CN109096366B - Rgd环肽偶联亲脂性阳离子多杀菌素衍生物及其制备方法和应用 - Google Patents
Rgd环肽偶联亲脂性阳离子多杀菌素衍生物及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了RGD环肽偶联亲脂性阳离子多杀菌素衍生物(LPC+‑SPD‑RGD)及其制备方法和应用。所述LPC+‑SPD‑RGD的结构如式(I)式所示。所述LPC+‑SPD‑RGD能用于制备抗肿瘤药物。
Description
技术领域
本发明涉及RGD环肽偶联阳离子多杀菌素的结构衍生物(LPC+-SPD-RGD)及其制备方法及用于抗肿瘤等方面的用途。
背景技术
多杀菌素(Spinosad)是由刺糖多胞菌(Saccharopolyspora spinosa)发酵液中提取的一种能够同时激活γ-氨基丁酸受体和烟碱型乙酰胆碱受体的大环内酯类无公害高效生物杀虫剂,由陶氏益农公司于上世纪九十年代初期开发并推向市场,商品化的多杀菌素主要活性成分为多杀菌素A。研究显示多杀菌素能作用于呼吸链复合物II,有抑制线粒体氧化磷酸化作用,体外、体内实验均显示了一定的抗肿瘤活性。多杀菌素A的化学结构式如下:
基于亲脂性阳离子更容易穿过肿瘤细胞线粒体内膜的特性,我们设计并合成了一类抗肿瘤效果更好的含有亲脂性阳离子官能团的多杀菌素衍生物(专利申请号CN201610356840.0阳离子多杀菌素衍生物及其制备方法和应用)。整合素αvβ3在肿瘤组织新生血管内皮细胞及多种恶性肿瘤细胞表面均有过度表达,其内源性配体,如层粘连蛋白,玻连蛋白,纤维蛋白原等,都是通过它们分子中特征性的精氨酸-甘氨酸-天冬氨酸(RGD) 三肽单元与整合素的αv亚基结合,因此含有RGD三肽结构单元的环肽对αvβ3高表达的肿瘤细胞有很好的识别作用。因此,本专利申请利用多种肿瘤细胞高水平表达整合素αvβ3及实体肿瘤组织酸性微环境的特点,创造性地设计并合成了一类RGD环肽偶联的阳离子多杀菌素结构衍生物(LPC+-SPD-RGD),并发现它们对整合素αvβ3高表达的肿瘤细胞有更好的选择性杀伤作用。
发明内容
本发明的目的之一为提供一类全新的LPC+-SPD-RGD。
所述LPC+-SPD-RGD结构如式(I)所示:
式(I)中的linker为含有有机阳离子的连接链。
优选地,所述linker为式(II)、式(III)所示的基团:
式(II)、式(III)中X为阴离子,n=0~18,m=0~12。
优选地,所述阴离子X选自氯、溴、碘、硫酸根、硫酸氢根、磷酸根、甲磺酸根、苯磺酸根、对甲苯磺酸根或氢氧根。
优选地,所述LPC+-SPD-RGD具体为式(Ⅳ)、式(Ⅴ)和(Ⅵ)所示的化合物:
本发明的目的之二为提供以上LPC+-SPD-RGD的制备方法。
所述LPC+-SPD-RGD的制备方法技术路线如下:
1.LPC+-SPD中间体3的合成路线
2.LPC+-SPD中间体5的合成路线
3.RGD环肽中间体11的合成路线
4.LPC+-SPD-RGD的合成路线
(1)制备中间体1、中间体2、中间体3:
将N-去甲基多杀菌素A溶于溶剂中,加入末端卤代烷醇反应后抽滤,去除溶剂,加入水后用溶剂萃取数次,合并萃取液,加入干燥剂干燥,旋干溶剂并分离纯化后得中间体1,所述N-去甲基多杀菌素A和末端卤代烷醇的物质的量比为n(N-去甲基多杀菌素A): n(末端卤代烷醇)=1:(1~10),所述溶剂用量为每1g N-去甲基多杀菌素A使用1~1000 mL;
将中间体1溶于溶剂中,加入沙瑞特试剂、醋酸钠反应后抽滤,去除溶剂,加入碳酸氢钠溶液后用溶剂萃取数次,合并萃取液,加入干燥剂干燥,旋干溶剂并分离纯化后得中间体2,所述中间体1、沙瑞特试剂、醋酸钠的物质的量比为n(中间体1):n(沙瑞特试剂):n(醋酸钠)=1:(1~10):(1~10),所述溶剂用量为每1g中间体1使用1~1000 mL,所述碳酸氢钠溶液用量为每1g中间体1使用1~1000mL;
将中间体2溶于溶剂中,加入碘甲烷反应后去除溶剂,用正己烷/异丙醇重结晶两次、分离纯化得到中间体3,所述中间体2和碘甲烷的物质的量比为n(中间体2):n(碘甲烷)=1:(1~10),所述溶剂用量为每1g中间体2使用1~1000mL;
(2)制备中间体1、中间体2、中间体3、中间体4、中间体5:
将N-去甲基多杀菌素A溶于溶剂中,加入末端二卤代烷烃反应后抽滤,去除溶剂,加入水后用溶剂萃取数次,合并萃取液,加入干燥剂干燥,旋干溶剂并离纯化后得中间体4,所述N-去甲基多杀菌素A和末端二卤代烷烃的物质的量比为n(N-去甲基多杀菌素 A):n(末端二卤代烷烃)=1:(1~10),所述溶剂用量为每1g N-去甲基多杀菌素A使用 1~1000mL;
将中间体4溶于溶剂中,加入含醛基的三苯基磷反应后去除溶剂,用正己烷和/或异丙醇重结晶两次,分离纯化后得中间体5,所述中间体4和含醛基的三苯基磷的物质的量比为 n(中间体4):n(含醛基的三苯基磷)=1:(1~10),所述溶剂用量为每1g中间体4使用1~1000mL;
(3)制备中间体6、中间体7、中间体9、中间体10、中间体11:
将甲酯化的赖氨酸溶于溶剂中,加入4-(2-((苄氧基)羰基)肼基)-丁酮酸反应后抽滤得中间体6,所述甲酯化的赖氨酸和4-(2-((苄氧基)羰基)肼基)-丁酮酸的物质的量比为n(甲酯化的赖氨酸):n(4-(2-((苄氧基)羰基)肼基)-丁酮酸)=1:(1~10),所述溶剂用量为每 1g甲酯化的赖氨酸使用1~1000mL;
将中间体6溶于溶剂中,加入氯化钙及氢氧化钠反应后去除溶剂,加入水后用溶剂萃取数次,合并萃取液,加入干燥剂干燥,旋干溶剂并分离纯化后得中间体7,所述中间体6、氯化钙、氢氧化钠的物质的量比为n(中间体6):n(氯化钙):n(氢氧化钠)=1:(1~ 10):(1~10),所述溶剂用量为每1g中间体6使用1~1000mL;
将中间体7溶于溶剂中,加入中间体8、PyAOP、2,4,6-三甲基吡啶反应后去除溶剂,加入水后用溶剂萃取数次,合并萃取液,加入干燥剂干燥,旋干溶剂并分离纯化后得中间体9,所述中间体7、中间体8、PyAOP、2,4,6-三甲基吡啶(TMP)的物质的量的比=n (中间体7):n(中间体8):n(PyAOP):n(TMP)=1:(1~10):(1~10):(1~10),所述溶剂用量为每1g中间体7使用1~1000mL;所述中间体8为 Fmoc-Arg(NO2)-Gly-Asp(OBn)-D-Phe-Ot-Bu;
将中间体9溶于溶剂中,加入叠氮磷酸二苯酯、DIPEA反应后去除溶剂,加入乙醚析晶,再加甲醇洗涤得中间体10,所述中间体9、叠氮磷酸二苯酯(DPPA)、DIPEA的物质的量比为n(中间体9):n(DPPA):n(DIPEA)=1:(1~10):(1~10),所述溶剂用量为每1g中间体9使用1~1000mL;
将中间体10溶于溶剂中,加入Pb/C,Pb/C中Pb与C的质量比为1:10,氢气条件下反应后浓缩溶剂,分离纯化后得中间体11,所述中间体10和Pb/C的质量比为m(中间体 10):m(Pb/C)=1:(1~10),所述溶剂用量为每1g中间体10使用1~1000mL;
(4)制备化合物Ⅳ、化合物Ⅴ和化合物Ⅵ:
将中间体3或中间体5溶于溶剂中,加入中间体11反应后去除溶剂,浓缩反应液加乙醚析晶,经凝胶柱分离纯化后得到LPC+-SPD-RGD:化合物Ⅳ、化合物Ⅴ和化合物Ⅵ(化合物Ⅳ、化合物Ⅴ和化合物Ⅵ的质谱及HPLC谱图见图1至图6);所述中间体3或中间体 5和中间体11的物质的量的比为n(中间体3或中间体5):n(中间体11)=(3~1):1,所述溶剂用量为每1g中间体3或中间体5或中间体11使用1~1000mL;
步骤(1)、(2)、(3)和(4)中所述溶剂为质子性溶剂或非质子性溶剂。
优选地,步骤(1)、(2)、(3)和(4)中所述溶剂为乙醇、甲醇、石油醚、乙酸乙酯、丙酮、二氯甲烷、氯仿、乙腈或N,N-二甲基甲酰胺等;步骤(1)、(2)、(3)和(4)中所述反应的温度为-10℃-200℃;步骤(1)、(2)、(3)和(4)中所述干燥剂为无水硫酸钠或无水氯化钙等。
本发明的目的之三为提供上述LPC+-SPD-RGD类化合物作为有效活性成分用于对抗肿瘤,增加临床上可供药物的选择性。优选地,用作治疗整合素αvβ3高表达的实体肿瘤。
附图说明
图1为化合物Ⅳ的质谱;
图2为化合物Ⅳ的HPLC谱图;
图3为化合物Ⅴ的质谱;
图4为化合物Ⅴ的HPLC谱图;
图5为化合物Ⅵ的质谱;
图6为化合物Ⅵ的HPLC谱图。
具体实施方式
实施例1
N-脱甲基-N-(6-羟基己基)多杀菌素A的制备
称取N-去甲基多杀菌素A 1.6g(2.2mmol)置于50mL圆底烧瓶中,加乙腈30mL 溶解,加入碳酸钾460mg(3.3mmol)和6-溴-1-己醇623mg(3.3mmol),80℃搅拌。 48h,TLC点板监测显示产物点不再增加,停止反应,冷却至室温,抽滤,滤渣用二氯甲烷(5mL×2)洗涤,旋转蒸发除去乙腈,用100mL水和乙酸乙酯(3×50mL)萃取,合并有机相,用无水硫酸钠干燥。减压旋转蒸发除去乙酸乙酯,用200目~300目硅胶柱层析 [洗脱剂:V(石油醚):V(乙酸乙酯)=5:1→V(石油醚):V(乙酸乙酯)=1:1]得淡黄色固体1.0g,收率54%。mp.81-88℃。1HNMR(500MHz,CDCl3)δ0.83(t,J=7.5Hz, 3H),0.88-0.96(m,1H),1.19(d,J=6.5Hz,3H),1.26(d,J=6.0Hz,3H),1.30(d,J=6.5Hz, 3H),1.32-1.40(m,7H),1.43-1.61(m,13H),1.67-1.83(m,3H),1.92-1.96(m,2H),2.19(s,4H), 2.27(penta,J=6.5Hz,2H),2.34-2.43(m,3H),2.86-2.90(m,1H),3.01-3.03(m,1H),3.11-3.16 (m,2H),3.27-3.33(m,1H),3.47(dd,J=3.0Hz,J=9.0Hz,2H),3.51-3.52(m,7H),3.54-3.55 (m,1H),3.57(s,3H),3.62-3.67(m,3H),4.32(tetra,J=7.0Hz,1H),4.43(d,J=7.0Hz,1H), 4.66-4.71(m,1H),4.86(d,J=1.5Hz,1H),5.81(dt,J=2.5Hz,J=10.0Hz,1H),5.90(d,J= 10.0Hz,1H),6.78(s,1H);HRMS(ESI)m/z[M+H]+计算值C46H76NO11 818.5418测定值 818.5437.
实施例2
N-脱甲基-N-(9-羟基壬基)多杀菌素A的制备
按实例1,用9-溴-1-壬醇代替6-溴-1-己醇,得淡黄色固体1.1g,收率57.3%。mp.81-88℃。1H NMR(400MHz,CDCl3)δ0.83(t,J=7.2Hz,3H),0.88-0.97(m,1H),1.20(d,J=8.0Hz,3H),1.26(d,J=6.4Hz,3H),1.29-1.40(m,18H),1.47-1.60(m,11H),1.65-1.73(m,1H),1.73-1.84(m,2H),1.91-1.99(m,2H),2.19(s,4H),2.24-2.30(penta,J=6.4Hz,2H),2.33-2.44(m,3H),2.86-2.91(m,1H),3.01-3.04(m,1H),3.10-3.16(m,2H),3.26-3.34(m,1H), 3.47(dd,J=3.6Hz,J=9.2Hz,2H),3.51-3.53(m,7H),3.54-3.56(m,1H),3.57(s,3H), 3.62-3.67(m,3H),4.32(dd,J=6.8Hz,J=12.8Hz,1H),4.43(d,J=6.8Hz,1H),4.65-4.72(m, 1H),4.87(d,J=1.6Hz,1H),5.79-5.83(dt,J=2.4Hz,J=10.0Hz,1H),5.90(d,J=9.6Hz, 1H),6.78(s,1H);HRMS(ESI)m/z[M+H]+计算值C49H82NO11 860.5888测定值860.5905.
实施例3
N-脱甲基-N-(6-羰基己基)多杀菌素A的制备
称取N-脱甲基-N-(6-羟基己基)多杀菌素A 480mg(0.59mmol)置于50mL反应瓶中,加二氯甲烷20mL溶解,加入PCC 200mg(0.93mmol)、醋酸钠96mg(1.17mmol) 和硅藻土480mg,室温搅拌反应,4h后,补加0.5当量的PCC。5h,TLC点板监测显示反应完全,停止反应,将反应液进行抽滤,滤渣用二氯甲烷(5mL)洗涤,旋转蒸发除去溶剂,加水100mL,用二氯甲烷(3×50mL)萃取,合并有机相,用无水硫酸钠干燥。减压旋转蒸发除去溶剂,用200目~300目硅胶柱层析[洗脱剂:V(石油醚):V(乙酸乙酯)=2:1→V(石油醚):V(乙酸乙酯):V(三乙胺)=1:1:0.01]得淡黄色固体360mg,收率75%。mp.81-88℃。1H NMR(400MHz,CDCl3)δ0.82(t,J=7.2Hz,3H),0.88-0.96(m, 1H),1.18(d,J=6.8Hz,3H),1.24-1.37(m,12H),1.43-1.57(m,9H),1.64(penta,J=7.6Hz, 2H),1.74-1.82(m,3H),1.91-1.98(m,2H),2.17(s,4H),2.23-2.30(m,2H),2.38-2.40(m,2H), 2.43-2.46(m,2H),2.85-2.90(m,1H),3.00-3.03(m,1H),3.10-3.16(m,2H),3.26-3.33(m,1H), 3.47(dd,J=3.2Hz,J=9.2Hz,2H),3.50(s,3H),3.51(s,3H),3.50-3.56(m,3H),3.56(s,3H), 3.61-3.66(m,1H),4.32(tetra,J=7.2Hz,1H),4.42(d,J=7.2Hz,1H),4.65-4.71(m,1H),4.86 (d,J=1.6Hz,1H),5.80(dt,J=2.8Hz,J=10.0Hz,1H),5.90(d,J=9.6Hz,1H),6.77(s,1H), 9.77(t,J=2.0Hz,1H);HRMS(ESI)m/z[M+H]+计算值C46H74NO11 816.5262测定值 816.5278.
实施例4
N-脱甲基-N-(9-羰基壬基)多杀菌素A的制备
按实例3,用N-脱甲基-N-(9-羟基壬基)多杀菌素A代替N-脱甲基-N-(6-羟基己基)多杀菌素A,得淡黄色固体320mg,收率61%。mp.81-88℃。1H NMR(400MHz,CDCl3) δ0.83(t,J=7.6Hz,3H),0.88-0.97(m,1H),1.20(d,J=6.8Hz,3H),1.26(d,J=6.0Hz,3H), 1.29-1.41(m,15H),1.47-1.58(m,8H),1.64(t,J=7.2Hz,2H),1.69(s,2H),1.74-1.82(m,2H),1.91-1.99(m,2H),2.19(s,4H),2.24-2.30(m,2H),2.34-2.46(m,4H),2.85-2.91(m,1H),3.01-3.04(m,1H),3.10-3.16(m,2H),3.26-3.34(m,1H),3.47(dd,J=3.2Hz,J=9.2Hz,2H), 3.509(s,3H),3.514(s,3H),3.51-3.59(m,3H),3.57(s,3H),3.62-3.67(m,1H),4.32(tetra,J= 7.2Hz,1H),4.43(d,J=6.8Hz,1H),4.65-4.72(m,1H),4.87(d,J=1.6Hz,1H),5.82(dt,J= 2.8Hz,J=9.6Hz,1H),5.90(d,J=10.0Hz,1H),6.78(s,1H),9.78(t,J=2.0Hz,1H);HRMS (ESI)m/z[M+H]+计算值C49H80NO11 858.5731测定值858.5760.
实施例5
N-脱甲基-N-(6-羰基己基)多杀菌素A碘化季铵盐的制备
称取N-脱甲基-N-(6-羰基己基)多杀菌素A 420mg(0.51mmol),加乙腈10mL溶解,加入碘甲烷228mg(1.52mmol),氮气保护,70℃搅拌回流。3d,TLC点板显示产物点不再增加,旋转蒸发除去乙腈,用正己烷和异丙醇[V(正己烷):V(异丙醇)=3:1] 重结晶两次,用Sephadex LH20凝胶柱层析(洗脱剂:甲醇)纯化得淡黄色固体152mg,收率31%。mp.90-95℃。1H NMR(400MHz,CDCl3)δ0.84(t,J=6.0Hz,3H),0.87-0.94(m, 1H),1.16(d,J=5.6Hz,3H),1.14-1.21(m,1H),1.28(d,J=4.8Hz,3H),1.32-1.39(m,3H), 1.47-1.51(m,3H),1.51-1.59(m,2H),1.61(d,J=5.6Hz,3H),1.65-1.67(m,2H),1.73-1.76(m, 3H),1.86-1.95(m,5H),2.14-2.20(m,1H),2.22-2.29(m,3H),2.41-2.43(m,1H),2.58(t,J=5.6 Hz,2H),2.88(t,J=8.0Hz,1H),3.00-3.03(m,1H),3.06-3.13(m,2H),3.22-3.28(m,1H), 3.32(s,3H),3.33(s,3H),3.45-3.50(m,3H),3.50(s,6H),3.55-3.63(m,3H),3.56(s,3H),3.69-3.71(m,1H),3.87-3.92(m,1H),4.31-4.36(m,2H),4.64-4.70(m,1H),4.85(s,1H),4.91-4.93(m,1H),5.78(d,J=8.0Hz,1H),5.80(d,J=8.0Hz,1H),6.79(s,1H),9.80(s,1H); HRMS(ESI)m/z[M-I]+计算值C47H76NO11 830.5418测定值830.5443.
实施例6
N-脱甲基-N-(9-羰基壬基)多杀菌素A碘化季铵盐的制备
按实例5,用N-脱甲基-N-(9-羰基壬基)多杀菌素A代替N-脱甲基-N-(6-羰基己基)多杀菌素A,得淡黄色固体134mg,收率36%。mp.90-95℃。1H NMR(400MHz,CDCl3) δ0.84(t,J=7.2Hz,3H),0.86-0.94(m,1H),1.12-1.18(m,1H),1.16(d,J=6.8Hz,3H),1.28(d, J=6.4Hz,3H),1.32-1.39(m,7H),1.41-1.45(m,4H),1.49-1.65(m,9H),1.74-1.84(m,6H),1.94(dd,J=6.8Hz,J=13.2Hz,1H),2.13-2.18(m,1H),2.24-2.31(m,3H),2.42-2.48(m,3H), 2.87-2.92(m,1H),3.02-3.04(m,1H),3.07-3.14(m,2H),3.26(t,J=8.4Hz,1H),3.33(s,3H), 3.34(s,3H),3.47(dd,J=3.2Hz,J=9.2Hz,2H),3.50-3.52(m,1H),3.503(s,3H),3.507(s, 3H),3.53-3.66(m,3H),3.57(s,3H),3.67-3.74(m,1H),3.92-3.94(m,1H),4.30-4.35(m,2H), 4.66-4.70(m,1H),4.86(d,J=1.6Hz,1H),4.92(m,1H),5.79(dt,J=2.4Hz,J=9.6Hz,1H), 5.90(d,J=7.6Hz,1H),6.80(s,1H),9.78(t,J=1.6Hz,1H);HRMS(ESI)m/z[M-I]+计算值 C50H82NO11 872.5888测定值872.5892.
实施例7
N-脱甲基-N-(6-三苯基膦醛)己基多杀菌素A溴化季磷盐的制备
在25mL单颈瓶中,依次加入300mg(0.34mmol)N-脱甲基-N-(6-溴己基)多杀菌素A和15mL乙腈,称取178mg(0.68mmol)三苯基膦醛加入反应体系,搅拌下于85℃下回流反应3d。旋转蒸发除去乙腈,用正己烷和异丙醇[V(正己烷):V(异丙醇)=3:1] 重结晶一次后经Sephadex LH20凝胶柱层析(洗脱剂:甲醇)纯化得白色固体254mg,收率65%。1H NMR(500MHz,CDCl3)δ7.90-7.84(m,6H),7.84-7.79(m,3H),7.75-7.70(m, 6H),6.78(s,1H),5.89(d,J=9.5Hz,1H),5.81(d,J=10.0Hz,1H),4.87(s,1H),4.71-4.65(m, 1H),4.43(s,1H),4.36-4.30(m,1H),3.84(s,2H),3.67-3.61(m,1H),3.58-3.55(m,4H), 3.53-3.46(m,10H),3.33-3.26(m,1H),3.16-3.10(m,2H),3.05-3.00(m,1H),2.91-2.85(m,1H), 2.44-2.39(m,1H),2.31-2.24(m,2H),2.21-2.12(m,3H),2.00-1.91(m,2H),1.72-1.64(m,9H),1.58-1.46(m,8H),1.31-1.28(m,4H),1.24-1.22(m,4H),1.20-1.18(m,4H),0.95-0.87(m,1H), 0.83(t,J=7.5Hz,3H);HR-ESI-MS:C64H89BrNO10P[M-Br]+计算值1062.62 186测定值1062.62 097.
实施例8
Fmoc-Lys(CO-CH2-CH2-CO-NH-NHCbz)-OCH3的制备
称取4-(2-((苄氧基)羰基)肼基)-丁酮酸2.47g(9.29mmol)置于100mL圆底烧瓶中,加四氢呋喃40mL溶解,再逐滴加入N-甲基吗啉2.55mL(23.2mmol)调节溶液pH至9-10,降温至-10℃,滴加氯甲酸甲酯723μL(9.29mmol),搅拌反应10min,得A液;另称取 Fmoc-Lys-OCH3 2.98g(7.74mmol)置于50mL圆底烧瓶中,加甲醇20mL溶解,N-甲基吗啉2.55mL(23.2mmol)调节溶液pH至9-10,将此溶液逐滴滴加到反应液A中,-10℃反应半小时,再逐渐升温至室温反应。8h,TLC点板显示反应完全,停止反应,旋转蒸发除去溶剂,加水50mL和二氯甲烷(3×50mL)萃取,合并有机相,用无水硫酸钠干燥。减压旋转蒸发脱去溶剂,用200目~300目硅胶柱层析[洗脱剂:V(二氯甲烷):V(甲醇) =97:3→V(二氯甲烷):V(甲醇)=95:5]得白色固体3.48g,产率61%。mp.111-114℃。1H NMR(500MHz,DMSO-d6)δ1.24-1.36(m,4H),1.60-1.69(m,2H),2.32(s,4H),3.02(dd,J =6.0Hz,J=12.0Hz,2H),3.63(s,3H),3.98-4.02(m,1H),4.24(t,J=7.0Hz,1H),4.30-4.32 (m,2H),5.07(s,2H),7.33-7.37(m,7H),7.43(t,J=7.5Hz,2H),7.73(dd,J=3.0Hz,J=7.5 Hz,2H),7.78(d,J=8.0Hz,1H),7.85(t,J=5.0Hz,1H),7.90(d,J=7.5Hz,2H),9.14(s,1H), 9.67(s,1H);HRMS(ESI)m/z[M+H]+计算值C34H39N4O8 631.2768测定值631.2778.
实施例9
Fmoc-Lys(CO-CH2-CH2-CO-NH-NHCbz)-OH的制备
称取8.8g(0.08mmol)无水氯化钙,加溶剂[V(异丙醇):V(水)=7:3]100mL溶解得溶液。称取Fmoc-Lys(CO-CH2-CH2-CO-NH-NHCbz)-OCH3 2.58g(4mmol)置于100 mL圆底烧瓶,加0.8M的氯化钙溶液30mL溶解,加入氢氧化钠384mg(8mmol),室温搅拌反应。12h,TLC点板显示反应完全,停止反应,将反应液过滤,加10%的盐酸溶液调节pH至中性,用溶剂[V(二氯甲烷):V(甲醇)=9:1](3×50mL)萃取,无水硫酸钠干燥。减压旋转蒸发脱去溶剂,用200目~300目硅胶柱层析[洗脱剂:V(二氯甲烷):V(甲醇)=95:5→V(二氯甲烷):V(甲醇):V(乙酸)=95:5:1]纯化得白色固体 2.10g,产率83%。mp.119-121℃。1H NMR(400MHz,DMSO-d6)δ1.26-1.40(m,4H), 1.58-1.70(m,2H),2.32(s,4H),2.99-3.04(m,2H),3.87-3.93(m,1H),4.21-4.29(m,3H),5.07 (s,2H),7.32-7.36(m,7H),7.43(t,J=6.0Hz,2H),7.62(d,J=6.8Hz,1H),7.74(d,J=7.2Hz, 2H),7.86-7.91(m,3H),9.16(s,1H),9.70(s,1H),12.56(s,1H);HRMS(ESI)m/z[M+H]+计算值C33H37N4O8 617.2611测定值617.2622.
实施例10
Fmoc-Lys(CO-CH2-CH2-CO-NH-NHCbz)-Arg(NO2)-Gly-Asp(OBn)-D-Phe-Ot-Bu的制备
称取Fmoc-Lys(CO-CH2-CH2-CO-NH-NHCbz)2.10g(3.30mmol)、PyAOP 1.91g(3.67mmol)及Fmoc-Arg(NO2)-Gly-Asp(OBn)-D-Phe-Ot-Bu 2.10g(3.07mmol)置于100mL单颈瓶中,加N,N-二甲基甲酰胺20mL溶解,冰浴至0℃;加入2,3,6-三甲基吡啶405μL (30.7mmol),0℃反应5h再升温至4℃反应。48h,点板显示产物不再增加,停止反应,加水100mL和乙酸乙酯(3×50mL)萃取,合并有机相,用无水硫酸钠干燥。减压旋转蒸发脱去溶剂,加20mL乙酸乙酯超声搅拌溶解,0℃静置过夜,抽滤,取滤渣加甲醇50mL溶解,放冰箱静置过夜,抽滤得固体,用甲醇润洗,重复此操作三次,得白色粉末状固体2.5g。收率55%。mp 205-210℃。1HNMR(500MHz,DMSO-d6)δ1.33-1.39 (m,13H),1.50-1.60(m,4H),1.69-1.73(m,2H),2.35(s,4H),2.54(m,1H),2.65-2.67(m,1H), 2.88-2.92(m,1H),2.97-3.02(m,3H),3.16(s,2H),3.71-3.80(m,2H),4.00-4.05(m,1H), 4.19-4.28(m,2H),4.31-4.42(m,3H),4.73-7.75(m,1H),5.01-5.15(m,4H),7.18-7.22(m,3H), 7.24-7.26(m,2H),7.34-7.36(m,12H),7.42(t,J=7.0Hz,3H),7.49(d,J=7.0Hz,1H),7.73(t, J=8.0Hz,2H),7.84(s,1H),7.89(d,J=7.5Hz,2H),8.02(d,J=5.0Hz,1H),8.18(s,1H), 8.24(dd,J=8.0Hz,J=16.0Hz,2H),8.53(s,1H),9.16(s,1H),9.71(s,1H);HRMS(ESI) m/z[M+Na]+计算值C65H79N12NaO16 1305.5556测定值1305.5604.
实施例11
c[Lys(CO-CH2-CH2-CO-NH-NHCbz)-Arg(NO2)-Gly-Asp(OBn)-D-Phe]的制备
称取实例10所得化合物 Fmoc-Lys(CO-CH2-CH2-CO-NH-NHCbz)-Arg(NO2)-Gly-Asp(OBn)-D-Phe-Ot-Bu 650mg (0.46mmol)置于100mL圆底烧瓶中,加二氯甲烷30mL溶解,降温至0℃,逐滴加入三氟乙酸10mL,室温反应。7h,点板显示反应完全,停止反应,减压旋转蒸发脱去溶剂,油泵抽滤2h加乙醚洗去三氟乙酸及杂质,纯化得白色固体620mg。将该白色固体置于100mL圆底烧瓶中,加N,N-二甲基甲酰胺15mL溶解,逐滴加入二乙胺1.5mL,室温反应。2h,点板显示反应完全,停止反应,减压旋转蒸发脱去溶剂,剩余溶液加乙醚析晶,静置过夜,抽滤,滤渣用二氯甲烷洗涤3次,得白色固体500mg。将该白色固体置于 500mL圆底烧瓶中,加N,N-二甲基甲酰胺5mL溶解,加乙腈500mL稀释,加DPPA 500 mg(1.84mmol),DIPEA193mg(1.50mmol),室温搅拌16h,旋转蒸发脱去乙腈,剩余溶液加乙醚析晶,静置过夜,抽滤,滤渣用二氯甲烷洗涤3次,再加甲醇30mL洗涤两次得白色固体280mg。产率60%。1H NMR(400MHz,DMSO-d6)δ0.94-1.06(m,2H), 1.26-1.54(m,7H),1.65-1.74(m,1H),2.32(brs,4H),2.55(dd,J=6.0Hz,J=16.0Hz 1H), 2.76-2.95(m,5H),3.14(brs,1H),3.17(d,J=4.8Hz,1H),3.24(dd,J=3.6Hz,J=14.8Hz, 1H),4.04(dd,J=7.2Hz,J=14.8Hz,1H),4.17(tetra,J=7.2,1H),4.44(dd,J=7.6Hz,J= 14.4Hz,1H),4.71(dd,J=8.4Hz,J=14.8Hz,1H),5.07(s,4H),7.15(d,J=7.6Hz,2H),7.18 (d,J=7.2Hz,1H),7.25(d,J=7.6Hz,2H),7.32-7.36(m,10H),7.56(d,J=7.6Hz,1H),7.83 (t,J=7.0Hz,2H),8.04(d,J=7.2Hz,1H),8.10(d,J=7.2Hz,1H),8.15(d,J=8.0Hz,1H), 8.41(s,1H),8.57(s,1H),9.16(s,1H),9.70(s,1H);HRMS(ESI)m/z[M+H]+计算值 C46H59N12O13 987.4325测定值987.4219.
实施例12
c[Lys(CO-CH2-CH2-CO-NH-NH2)-Arg-Gly-Asp-D-Phe]的制备
称取实例11所得化合物75mg,加DMF 1mL溶解,再加溶剂醋酸2mL、水1mL,加入钯碳(10%)150mg,氢气保护反应。8h,点板显示原料反应完全,停止反应,将反应液进行过滤,用Sephadex LH20凝胶柱层析(洗脱剂:甲醇)得产物50mg,产率83%, mp.170-174℃。HRMS(ESI)m/z[M+H]+计算值C31H48N11O9 718.3636测定值718.3648.
实施例13
RGD-N-脱甲基-N-(6-腙基己基)多杀菌素A碘化季铵盐的制备(化合物Ⅳ)
称取实例5所得化合物120mg,加入到实例12所得化合物90mg的甲醇溶液,室温搅拌反应。5h TLC点板显示产物不再增加,停止反应,浓缩甲醇液,经Sephadex LH20 凝胶柱层析(洗脱剂:甲醇)纯化得到的产物再用乙醚洗涤两次,得到白色固体99mg,产率67%,HPLC纯度:99.6%(10%CH3CN in H2O,Rt=4.50min),mp.178-182℃。HRMS (ESI)m/z[M-I]+计算值C78H121N12O19 1529.8871测定值1529.8870.
实施例14
RGD-N-脱甲基-N-(9-腙基壬基)多杀菌素A碘化季铵盐的制备(化合物Ⅴ)
按实例13,用实例6所得化合物代替实例5所得化合物,得到白色粉末101mg,产率69%,HPLC纯度:99.6%(10%CH3CN in H2O,Rt=4.04min),mp.172-175℃。HRMS (ESI)m/z[M-I]+计算值C81H127N12O19 1571.9340测定值1571.9325.
实施例15
RGD-N-脱甲基-N-(6-三苯基膦)己基多杀菌素A溴化季磷盐的制备(化合物Ⅵ)
称取实例7所得化合物120mg,加入到实例11所得化合物90mg的甲醇溶液,室温搅拌反应。5h TLC点板显示产物不再增加,停止反应,浓缩甲醇液,经Sephadex LH20 凝胶柱层析(洗脱剂:甲醇)纯化得到的产物再用乙醚洗涤两次,得到白色固体80mg,产率52%,HPLC纯度:96.2%(10%CH3CN in H2O,Rt=8.70min),mp.178-182℃。HRMS (ESI)m/z[M-Br]+计算值C96H134N12O19 1790.9659测定值1790.9655.
抗肿瘤活性活性实验
(1)胰酶消化对数期细胞表面整合素αvβ3高表达的人肺癌上皮细胞(H1299细胞)和细胞表面整合素αvβ3低表达的人胚肾293转Tau细胞(293T细胞),终止后离心收集,制成细胞悬液。
(2)接种细胞:根据细胞增长速率以每孔100μL体积设置好细胞密度,接种96孔板,设置4个复孔,同时设置调零孔(培养基、MTT、二甲基亚砜),对照孔(细胞、相同浓度的药物溶解介质、培养液、MTT、二甲基亚砜,DMSO终浓度<0.1%)。待细胞贴壁后以 0μmol/L、6.25μmol/L、12.5μmol/L、25μmol/L、50μmol/L的浓度梯度对多杀菌素类似物进行处理。
(3)培养细胞:在37℃、5%CO2的饱和湿度下,培养48h。
(4)显色:每孔加入MTT溶液(5mg/mL)20μL,继续培养4h后弃去孔内培养液,每孔加入100μL DMSO,于脱色摇床上振荡10min,使结晶物充分融解。
(5)比色:选490nm波长,校正波长630nm,用酶联免疫检测仪测定各孔吸光度,记录结果,计算抑制率。
计算IC50值,结果见表1。
表1:被测化合物对H1299细胞和293T细胞的增殖抑制活性,以多杀菌素A为阳性对照. (IC50值,单位μM)
肿瘤细胞 | 化合物Ⅳ | 化合物Ⅴ | 化合物Ⅵ | 多杀菌素A |
H1299 | 12.0 | 16.2 | 3.6 | 12.5 |
293T | >100 | >50 | >50 | 18.0 |
*:表1显示LPC+-SPD-RGD类化合物(化合物IV、化合物Ⅴ、化合物Ⅵ)对整合素αvβ3高表达的人肺癌上皮细胞(H1299细胞)有选择性杀灭作用。
Claims (5)
3.如权利要求2所述RGD环肽偶联亲脂性阳离子多杀菌素衍生物的制备方法,其特征在于,所述方法包括如下步骤:
(1)制备中间体1、中间体2、中间体3:
将N-去甲基多杀菌素A溶于溶剂中,加入末端卤代烷醇反应后抽滤,去除溶剂,加入水后用溶剂萃取数次,合并萃取液,加入干燥剂干燥,旋干溶剂并分离纯化后得中间体1,所述N-去甲基多杀菌素A和末端卤代烷醇的物质的量比为n(N-去甲基多杀菌素A):n(末端卤代烷醇)=1:(1~10),所述溶剂用量为每1g N-去甲基多杀菌素A使用1~1000mL;
将中间体1溶于溶剂中,加入沙瑞特试剂、醋酸钠反应后抽滤,去除溶剂,加入碳酸氢钠溶液后用溶剂萃取数次,合并萃取液,加入干燥剂干燥,旋干溶剂并分离纯化后得中间体2,所述中间体1、沙瑞特试剂、醋酸钠的物质的量比为n(中间体1):n(沙瑞特试剂):n(醋酸钠)=1:(1~10):(1~10),所述溶剂用量为每1g中间体1使用1~1000mL,所述碳酸氢钠溶液用量为每1g中间体1使用1~1000mL;将中间体2溶于溶剂中,加入碘甲烷反应后去除溶剂,用正己烷/异丙醇重结晶两次、分离纯化得到中间体3,所述中间体2和碘甲烷的物质的量比为n(中间体2):n(碘甲烷)=1:(1~10),所述溶剂用量为每1g中间体2使用1~1000mL;
(2)制备中间体4、中间体5:
将N-去甲基多杀菌素A溶于溶剂中,加入末端二卤代烷烃反应后抽滤,去除溶剂,加入水后用溶剂萃取数次,合并萃取液,加入干燥剂干燥,旋干溶剂并离纯化后得中间体4,所述N-去甲基多杀菌素A和末端二卤代烷烃的物质的量比为n(N-去甲基多杀菌素A):n(末端二卤代烷烃)=1:(1~10),所述溶剂用量为每1g N-去甲基多杀菌素A使用1~1000mL;
将中间体4溶于溶剂中,加入含醛基的三苯基磷反应后去除溶剂,用正己烷和/或异丙醇重结晶两次,分离纯化后得中间体5,所述中间体4和含醛基的三苯基磷的物质的量比为n(中间体4):n(含醛基的三苯基磷)=1:(1~10),所述溶剂用量为每1g中间体4使用1~1000mL;
(3)制备中间体6、中间体7、中间体9、中间体10、中间体11:
将甲酯化的赖氨酸溶于溶剂中,加入4-(2-((苄氧基)羰基)肼基)-丁酮酸反应后抽滤得中间体6,所述甲酯化的赖氨酸和4-(2-((苄氧基)羰基)肼基)-丁酮酸的物质的量比为n(甲酯化的赖氨酸):n(4-(2-((苄氧基)羰基)肼基)-丁酮酸)1:(1~10),所述溶剂用量为每1g甲酯化的赖氨酸使用1~1000mL;
将中间体6溶于溶剂中,加入氯化钙及氢氧化钠反应后去除溶剂,加入水后用溶剂萃取数次,合并萃取液,加入干燥剂干燥,旋干溶剂并分离纯化后得中间体7,所述中间体6、氯化钙、氢氧化钠的物质的量比为n(中间体6):n(氯化钙):n(氢氧化钠)=1:(1~10):(1~10),所述溶剂用量为每1g中间体6使用1~1000mL;
将中间体7溶于溶剂中,加入中间体8、PyAOP、2,4,6-三甲基吡啶反应后去除溶剂,加入水后用溶剂萃取数次,合并萃取液,加入干燥剂干燥,旋干溶剂并分离纯化后得中间体9,所述中间体7、中间体8、PyAOP、2,4,6-三甲基吡啶的物质的量的比=n(中间体7):n(中间体8):n(PyAOP):n(2,4,6-三甲基吡啶)=1:(1~10):(1~10):(1~10),所述溶剂用量为每1g中间体7使用1~1000mL;所述中间体8为Fmoc-Arg(NO2)-Gly-Asp(OBn)-D-Phe-Ot-Bu;
将中间体9溶于溶剂中,加入叠氮磷酸二苯酯、DIPEA反应后去除溶剂,加入乙醚析晶,再加甲醇洗涤得中间体10,所述中间体9、叠氮磷酸二苯酯、DIPEA的物质的量比为n(中间体9):n(叠氮磷酸二苯酯):n(DIPEA)=1:(1~10):(1~10),所述溶剂用量为每1g中间体9使用1~1000mL;
将中间体10溶于溶剂中,加入Pb/C,Pb/C中Pb与C的质量比为1:10,氢气条件下反应后浓缩溶剂,分离纯化后得中间体11,所述中间体10和Pb/C的质量比为m(中间体10):m(Pb/C)=1:(1~10),所述溶剂用量为每1g中间体10使用1~1000mL;
(4)制备化合物Ⅳ、化合物Ⅴ和化合物Ⅵ:
将中间体3或中间体5溶于溶剂中,加入中间体11反应后去除溶剂,浓缩反应液加乙醚析晶,经凝胶柱分离纯化后得到RGD环肽偶联亲脂性阳离子多杀菌素衍生物:化合物Ⅳ、化合物Ⅴ和化合物Ⅵ;所述中间体3或中间体5和中间体11的物质的量的比为n(中间体3或中间体5):n(中间体11)=(3~1):1,所述溶剂用量为每1g 中间体3或中间体5或中间体11使用1~1000mL;
步骤(1)、(2)、(3)和(4)中所述溶剂为质子性溶剂或非质子性溶剂;
所述末端二卤代烷烃为1,6-2-溴己烷;
所述末端卤代烷醇为6-溴-1-己醇或9-溴-1-壬醇;
4.如权利要求3所述的方法,其特征在于,步骤(1)、(2)、(3)和(4)中所述溶剂为乙醇、甲醇、石油醚、乙酸乙酯、丙酮、二氯甲烷、氯仿、乙腈或N,N-二甲基甲酰胺;步骤(1)、(2)、(3)和(4)中所述反应的温度为-10℃~200℃;步骤(1)、(2)、(3)和(4)中所述干燥剂为无水硫酸钠或无水氯化钙。
5.如权利要求1所述的RGD环肽偶联亲脂性阳离子多杀菌素衍生物在制备抗肿瘤药物中的应用。
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