供了新的方案。
(四)附图说明
图1为马来酰亚胺化衍生物(Ia)的抗肿瘤活性研究;
图2为马来酰亚胺化衍生物(Ib)的抗肿瘤活性研究;
图3为马来酰亚胺化衍生物(Ic)的抗肿瘤活性研究;
图4为马来酰亚胺化衍生物(Id)的抗肿瘤活性研究;
图5为马来酰亚胺化衍生物(Ie)的抗肿瘤活性研究;
图6为马来酰亚胺化衍生物(If)的抗肿瘤活性研究;
图7为马来酰亚胺化衍生物(Ig)的抗肿瘤活性研究;
图8为马来酰亚胺化衍生物(Ih)的抗肿瘤活性研究;
图9为马来酰亚胺化衍生物(Ii)的抗肿瘤活性研究;
图10为马来酰亚胺化衍生物(Ij)的抗肿瘤活性研究;
图11为马来酰亚胺化衍生物(Ik)的抗肿瘤活性研究;
图12为马来酰亚胺化衍生物(Il)的抗肿瘤活性研究;
图13为马来酰亚胺化衍生物(Im)的抗肿瘤活性研究。
(五)具体实施方式
下面结合具体实施例对本发明进行进一步描述,但本发明的保护范围并不仅限于此:
实施例1:化合物(Ia)的制备
如式IIa所示含色氨酸线性多肽(80.42mg,0.2mmol),马来酰亚胺(58.22mg,0.6mmol),双三氟甲烷磺酰亚胺银盐(15.12mg,0.04mmol),二氯(五甲基环戊二烯基)合铑(III)二聚体(61.82mg,0.1mmol),氧化银(46.2mg,0.2mmol)称于圆底烧瓶中,加入10mL二氯甲烷。盖上胶塞反应物加热至80摄氏度8小时。将40mL乙酸乙酯和20mL水加入到反应液中。有机层分别用20mL 1N盐酸,20mL饱和碳酸氢钠,20mL饱和氯化钠溶液洗涤,并用无水硫酸钠干燥,过滤,真空浓缩,得到的粗产物通过硅胶柱或制备硅胶板进一步纯化(乙酸乙酯:石油醚=4:1)收集得到的含目标化合物的洗脱液经减压除去溶剂,干燥,获式Ia所示的化合物纯品82.5mg(收率83%)。
1H NMR(500MHz,CDCl3)δ8.13(s,1H),7.61(d,J=7.5Hz,1H),7.55(s,1H),7.31(t,J=7.5Hz,1H),7.28(dd,J=7.0,1.5Hz,1H),6.45(d,J=1.5Hz,1H),5.26(d,J=8.3Hz,1H),4.74(q,J=6.5Hz,1H),3.71(s,3H),3.25(ddd,J=52.0,15.2,5.9Hz,2H),1.45(s,9H),1.44(s,9H).
13C NMR(126MHz,CDCl3)δ178.66,172.32,171.21,170.77,155.13,150.32,133.55,131.54,127.52,124.78,123.37,121.98,121.29,117.48,115.23,80.21,53.30,52.46,41.27,28.39,28.31,27.66.
HRMS(ESI)m/z calcd for C26H31N3O7Na(M+Na)+520.2054,found 520.2049.
实施例2:化合物(Ib)的制备
如式IIb所示含色氨酸线性多肽(84.2mg,0.2mmol),马来酰亚胺(58.22mg,0.6mmol),双三氟甲烷磺酰亚胺银盐(15.12mg,0.04mmol),二氯(五甲基环戊二烯基)合铑(III)二聚体(61.82mg,0.1mmol),氧化银(46.2mg,0.2mmol)称于圆底烧瓶中,加入10mL二氯甲烷.盖上胶塞反应物加热至80摄氏度6小时。将40mL乙酸乙酯和20mL水加入到反应液中。有机层分别用20mL 1N盐酸,20mL饱和碳酸氢钠,20mL饱和氯化钠溶液洗涤,并用无水硫酸钠干燥,过滤,真空浓缩,得到的粗产物通过硅胶柱或制备硅胶板进一步纯化(乙酸乙酯:石油醚=4:1)收集得到的含目标化合物的洗脱液经减压除去溶剂,干燥,获式Ib所示的化合物纯品76.5mg(收率72%)。
1H NMR(600MHz,Chloroform-d)δ8.17(s,1H),7.60(dd,J=6.6,2.5Hz,1H),7.57(s,1H),7.34(q,J=5.1Hz,5H),7.28(q,J=5.0,4.6Hz,2H),6.45(d,J=1.5Hz,1H),5.63(d,J=8.2Hz,1H),5.14(q,J=12.2Hz,2H),4.82(q,J=6.5Hz,1H),3.72(s,3H),3.29(ddd,J=52.4,15.1,5.6Hz,2H),1.43(s,9H).
13C NMR(151MHz,CDCl3)δ178.70,172.09,171.34,170.86,155.82,150.27,136.09,133.55,131.42,128.55,128.25,128.13,127.60,124.84,123.45,122.02,121.23,117.51,115.01,67.13,53.72,52.63,41.26,28.35,27.74.
HRMS(ESI)m/z calcd for C29H29N3O7Na(M+Na)+554.1898,found 554.1897.
实施例3:化合物(Ic)的制备
如式IIc所示含色氨酸线性多肽(68.9mg,0.2mmol),马来酰亚胺(58.22mg,0.6mmol),双三氟甲烷磺酰亚胺银盐(15.12mg,0.04mmol),二氯(五甲基环戊二烯基)合铑(III)二聚体(61.82mg,0.1mmol),氧化银(46.2mg,0.2mmol)称于圆底烧瓶中,加入10mL二氯甲烷。盖上胶塞反应物加热至80摄氏度6小时。将40mL乙酸乙酯和20mL水加入到反应液中。有机层分别用20mL 1N盐酸,20mL饱和碳酸氢钠,20mL饱和氯化钠溶液洗涤,并用无水硫酸钠干燥,过滤,真空浓缩,得到的粗产物通过硅胶柱或制备硅胶板进一步纯化(乙酸乙酯:石油醚=4:1)收集得到的含目标化合物的洗脱液经减压除去溶剂,干燥,获式Ic所示的化合物纯品70.4mg(收率80%)。
1H NMR(600MHz,CDCl3)δ7.94(s,1H),7.61(dd,J=7.7,1.3Hz,1H),7.54(s,1H),7.33(t,J=7.6Hz,1H),7.29(d,J=7.8Hz,1H),6.46(d,J=1.4Hz,1H),6.28(d,J=7.9Hz,1H),5.05(dt,J=7.9,5.7Hz,1H),3.75(s,3H),3.30(ddd,J=55.3,15.2,5.6Hz,2H),2.01(s,3H),1.46(s,9H).
13C NMR(151MHz,CDCl3)δ178.73,172.22,171.08,170.70,169.99,150.29,133.54,131.54,127.62,124.75,123.47,122.01,121.22,117.51,115.10,52.64,52.14,41.29,28.36,27.40,27.11,23.16.
HRMS(ESI)m/z calcd for C23H25N3O6Na(M+Na)+462.1636,found 462.1640.
实施例4:化合物(Id)的制备
如式IId所示含色氨酸线性多肽(63.2mg,0.2mmol),马来酰亚胺(58.22mg,0.6mmol),双三氟甲烷磺酰亚胺银盐(15.12mg,0.04mmol),二氯(五甲基环戊二烯基)合铑(III)二聚体(61.82mg,0.1mmol),氧化银(46.2mg,0.2mmol)称于圆底烧瓶中,加入10mL二氯甲烷。盖上胶塞反应物加热至80摄氏度6小时。将40mL乙酸乙酯和20mL水加入到反应液中。有机层分别用20mL 1N盐酸,20mL饱和碳酸氢钠,20mL饱和氯化钠溶液洗涤,并用无水硫酸钠干燥,过滤,真空浓缩,得到的粗产物通过硅胶柱或制备硅胶板进一步纯化(乙酸乙酯:石油醚=4:1)收集得到的含目标化合物的洗脱液经减压除去溶剂,干燥,获式Id所示的化合物纯品65.8mg(收率80%)。
1H NMR(600MHz,Chloroform-d)δ8.15(s,1H),7.62(dd,J=7.7,1.3Hz,1H),7.55(s,1H),7.32(t,J=7.6Hz,1H),7.28(dd,J=7.4,1.2Hz,1H),6.44(d,J=1.5Hz,1H),6.37(d,J=7.9Hz,1H),5.02(dt,J=8.2,5.9Hz,1H),4.29–4.06(m,2H),3.28(ddd,J=50.3,15.1,5.9Hz,2H),2.00(s,3H),1.45(s,9H),1.24(t,J=7.1Hz,3H).
13C NMR(151MHz,CDCl3)δ178.76,171.89,171.31,170.84,170.14,150.24,133.53,131.55,127.59,124.71,123.42,122.01,121.24,117.50,115.20,61.92,52.15,41.27,28.33,27.45,23.12,14.06.
HRMS(ESI)m/z calcd for C24H27N3O6Na(M+Na)+476.1792,found 476.1796.
实施例5:化合物(Ie)的制备
如式IId所示含色氨酸线性多肽(141.2mg,0.2mmol),马来酰亚胺(58.22mg,0.6mmol),双三氟甲烷磺酰亚胺银盐(15.12mg,0.04mmol),二氯(五甲基环戊二烯基)合铑(III)二聚体(61.82mg,0.1mmol),氧化银(46.2mg,0.2mmol)称于圆底烧瓶中,加入10mL二氯甲烷。盖上胶塞反应物加热至80摄氏度6小时。将40mL乙酸乙酯和20mL水加入到反应液中。有机层分别用20mL 1N盐酸,20mL饱和碳酸氢钠,20mL饱和氯化钠溶液洗涤,并用无水硫酸钠干燥,过滤,真空浓缩,得到的粗产物通过硅胶柱或制备硅胶板进一步纯化(乙酸乙酯:石油醚=4:1)收集得到的含目标化合物的洗脱液经减压除去溶剂,干燥,获式Ie所示的化合物纯品136.2mg(收率85%)。
1H NMR(500MHz,CDCl3)δ7.98(s,1H),7.63(dd,J=7.7,1.3Hz,1H),7.60(s,1H),7.31(t,J=7.6Hz,1H),7.27–7.23(m,4H),7.23–7.19(m,1H),7.14–7.10(m,2H),6.94(s,1H),6.73(d,J=5.9Hz,1H),6.43(d,J=1.5Hz,1H),5.16(d,J=7.1Hz,1H),4.97(q,J=6.8Hz,1H),4.31(q,J=7.0Hz,1H),4.19(t,J=6.9Hz,1H),3.97(dd,J=16.6,5.9Hz,1H),3.81(dd,J=16.4,5.3Hz,1H),3.71(s,3H),3.36–3.21(m,2H),2.93(qd,J=14.5,13.9,7.5Hz,2H),2.08–1.99(m,1H),1.46(s,9H),1.38(s,9H),0.81(d,J=6.8Hz,3H),0.73(d,J=6.8Hz,3H).
13C NMR(126MHz,CDCl3)δ178.69,172.00,171.89,171.34,171.10,170.74,168.93,155.85,150.27,136.25,133.64,131.37,129.21,128.66,127.51,127.01,124.74,123.43,121.83,121.18,117.54,115.23,80.69,58.80,55.94,52.58,52.00,43.21,41.26,37.80,30.07,28.38,28.23,27.44,19.16,17.43.
HRMS(ESI)m/z calcd for C42H52N6O10Na(M+Na)+823.3637,found 823.3636.
实施例6:化合物(If)的制备
如式IIe所示含色氨酸线性多肽(68.8mg,0.2mmol),马来酰亚胺衍生物III2(169.6mg,0.6mmol),双三氟甲烷磺酰亚胺银盐(15.12mg,0.04mmol),二氯(五甲基环戊二烯基)合铑(III)二聚体(61.82mg,0.1mmol),氧化银(46.2mg,0.2mmol)称于圆底烧瓶中,加入10mL二氯甲烷。盖上胶塞反应物加热至80摄氏度6小时。将40mL乙酸乙酯和20mL水加入到反应液中。有机层分别用20mL 1N盐酸,20mL饱和碳酸氢钠,20mL饱和氯化钠溶液洗涤,并用无水硫酸钠干燥,过滤,真空浓缩,得到的粗产物通过硅胶柱或制备硅胶板进一步纯化(乙酸乙酯:石油醚=4:1)收集得到的含目标化合物的洗脱液经减压除去溶剂,干燥,获式Ie所示的化合物纯品136.2mg(收率85%)。
1H NMR(500MHz,CDCl3)δ7.59(dd,J=7.5,1.5Hz,1H),7.53(s,1H),7.31(t,J=7.5Hz,1H),7.27(dd,J=7.4,1.5Hz,1H),6.46(s,1H),6.21(dd,J=6.5,4.2Hz,2H),5.02(dt,J=7.9,5.7Hz,1H),3.91(d,J=5.0Hz,2H),3.87–3.83(m,2H),3.73(s,3H),3.37–3.21(m,2H),2.59(dd,J=8.5,6.6Hz,2H),1.99(s,3H),1.45(s,9H),1.45(s,9H).
13C NMR(126MHz,CDCl3)δ178.59,172.09,170.93,170.23,169.81,169.78,168.89,149.60,133.53,131.57,127.67,124.72,123.45,121.15,121.11,117.76,115.18,82.27,52.56,52.14,42.02,41.25,34.78,34.12,29.66,28.42,28.17,28.01,27.39,23.15.
HRMS(ESI)m/z calcd for C42H40N4O9Na(M+Na)+647.2687,found 647.2688.
实施例7:化合物(Ig)的制备
如式IIf所示含色氨酸线性多肽(103.6mg,0.2mmol),马来酰亚胺衍生物III3(203.6mg,0.6mmol),双三氟甲烷磺酰亚胺银盐(15.12mg,0.04mmol),二氯(五甲基环戊二烯基)合铑(III)二聚体(61.82mg,0.1mmol),氧化银(46.2mg,0.2mmol)称于圆底烧瓶中,加入10mL二氯甲烷。盖上胶塞反应物加热至80摄氏度6小时。将40mL乙酸乙酯和20mL水加入到反应液中。有机层分别用20mL 1N盐酸,20mL饱和碳酸氢钠,20mL饱和氯化钠溶液洗涤,并用无水硫酸钠干燥,过滤,真空浓缩,得到的粗产物通过硅胶柱或制备硅胶板进一步纯化(乙酸乙酯:石油醚=4:1)收集得到的含目标化合物的洗脱液经减压除去溶剂,干燥,获式Ig所示的化合物纯品155.8mg(收率91%)。
1H NMR(400MHz,CDCl3)δ7.69(dd,J=7.6,1.5Hz,1H),7.62(s,1H),7.33(t,J=7.5Hz,1H),7.29(dd,J=7.5,1.5Hz,1H),6.54(d,J=8.5Hz,1H),6.46(s,1H),5.19(d,J=8.3Hz,1H),5.06(d,J=8.4Hz,1H),4.63–4.45(m,2H),4.29(td,J=7.9,4.9Hz,1H),3.74(s,3H),3.68(s,3H),3.51(t,J=7.4Hz,2H),3.23(d,J=5.8Hz,2H),1.87–1.78(m,2H),1.67–1.61(m,2H),1.48–1.42(m,27H),1.38–1.32(m,2H),1.16–1.08(m,1H),0.90–0.86(m,5H),0.84(d,J=6.9Hz,3H).
13C NMR(101MHz,CDCl3)δ178.51,173.28,171.73,171.35,170.87,170.55,155.60,155.37,149.54,133.62,131.49,127.61,125.13,123.51,121.31,121.01,117.77,115.54,80.52,79.88,56.60,54.01,53.28,52.32,52.19,41.24,37.83,37.44,32.19,29.07,28.46,28.31,28.27,25.03,22.53,15.36,11.58,11.47.
HRMS(ESI)m/z calcd for C44H63N5O12Na(M+Na)+876.4365,found 876.4366.
实施例8:化合物(Ih)的制备
如式IIh所示含色氨酸线性多肽(111.7mg,0.2mmol),马来酰亚胺衍生物III4(170.0mg,0.6mmol),双三氟甲烷磺酰亚胺银盐(15.12mg,0.04mmol),二氯(五甲基环戊二烯基)合铑(III)二聚体(61.82mg,0.1mmol),氧化银(46.2mg,0.2mmol)称于圆底烧瓶中,加入10mL二氯甲烷。盖上胶塞反应物加热至80摄氏度6小时。将40mL乙酸乙酯和20mL水加入到反应液中。有机层分别用20mL 1N盐酸,20mL饱和碳酸氢钠,20mL饱和氯化钠溶液洗涤,并用无水硫酸钠干燥,过滤,真空浓缩,得到的粗产物通过硅胶柱或制备硅胶板进一步纯化(乙酸乙酯:石油醚=4:1)收集得到的含目标化合物的洗脱液经减压除去溶剂,干燥,获式Ih所示的化合物纯品144.7mg(收率86%)。
1H NMR(500MHz,CDCl3)δ7.59–7.57(m,1H),7.30(t,J=7.6Hz,1H),7.25(dd,J=7.4,1.4Hz,1H),7.18(d,J=7.7Hz,1H),6.97(q,J=5.5,4.9Hz,1H),6.44(s,1H),6.38(t,J=5.2Hz,1H),5.19(d,J=8.3Hz,1H),4.94(dt,J=7.8,6.2Hz,1H),3.90(t,J=6.7Hz,6H),3.86–3.82(m,2H),3.69(s,3H),3.25(ddd,J=50.6,15.2,6.3Hz,2H),2.66–2.55(m,3H),1.45(s,9H),1.43(s,9H),1.41(s,9H),0.90(d,J=6.8Hz,3H),0.86(d,J=6.7Hz,3H).
13C NMR(126MHz,CDCl3)δ178.64,172.35,171.74,170.96,170.79,170.28,169.94,169.88,168.99,168.93,168.79,149.57,133.57,131.32,127.61,124.96,123.45,121.09,121.06,117.73,115.14,82.21,80.03,60.02,52.55,52.22,43.03,42.00,41.97,41.24,35.57,35.25,34.73,34.24,34.14,33.56,33.19,31.88,30.75,30.29,29.65,29.61,29.31,28.95,28.40,28.29,28.08,28.02,28.00,27.40,25.39,22.65,19.21,17.68,14.07.
HRMS(ESI)m/z calcd for C42H58N6O12Na(M+Na)+861.4005,found 861.4006.
实施例9:化合物(Ii)的制备
如式IIi所示含色氨酸线性多肽(111.7mg,0.2mmol),马来酰亚胺衍生物III5(318.3mg,0.6mmol),双三氟甲烷磺酰亚胺银盐(15.12mg,0.04mmol),二氯(五甲基环戊二烯基)合铑(III)二聚体(61.82mg,0.1mmol),氧化银(46.2mg,0.2mmol)称于圆底烧瓶中,加入10mL二氯甲烷。盖上胶塞反应物加热至80摄氏度6小时。将40mL乙酸乙酯和20mL水加入到反应液中。有机层分别用20mL 1N盐酸,20mL饱和碳酸氢钠,20mL饱和氯化钠溶液洗涤,并用无水硫酸钠干燥,过滤,真空浓缩,得到的粗产物通过硅胶柱或制备硅胶板进一步纯化(乙酸乙酯:石油醚=4:1)收集得到的含目标化合物的洗脱液经减压除去溶剂,干燥,获式Ii所示的化合物纯品152.8mg(收率73%)。
1H NMR(400MHz,CDCl3)δ7.68(dd,J=7.5,1.6Hz,1H),7.62(s,1H),7.34–7.19(m,6H),7.17–7.12(m,2H),6.58(dd,J=13.1,7.9Hz,2H),6.44(s,1H),5.23(d,J=8.4Hz,1H),5.03(d,J=8.1Hz,1H),4.69(q,J=6.5Hz,1H),4.52(td,J=10.2,8.5,5.4Hz,2H),4.05(q,J=7.1,6.4Hz,1H),3.68(s,3H),3.48(q,J=6.5,5.8Hz,2H),3.21(t,J=6.3Hz,2H),3.05(h,J=6.9,6.1Hz,2H),1.88–1.78(m,2H),1.66–1.54(m,4H),1.43(d,J=6.8Hz,27H),1.39(s,9H),0.90–0.82(m,6H).
13C NMR(101MHz,CDCl3)δ178.52,171.75,171.49,171.41,170.93,170.56,170.26,155.57,149.52,136.12,133.61,131.49,129.54,128.36,127.59,126.94,125.10,123.48,121.29,120.99,117.79,115.56,82.30,80.47,79.98,56.60,54.49,54.00,53.66,53.48,52.18,41.23,38.02,37.81,37.31,31.90,28.45,28.29,27.93,25.02,22.65,15.36,11.57.
HRMS(ESI)m/z calcd for C56H78N6O13Na(M+Na)+1065.5519,found 1065.5517.
实施例10:化合物(Ij)的制备
如式IIj所示含色氨酸线性多肽(80.5mg,0.2mmol),马来酰亚胺衍生物III6(318.3mg,0.6mmol),双三氟甲烷磺酰亚胺银盐(15.12mg,0.04mmol),二氯(五甲基环戊二烯基)合铑(III)二聚体(61.82mg,0.1mmol),氧化银(46.2mg,0.2mmol)称于圆底烧瓶中,加入10mL二氯甲烷。盖上胶塞反应物加热至80摄氏度6小时。将40mL乙酸乙酯和20mL水加入到反应液中。有机层分别用20mL 1N盐酸,20mL饱和碳酸氢钠,20mL饱和氯化钠溶液洗涤,并用无水硫酸钠干燥,过滤,真空浓缩,得到的粗产物通过硅胶柱或制备硅胶板进一步纯化(乙酸乙酯:石油醚=4:1)收集得到的含目标化合物的洗脱液经减压除去溶剂,干燥,获式Ij所示的化合物纯品152.8mg(收率73%)。
1H NMR(500MHz,CDCl3)δ7.61(d,J=7.6Hz,1H),7.55(s,1H),7.31(t,J=7.5Hz,1H),7.27(dd,J=7.6,1.3Hz,1H),6.47(s,1H),5.19(d,J=8.2Hz,1H),4.70(ddt,J=15.3,10.9,5.6Hz,2H),3.82(t,J=7.7Hz,2H),3.71(s,3H),3.25(ddd,J=50.3,15.1,5.8Hz,2H),2.72–2.60(m,2H),2.01–1.94(m,1H),1.82(pt,J=7.2,3.6Hz,1H),1.66(dp,J=13.1,3.1Hz,2H),1.46(s,9H),1.44(s,9H),1.39–1.32(m,2H),1.29(s,1H),1.04(qd,J=13.5,12.7,3.8Hz,1H),0.99–0.91(m,1H),0.88(t,J=6.5Hz,6H),0.74(d,J=7.0Hz,3H).
13C NMR(126MHz,CDCl3)δ178.48,172.22,170.78,170.27,170.17,155.07,149.65,133.55,131.57,127.55,124.78,123.38,121.05,117.69,115.22,80.14,74.64,53.29,52.44,46.90,41.22,40.79,34.19,33.56,33.25,31.34,29.66,28.46,28.31,26.28,23.46,21.96,20.72,16.37,14.09.
HRMS(ESI)m/z calcd for C39H53N3O9Na(M+Na)+730.3674,found 730.3678.
实施例11:化合物(Ik)的制备
如式IIk所示含色氨酸线性多肽(80.5mg,0.2mmol),马来酰亚胺衍生物III7(246.9mg,0.6mmol),双三氟甲烷磺酰亚胺银盐(15.12mg,0.04mmol),二氯(五甲基环戊二烯基)合铑(III)二聚体(61.82mg,0.1mmol),氧化银(46.2mg,0.2mmol)称于圆底烧瓶中,加入10mL二氯甲烷。盖上胶塞反应物加热至80摄氏度12小时。将40mL乙酸乙酯和20mL水加入到反应液中。有机层分别用20mL 1N盐酸,20mL饱和碳酸氢钠,20mL饱和氯化钠溶液洗涤,并用无水硫酸钠干燥,过滤,真空浓缩,得到的粗产物通过硅胶柱或制备硅胶板进一步纯化(乙酸乙酯:石油醚=4:1)收集得到的含目标化合物的洗脱液经减压除去溶剂,干燥,获式Ik所示的化合物纯品129.1mg(收率80%)。
1H NMR(500MHz,CDCl3)δ7.62–7.58(m,1H),7.54(s,1H),7.30(t,J=7.5Hz,1H),7.28–7.25(m,1H),6.46(s,1H),5.18(d,J=8.2Hz,1H),4.71(q,J=6.4Hz,1H),4.59(dd,J=7.9,2.6Hz,1H),4.41(d,J=11.7Hz,1H),4.30(d,J=2.6Hz,1H),4.22(dd,J=8.0,1.6Hz,1H),4.04(d,J=11.7Hz,1H),3.89(dd,J=13.0,2.0Hz,1H),3.86–3.82(m,2H),3.74(d,J=13.0Hz,1H),3.70(s,3H),3.24(ddd,J=52.8,15.0,5.8Hz,2H),2.73–2.69(m,2H),1.52(s,3H),1.46(s,3H),1.44(s,9H),1.43(s,9H),1.37(s,3H),1.32(s,3H).13C NMR(126MHz,CDCl3)δ178.44,172.17,170.66,170.07,169.96,155.03,149.67,134.15,133.50,131.54,127.54,124.71,123.37,121.00,117.62,115.26,109.08,108.66,101.39,80.10,70.69,70.44,70.01,65.29,61.21,53.24,52.40,41.18,33.31,32.78,29.61,28.42,28.27,26.39,25.83,25.18,24.01,14.04.
HRMS(ESI)m/z calcd for C41H53N3O14Na(M+Na)+834.3420,found 834.3426.
实施例12:化合物(Il)的制备
如式IIl所示含色氨酸线性多肽(80.7mg,0.2mmol),马来酰亚胺衍生物III8(177.9mg,0.6mmol),双三氟甲烷磺酰亚胺银盐(15.12mg,0.04mmol),二氯(五甲基环戊二烯基)合铑(III)二聚体(61.82mg,0.1mmol),氧化银(46.2mg,0.2mmol)称于圆底烧瓶中,加入10mL二氯甲烷。盖上胶塞反应物加热至80摄氏度14小时。将40mL乙酸乙酯和20mL水加入到反应液中。有机层分别用20mL 1N盐酸,20mL饱和碳酸氢钠,20mL饱和氯化钠溶液洗涤,并用无水硫酸钠干燥,过滤,真空浓缩,得到的粗产物通过硅胶柱或制备硅胶板进一步纯化(乙酸乙酯:石油醚=4:1)收集得到的含目标化合物的洗脱液经减压除去溶剂,干燥,获式Il所示的化合物纯品105.4mg(收率76%)。
1H NMR(500MHz,CDCl3)δ8.28–8.21(m,3H),8.16–8.10(m,3H),8.08(dd,J=9.4,2.7Hz,1H),8.05(t,J=7.6Hz,1H),7.91(dd,J=8.0,1.5Hz,1H),7.68(d,J=7.8Hz,1H),7.57(s,1H),7.51(dd,J=7.4,1.2Hz,1H),7.43(t,J=7.7Hz,1H),6.82(s,1H),5.18(d,J=8.2Hz,1H),4.75(q,J=6.4Hz,1H),3.71(s,3H),3.28(ddd,J=48.1,14.9,4.7Hz,2H),1.45(s,9H),1.37(s,9H).
13C NMR(126MHz,CDCl3)δ178.67,172.23,170.90,170.18,150.34,133.68,131.92,130.99,130.85,128.96,128.69,128.35,127.84,127.08,126.58,126.29,125.79,125.73,125.35,125.21,125.02,124.40,123.57,122.24,121.44,121.30,117.80,115.35,80.19,53.33,52.47,41.26,31.92,29.70,28.79,28.53,28.32,22.69,14.11.
HRMS(ESI)m/z calcd for C42H39N3O7Na(M+Na)+720.2683,found 720.2685.
实施例13:化合物(Im)的制备
如式IIm所示含色氨酸线性多肽(81.1mg,0.2mmol),马来酰亚胺衍生物III9(255.1mg,0.6mmol),双三氟甲烷磺酰亚胺银盐(15.12mg,0.04mmol),二氯(五甲基环戊二烯基)合铑(III)二聚体(61.82mg,0.1mmol),氧化银(46.2mg,0.2mmol)称于圆底烧瓶中,加入10mL二氯甲烷。盖上胶塞反应物加热至80摄氏度4小时。将40mL乙酸乙酯和20mL水加入到反应液中。有机层分别用20mL 1N盐酸,20mL饱和碳酸氢钠,20mL饱和氯化钠溶液洗涤,并用无水硫酸钠干燥,过滤,真空浓缩,得到的粗产物通过硅胶柱或制备硅胶板进一步纯化(乙酸乙酯:石油醚=4:1)收集得到的含目标化合物的洗脱液经减压除去溶剂,干燥,获式Im所示的化合物纯品119.2mg(收率72%)。
1H NMR(400MHz,CDCl3)δ7.65(p,J=3.8Hz,1H),7.58(s,1H),7.36(q,J=3.8,2.8Hz,2H),7.18–7.11(m,13H),7.07(ddt,J=8.0,5.2,2.7Hz,6H),6.61(s,1H),5.19(d,J=8.2Hz,1H),4.84–4.68(m,1H),3.74(s,3H),3.41–3.18(m,2H),1.45(d,J=23.8Hz,18H).
13C NMR(101MHz,CDCl3)δ178.68,172.30,170.16,169.26,155.12,149.51,143.56,143.40,143.37,143.00,141.64,140.12,133.66,131.85,131.62,131.44,131.37,131.34,129.96,127.78,127.75,127.69,127.64,126.63,126.59,126.56,125.38,125.28,124.81,123.50,121.43,121.01,117.62,115.26,80.23,53.31,52.56,41.24,28.48,28.37,27.73.HRMS(ESI)m/z calcd for C52H49N3O7Na(M+Na)+850.3463,found 850.3473.
实施例14:化合物的抗肿瘤活性检测
选取肿瘤细胞A549(肺癌细胞),采用MTT法进行抗肿瘤细胞增殖活性检测。细胞以4000~5000个/孔的浓度接种至含有10%胎牛血清的1640培养液的96孔板中,并在板盖上加上注释,于5%CO2、37℃培养12小时,待细胞在96孔板上贴壁,在无菌操作台中用移液枪加待测药物(待测药物包含实施例1~实施例13中制备的化合物(Ia)~(Im)),使每孔药物浓度分别为2μM、5μM、10μM、20μM、40μM五个浓度梯度,每个浓度设置有三个平行组,并再次将96孔板置于5%CO2、37℃培养24小时。取出96孔板,向每个孔中加入10μL的MTT试剂盒试剂(购自Promega公司),避光在5%CO2、37℃条件下孵化4小时,吸除上清后加入150uL无菌DMSO溶解甲臜,进一步在37℃培养箱中溶解5~10min,最后利用酶标仪测其吸光度。从而计算细胞活力和细胞毒性,用GraphPad Prism software软件处理,计算IC50以及IC5095%可信区间,结果见下表。
实验结果表明,化合物(Ia)~(Im)具有一定的抗肿瘤活性。
化合物 | IC<sub>50</sub>以及IC<sub>50</sub>95%可信区间(μM) |
Ia | 21.203±0.264 |
Ib | 22.078±0.273 |
Ic | 22.214±0.232 |
Id | 21.197±0.256 |
Ie | 22.231±0.243 |
If | 22.132±0.223 |
Ig | 22.132±0.210 |
Ih | 21.875±0.228 |
Ii | 21.878±0.241 |
Ij | 24.212±0.253 |
Ik | 21.982±0.244. |
Il | 23.806±0.238 |
Im | 23.810±0.202 |
对比例1:添加剂的选取
如式IIa所示含色氨酸线性多肽(80.42mg,0.2mmol),马来酰亚胺(58.22mg,0.6mmol),六氟锑酸银(13.72mg,0.04mmol),二氯(五甲基环戊二烯基)合铑(III)二聚体(61.82mg,0.1mmol),氧化银(46.2mg,0.2mmol)称于圆底烧瓶中,加入10mL二氯甲烷。盖上胶塞反应物加热至80摄氏度8小时。将40mL乙酸乙酯和20mL水加入到反应液中。有机层分别用20mL1N盐酸,20mL饱和碳酸氢钠,20mL饱和氯化钠溶液洗涤,并用无水硫酸钠干燥,过滤,真空浓缩,得到的粗产物通过硅胶柱或制备硅胶板进一步纯化(乙酸乙酯:石油醚=4:1)收集得到的含目标化合物的洗脱液经减压除去溶剂,干燥,获式Ia所示的化合物纯品34.8mg(收率35%)。
对比例2:氧化剂的选取
如式IIa所示含色氨酸线性多肽(80.42mg,0.2mmol),马来酰亚胺(58.22mg,0.6mmol),双三氟甲烷磺酰亚胺银盐(15.12mg,0.04mmol),二氯(五甲基环戊二烯基)合铑(III)二聚体(61.82mg,0.1mmol),碳酸银(55.15mg,0.2mmol)称于圆底烧瓶中,加入10mL二氯甲烷。盖上胶塞反应物加热至80摄氏度8小时。将40mL乙酸乙酯和20mL水加入到反应液中。有机层分别用20mL 1N盐酸,20mL饱和碳酸氢钠,20mL饱和氯化钠溶液洗涤,并用无水硫酸钠干燥,过滤,真空浓缩,得到的粗产物通过硅胶柱或制备硅胶板进一步纯化(乙酸乙酯:石油醚=4:1)收集得到的含目标化合物的洗脱液经减压除去溶剂,干燥,获式Ia所示的化合物纯品16.1mg(收率16%)。
对比例3:溶剂的选取
如式IIa所示含色氨酸线性多肽(80.42mg,0.2mmol),马来酰亚胺(58.22mg,0.6mmol),双三氟甲烷磺酰亚胺银盐(15.12mg,0.04mmol),二氯(五甲基环戊二烯基)合铑(III)二聚体(61.82mg,0.1mmol),氧化银(46.2mg,0.2mmol)称于圆底烧瓶中,加入10mL四氢呋喃。盖上胶塞反应物加热至80摄氏度8小时。将40mL乙酸乙酯和20mL水加入到反应液中。有机层分别用20mL 1N盐酸,20mL饱和碳酸氢钠,20mL饱和氯化钠溶液洗涤,并用无水硫酸钠干燥,过滤,真空浓缩,得到的粗产物通过硅胶柱或制备硅胶板进一步纯化(乙酸乙酯:石油醚=4:1)收集得到的含目标化合物的洗脱液经减压除去溶剂,干燥,获式Ia所示的化合物纯品12.8mg(收率13%)。
Claims (10)
2.如权利要求1所述的含色氨酸多肽马来酰亚胺化衍生物,其特征在于:R1为-OMe或-OEt。
3.如权利要求1所述的含色氨酸多肽马来酰亚胺化衍生物,其特征在于:R2为Boc-、Cbz-或Ac-)。
6.如权利要求5所述的含色氨酸多肽马来酰亚胺化衍生物的制备方法,其特征在于:所述溶剂的体积以所述底物的物质的量计为30-50mL/mmol。
7.如权利要求5所述的含色氨酸多肽马来酰亚胺化衍生物的制备方法,其特征在于:式(II)所示的含色氨酸多肽、马来酰亚胺(III)、添加剂、催化剂、氧化剂的物质的量之比为1:3:0.2:0.5:1。
8.如权利要求5所述的含色氨酸多肽马来酰亚胺化衍生物的制备方法,其特征在于所述后处理为:将乙酸乙酯和水加入到反应液中进行萃取,取有机层依次用1N盐酸、饱和碳酸氢钠、饱和氯化钠溶液洗涤,取有机层经过无水硫酸钠干燥、过滤、取滤液真空浓缩,即得粗品;以体积比为4:1的乙酸乙酯与石油醚的混合溶剂作为洗脱剂对粗品进行硅胶柱层析,收集含目标化合物的洗脱液,减压除去溶剂,干燥,得到(I)所示含色氨酸多肽马来酰亚胺化衍生物。
9.如权利要求1所述的含色氨酸多肽马来酰亚胺化衍生物在制备抗肿瘤药物中的应用。
10.如权利要求9所述的应用,其特征在于:所述肿瘤为肺癌。
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