CN103804296A - 17-(6-(取代肉桂酰氨基)己二胺)-17-去甲氧基格尔德霉素衍生物及其应用 - Google Patents
17-(6-(取代肉桂酰氨基)己二胺)-17-去甲氧基格尔德霉素衍生物及其应用 Download PDFInfo
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Abstract
本发明公开了一组17-(6-(取代肉桂酰氨基)己二胺)-17-去甲氧基格尔德霉素衍生物,其结构通式如式(Ⅰ)所示。本发明还公开了该格尔德霉素衍生物在制备抗肿瘤药物中的应用。实验证实本发明的格尔德霉素衍生物具有较好的成药性,在维持或增加其原有抗肿瘤活性的同时能明显降低了其肝毒性,为以GA为先导化合物的抗肿瘤药物的研发奠定基础。
Description
技术领域
本发明涉及一组格尔德霉素(Geldanamycin,GA)衍生物及其应用,尤其涉及一组17-(6-(取代肉桂酰氨基)己二胺)-17-去甲氧基格尔德霉素及其在制备抗肿瘤药物方面的应用,还涉及含所述化合物的抗肿瘤药物组合物,属于有机化合物合成技术领域。
背景技术
癌症依旧是导致人类死亡的主要原因之一。在我国,2012年诊断出癌症患者的人数已经达到307万,死于癌症的病人达到221万,占全球癌症死亡人数的27%。预计未来5年,我国的癌症患者要达到505万人(Globocan2012,IARC)。因此,对于癌症的预防和治疗已经成为我国一个不容忽视的社会问题和科研课题。
格尔德霉素(Geldanamycin,GA)最早从吸水链霉菌(Streptomyces hygroscopicus)发酵液中分离得到,属于苯醌安莎霉素。GA具有多种生物活性,包括抗菌、抗原虫、抗肿瘤、抗DNA病毒(单纯疱疹病毒Ⅰ、Ⅱ、水痘带状疱疹病毒)与RNA病毒(水泡性口炎病毒、柯莎奇病毒及人免疫缺陷病毒Ⅰ),以及调节上皮氮氧合酶活性以及抗炎作用。其抗肿瘤作用是近年来关注的热点之一。
GA抗肿瘤作用的靶点是热休克蛋白90(Heat shock protein90,Hsp90),它通过竞争性结合Hsp90N末端ATP/ADP结构域,特异性地抑制Hsp90所必需的ATP酶活性,从而改变Hsp90构象,抑制Hsp90分子伴侣功能。Hsp90失活后,依赖Hsp90的众多信号转导系统的成员被泛素化降解,从而产生抑制增殖、诱导细胞凋亡等一系列效应。
GA具有广谱的抗肿瘤作用,在美国癌症研究所(NCI)的体外筛选试验中,GA对高敏感细胞的IC50为13nM,对所有的60株肿瘤细胞IC50为180nM。此外,GA对小鼠实体瘤模型也有较强的抑制作用。但是由于其水溶性较差和体内分布无特异性,尤其是较强的肝毒性,严重影响了其作为新药而进行开发。经检索,利用在GA分子17-位通过1,6-己二胺连接引入具有保肝活性的取代肉桂酰基,维持或增加其原有抗肿瘤活性的同时,以降低其肝毒性的专利及文献还未见报道。
发明内容
针对现有技术的不足,本发明要解决的问题是提供一组17-(6-(取代肉桂酰氨基)己二胺)-17-去甲氧基格尔德霉素衍生物及其在制备抗肿瘤药物方面的应用。
本发明所述的一组17-(6-(取代肉桂酰氨基)己二胺)-17-去甲氧基格尔德霉素衍生物结构通式如式(Ⅰ)所示:
其中:
R为烃基、卤素、羟基、氨基、硝基、甲氧基、乙氧基、三氟甲氧基、氰基、羧基、磺酸基、磷酸基,或者它们之间的组合。
上述17-(6-(取代肉桂酰氨基)己二胺)-17-去甲氧基格尔德霉素衍生物中,R优选是:2-氯、3-氯、4-氯、2-溴、3-溴、4-溴、2-碘、3-碘、4-碘、2-氨基、3-氨基、4-氨基、2-氰基、3-氰基、4-氰基、2-甲基、3-甲基、4-甲基、3,4-二甲基、2-乙基、3-乙基、4-乙基、2-硝基、3-硝基、4-硝基、2-羟基、3-羟基、4-羟基、3,4-二羟基、2,3,4-三羟基、3,4,5-三羟基、2-甲氧基、3-甲氧基、4-甲氧基、2-乙氧基、3-乙氧基、4-乙氧基、4-羟基-3-甲氧基、3-羟基-4-甲氧基、2,3-二甲氧基、2,5-二甲氧基、3,4-二甲氧基、3,5-二甲氧基、2,3,4-三甲氧基、3,4,5-三甲氧基、3,4,5-三乙氧基、4-三氟甲基、4-三氟甲氧基或4-二甲氨基。
进一步的,上述R优选是:3-氯、2-甲基、3-甲基、4-甲基、2-硝基、3-硝基、3-羟基、4-羟基、3,4-二羟基、2-甲氧基、4-甲氧基、4-羟基-3-甲氧基、3-羟基-4-甲氧基、2,3-二甲氧基、2,5-二甲氧基、3,4-二甲氧基、3,5-二甲氧基、2,3,4-三甲氧基、3,4,5-三甲氧基、4-三氟甲基、4-三氟甲氧基或4-二甲氨基。
再进一步的,上述R优选是:2-甲氧基、4-甲氧基、4-羟基-3-甲氧基、3-羟基-4-甲氧基、3-羟基、4-羟基、3,4-二羟基、2,3-二甲氧基、2,5-二甲氧基、3,4-二甲氧基、2,3,4-三甲氧基或3,4,5-三甲氧基。
上述17-(6-(取代肉桂酰氨基)己二胺)-17-去甲氧基格尔德霉素衍生物中,较优选的格尔德霉素衍生物具体是:17-(6-(4-羟基-3-甲氧基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3a)、17-(6-(4-羟基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3b)、17-(6-(3-羟基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3c)、17-(6-(3,4-二羟基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3d)、17-(6-(3,4-二甲氧基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3e)、或17-(6-(3,4,5-三甲氧基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3f)。
上述17-(6-(取代肉桂酰氨基)己二胺)-17-去甲氧基格尔德霉素衍生物中,最优选的格尔德霉素衍生物是:17-(6-(4-羟基-3-甲氧基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3a)、17-(6-(3,4-二甲氧基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3e)、或17-(6-(3,4,5-三甲氧基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3f)。
本发明所述17-(6-(取代肉桂酰氨基)己二胺)-17-去甲氧基格尔德霉素衍生物在制备抗肿瘤药物中的应用。
其中:所述17-(6-(取代肉桂酰氨基)己二胺)-17-去甲氧基格尔德霉素衍生物是:17-(6-(4-羟基-3-甲氧基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3a)或17-(6-(3,4,5-三甲氧基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3f);所述抗肿瘤药物是抗人乳腺癌细胞MDA-MB-231、人肺癌细胞A549、人宫颈癌细胞HeLa、人前列腺癌PC3、人胃癌细胞BGC-823、人结肠癌细胞SW480、人表皮癌A431或/和人肝癌细胞HepG2的药物。
本发明还提供了一种抗肿瘤药物组合物,其中,所述的药物组合物含有上述17-(6-(取代肉桂酰氨基)己二胺)-17-去甲氧基格尔德霉素衍生物和药学上可接受的载体。
本发明还提供了一种用于预防和治疗乳腺癌的制剂,其特征在于:所述制剂含有治疗有效量的上述17-(6-(取代肉桂酰氨基)己二胺)-17-去甲氧基格尔德霉素衍生物和药学上可接受的载体,其中所述的格尔德霉素衍生物优选:17-(6-(4-羟基-3-甲氧基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3a)、17-(6-(3,4-二甲氧基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3e)、或17-(6-(3,4,5-三甲氧基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3f)。
本发明所述17-(6-(取代肉桂酰氨基)己二胺)-17-去甲氧基格尔德霉素衍生物可以通过以下通用方法制备。
首先1,6-己二胺在非质子性溶剂(卤代烷烃类溶剂、二甲基亚砜、N,N-二甲基甲酰胺、乙酸乙酯、乙腈、丙酮),与格尔德霉素反应,得到中间体2,然后2与取代的肉桂酸(取代的反式β-苯丙烯酸)缩合即生成本发明所述目标产物3。
制备反应式如下:
路线1.试剂:(i)1,6-己二胺,(ii)取代的反式β-苯丙烯酸
本发明公开的17-(6-(取代肉桂酰氨基)己二胺)-17-去甲氧基格尔德霉素,成功地在GA分子17-位通过1,6-己二胺连接引入具有保肝活性的取代肉桂酰基。实验证实所述格尔德霉素衍生物在维持或增加其原有抗肿瘤活性的同时,明显降低了其肝毒性,为以GA为先导化合物的抗肿瘤药物的研发奠定基础。进一步的实验表明本发明公开的化合物特别是17-(6-(4-羟基-3-甲氧基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3a)或17-(6-(3,4,5-三甲氧基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3f)对多种组织类型包括乳腺,生殖和呼吸系统来源的肿瘤细胞具有显著的抑制作用,但对人正常组织来源的脐静脉上皮细胞和人正常肝细胞毒性小,具有较好的成药性,为其在制备抗肿瘤药物的开发和应用奠定了基础。
具体实施方式
为使本领域相关研究人员能够全面理解本发明,下面结合实施例来阐述本发明的几种实施方式,尽管相关描述较为具体和详细,但并不能因此来限制本发明。
实施例1:17-(6-(4-羟基-3-甲氧基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素的合成(3a)
在50mL的圆底烧瓶中称取GA(1)(28.0mg,0.05mmol,1equiv.)溶解至氯仿(5mL)中,然后加入1,6-己二胺(58.1mg,0.50mmol,10equiv.),反应液避光搅拌3.5h后,TLC监控反应进程,反应结束后,加水洗涤3次(20mL x3),饱和食盐水洗涤3次(20mL x3),无水硫酸钠干燥,浓缩后得产品2,未经纯化,直接用于下一步。将上述得到的中间体2溶解到DMF(5mL)中,加入NHS(6.3mg,0.055mmol,1.1equiv.),EDC(10.4mg,0.055mmol,1.1equiv.)和阿魏酸(9.7mg,0.050mmol,1.1equiv.)。反应液在室温下避光搅拌,TLC监控反应进程,反应完毕后,加入水(25mL),用乙酸乙酯萃取3次(20mL x3),合并有机相,无水硫酸钠干燥,浓缩后粗品用硅胶柱层析(石油醚:乙酸乙酯=1:1)分离得目标化合物3a,其为紫色固体(24.4%);mp118-120℃;1H NMR(600MHz,CDCl3)δ9.15(s,1H,1-CONH),7.55(d,J=15.6Hz,1H,9’-H),7.26(s,1H,19-H),7.03(d,J=6.8Hz,1H,11’-H),6.98(s,1H,14’-H),6.92(d,J=11.0Hz,1H,3-H),6.87(d,J=7.5Hz,1H,14’-H),6.58(t,J=11.1Hz,1H,4-H),6.29(br.s,1H,17-NH),6.28(d,J=15.6Hz,1H,8’-H),5.88(d,J=11.5Hz,1H,5-H),5.84(t,J=10.4Hz,1H,9-H),5.18(s,1H,7-H),4.95(br.s,2H,7-CONH2),4.30(d,J=8.9Hz,1H,6-H),3.89(s,3H,12’-Me),3.60–3.49(m,2H,11-H and12-H),3.48–3.37(m,4H,1’-H and6’-H),3.35(s,3H,12-OMe),3.26(s,3H,6-OMe),2.77–2.70(m,1H,10-H),2.65(d,J=13.5Hz,1H,15-H),2.40(t,J=12.0Hz,1H,15-H),2.02(s,3H,2-Me),1.81–1.74(m,5H,8-Me and13-H),1.73–1.54(m,5H,14-H,2’-H and5’-H),1.49–1.35(m,4H,3’-H and4’-H),0.99(br.s,3H,10-Me),0.95(br.s,3H,14-Me).13C NMR(150MHz,CDCl3)δ184.1,180.6,168.5,166.9(7’-CONH),156.4,147.6(12’-C),146.9(13’-C),144.9,141.6(9’-C),141.5,135.9,135.1,132.9,127.3(10’-C),127.0,126.8,122.2(15’-C),117.9(8’-C),114.9(14’-C),109.9(11’-C),108.7,108.4,81.9,81.5,81.3,72.8,57.3,56.8,56.1(12’-OMe),45.8(1’-C),39.7(6’-C),35.2,34.5,32.4,29.7(2’-C),29.6(5’-C),28.6,26.5(3’-C and4’-C),23.0,13.0,12.8,12.5;ESI-MS:m/z843.6[M+Na]+(calcd.844.0)。
将3a制备方法中的阿魏酸变为4-羟基肉桂酸,同法可制得3b:
17-(6-(4-羟基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3b),为紫色固体(68.5%);mp140-142℃;1H NMR(600MHz,CDCl3)δ9.05(s,1H,1-CONH),7.48(d,J=15.5Hz,1H,9’-H),7.32(d,J=7.5Hz,2H,11’-H and15’-H),7.26(s,1H,19-H),6.86(d,J=11.3Hz,1H,3-H),6.82(d,J=7.6Hz,2H,12’-H and14’-H),6.56(t,J=11.2Hz,1H,4-H),6.27(br.s,1H,17-NH),6.19(d,J=15.5Hz,1H,8’-H),5.89(d,J=8.8Hz,1H,5-H),5.84(t,J=10.3Hz,1H,9-H),5.18(s,1H,7-H),4.92(br.s,2H,7-CONH2),4.28(d,J=9.6Hz,1H,6-H),3.57(d,J=8.0Hz,1H,11-H),3.54–3.37(m,1H,12-H),3.47–3.36(m,4H,1’-H and6’-H),3.35(s,3H,12-OMe),3.25(s,3H,6-OMe),2.77–2.70(m,1H,10-H),2.65(d,J=13.8Hz,1H,15-H),2.39(t,J=12.0Hz,1H,15-H),2.01(s,3H,2-Me),1.82–1.75(m,5H,8-Me and13-H),1.72–1.52(m,5H,14-H,2’-H and5’-H),1.45–1.33(m,4H,3’-H and4’-H),1.00(d,J=6.1Hz,3H,10-Me),0.93(d,J=5.1Hz,3H,14-Me).13C NMR(150MHz,CDCl3)δ184.1,180.5,168.5,166.9(7’-CONH),158.5(12’-C),156.5,145.1,141.5,141.1(9’-C),136.0,135.1,134.0,132.9,129.7(11’-C and15’-C),127.0,126.9(10’-C),126.8,117.6(8’-C),116.0(12’-C and14’-C),108.7,108.4,82.2,81.6,81.3,72.8,57.3,56.8,45.7(1’-C),39.5(6’-C),35.2,34.6,32.5,29.7(2’-C),29.5(5’-C),28.6,26.3(3’-C and4’-C),23.0,13.0,12.8,12.6;ESI-MS:m/z813.6[M+Na]+(calcd.813.9)。
将3a制备方法中的阿魏酸变为3-羟基肉桂酸,同法可制得3c:
17-(6-(3-羟基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3c),为紫色固体(32.4%);mp125-127℃;1H NMR(600MHz,MeOD)δ7.43(d,J=15.6Hz,1H),7.19(t,J=7.7Hz,1H),7.13(d,J=11.3Hz,1H),7.06(s,1H),7.01(d,J=7.5Hz,1H),6.95(s,1H),6.79(d,J=8.0Hz,1H),6.62(t,J=11.4Hz,1H),6.53(d,J=15.7Hz,1H),5.87(t,J=9.4Hz,1H),5.59(d,J=9.2Hz,1H),5.22(s,1H),4.54(d,J=8.1Hz,1H),3.60(s,1H),3.54(t,J=6.5Hz,2H),3.46(s,1H),3.35(s,1H),3.33(s,3H),3.31(d,J=5.2Hz,17H),2.76–2.66(m,2H),2.37–2.28(m,1H),2.00(s,3H),1.81(s,1H),1.73(s,3H),1.68(d,J=6.5Hz,3H),1.63–1.53(m,3H),1.45(s,4H),1.01–0.95(m,6H).13C NMR(150MHz,MeOD)δ185.7,181.2,180.9,168.6,159.1,159.0,146.6,141.8,138.0,137.6,137.3,135.3,130.9,128.1,127.1,126.0,124.8,121.7,120.3,117.9,115.1,109.5,109.0,83.0,81.9,81.8,74.3,57.5,56.8,56.3,46.3,40.3,35.8,34.6,33.6,30.8,30.3,27.6,27.4,22.7,13.7,12.6,12.4;ESI-MS:m/z813.6[M+Na]+(calcd.813.9)。
将3a制备方法中的阿魏酸变为3,4-二羟基肉桂酸,同法可制得3d:
17-(6-(3,4-二羟基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3d),为紫色固体(35.8%);mp137-140℃;1H NMR(600MHz,DMSO)δ9.35(s,2H),9.12(s,1H),7.95(s,1H),7.20(d,J=15.6Hz,1H),7.01(d,J=38.7Hz,2H),6.92(s,2H),6.82(d,J=7.9Hz,1H),6.73(d,J=8.1Hz,1H),6.60(s,1H),6.31(d,J=15.7Hz,2H),5.79(s,1H),5.53(s,1H),4.98(s,1H),4.40(s,1H),4.19(s,1H),3.46(s,2H),3.30(s,1H),3.20(d,J=6.7Hz,6H),3.17–3.11(m,3H),2.25(d,J=28.3Hz,1H),1.93(s,3H),1.88(s,1H),1.63(s,3H),1.56(s,2H),1.45(s,2H),1.32(s,4H),0.93(d,J=5.5Hz,3H),0.80(d,J=6.2Hz,3H).13C NMR(150MHz,DMSO)δ185.0,179.0,173.7,165.7,156.6,147.7,145.0,139.4,139.3,126.9,120.8,119.0,116.2,114.2,109.6,106.8,81.3,79.7,79.4,79.2,72.4,70.3,56.9,56.4,51.8,45.0,41.4,40.5,40.4,39.5,39.2,39.0,38.8,33.8,30.1,29.6,28.7,26.6,26.4,25.7,13.5,12.9,12.7;ESI-MS:m/z829.6[M+Na]+(calcd.829.9)。
将3a制备方法中的阿魏酸变为3,4-二甲氧基肉桂酸,同法可制得3e:
17-(6-(3,4-二甲氧基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3e),为紫色固体(30.4%);mp119-120℃;1H NMR(600MHz,CDCl3)δ9.17(s,1H,1-CONH),7.55(d,J=15.4Hz,1H,9’-H),7.26(s,1H,19-H),7.07(d,J=7.3Hz,1H,15’-H),7.01(s,1H,11’-H),6.94(d,J=10.8Hz,1H,3-H),6.84(d,J=7.5Hz,1H,14’-H),6.57(t,J=11.1Hz,1H,4-H),6.28(br.s,1H,17-NH),6.26(d,J=17.9Hz,1H,8’-H),5.89(d,J=8.3Hz,1H,5-H),5.85(t,J=10.4Hz,1H,9-H),5.67(s,1H),5.17(s,1H,7-H),4.86(br.s,2H,7-CONH2),4.37(s,1H,11-OH),4.30(d,J=9.4Hz,1H,6-H),3.89(s,6H,12’-OMe and13’-OMe),3.59–3.51(m,2H,11-H and12-H),3.47–3.36(m,4H,1’-H and6’-H),3.35(s,3H,12-OMe),3.26(s,3H,6-OMe),2.77–2.68(m,1H,10-H),2.66(d,J=13.6Hz,1H,15-H),2.40(t,J=12.0Hz,1H,15-H),2.01(s,3H,2-Me),1.82–1.75(m,5H,8-Me and13-H),1.74–1.63(m,5H,14-H,5’-H and2’-H),1.48–1.37(m,4H,3’-Hand4’-H),0.99(br.s,3H,10-Me),0.95(br.s,14-Me).13C NMR(150MHz,CDCl3)δ184.0,180.7,168.5,166.3(7’-CONH),156.2,150.6(12’-C),149.2(13’-C),144.9,141.6,141.0(9’-C),135.9,135.1,133.9,132.8,127.9(10’-C),127.0,126.7,122.0(15’-C),118.5(8’-C),111.1(14’-C),109.7(11’-C),108.7,108.5,81.8,81.6,81.3,72.7,57.3,56.8,56.1(12’-OMe),56.0(13’-OMe),45.9(1’-C),39.6(6’-C),35.2,34.6,32.4,29.8(2’-C and5’-C),28.6,26.6(3’-C and4’-C),23.0,12.9,12.8,12.5;ESI-MS:m/z857.7[M+Na]+(calcd.858.0)。
将3a制备方法中的阿魏酸变为3,4,5-三甲氧基肉桂酸,同法可制得3f:
17-(6-(3,4,5-三甲氧基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3f),为紫色固体(50.4%);mp128-130℃;1H NMR(600MHz,CDCl3)δ9.17(s,1H),7.53(d,J=15.5Hz,1H,9’-H),7.26(s,1H),6.93(d,J=11.3Hz,1H),6.71(s,2H,11’-H and15’-H),6.57(t,J=11.3Hz,1H),6.34–6.23(m,2H,10’-H and),5.89(d,J=8.8Hz,1H),5.87–5.82(m,1H),5.76(br,s,1H,17-NH),5.17(s,1H),4.93(br,s,2H),4.30(d,J=9.8Hz,1H),3.91–3.81(m,9H,12’-OMe,13’-OMe and14’OMe),3.58–3.51(m,2H,11-H and6’-H),3.47–3.41(m,2H,12-H and6’-H),3.41–3.36(m,2H,1’-H),3.35(s,3H),3.25(s,3H),2.76–2.69(m,1H),2.66(d,J=13.9Hz,1H),2.40(t,J=12.2Hz,1H),2.01(s,3H),1.78(br,s,5H,8-Me and13-H),1.73–1.63(m,3H,14-Hand2’-H),1.62–1.55(m,2H,5’-H),1.47–1.37(m,4H,3’-H and4’-H),0.99(d,J=6.6Hz,3H),0.95(d,J=5.7Hz,3H).13C NMR(150MHz,CDCl3)δ183.9,180.6,168.4,165.9(7’-C),156.1,153.4(12’-C and14’-C),144.8,141.5,141.0(9’-C),139.5(13’-C),135.9,135.0,133.8,132.8,130.4(10’-C),126.9,126.6,119.9(8’-C),108.6,108.4,104.8(11’-C and15’-C),81.7,81.5,81.2,72.6,61.0(13’-OMe),57.1,56.7,56.1(12’-OMe and14’-OMe),45.8(1’-C),39.5(6’-C),35.0,34.4,32.3,29.7(2’-C),29.6(5’-C),28.5,26.5(3’-C),26.5(4’-C),22.9,12.8,12.7,12.4;ESI-MS:m/z887.7[M+Na]+(calcd.888.0)。
将3a制备方法中的阿魏酸变为3-氯肉桂酸,同法可制得3g:
17-(6-(3-氯肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3g),为紫色固体(12.5%);mp121-123℃;1H NMR(600MHz,CDCl3)δ9.18(s,1H,1-CONH),7.56(d,J=15.5Hz,1H,9’-H),7.48(s,1H,15’-H),7.35(d,J=6.6Hz,1H,13’-H),7.32–7.29(m,2H,11’-H and14’-H),7.27(s,1H,19-H),6.95(d,J=11.3Hz,1H,3-H),6.58(t,J=11.3Hz,1H,4-H),6.39(d,J=15.5Hz,1H,8’-H),6.29(s,1H,17-NH),5.90(d,J=9.3Hz,1H,5-H),5.86(t,J=10.5Hz,1H,9-H),5.74(s,1H,7’CO-NH),5.19(s,1H,7-H),4.81(br s,2H,7-CONH2),4.31(d,J=9.8Hz,1H,6-H),3.59–3.52(m,2H,11-H and12-H),3.48–3.42(m,2H,6’-H),3.42–3.38(m,2H,1’-H),3.35(s,3H,12-OMe),3.27(s,3H,6-OMe),2.77–2.70(m,1H,10-H),2.67(d,J=13.5Hz,1H,15-H),2.44–2.37(m,1H,15-H),2.02(s,3H,2-Me),1.80(s,3H,8-Me),1.79–1.76(m,2H,13-H),1.74–1.70(m,1H,14-H),1.70–1.65(m,2H,5'-H),1.63–1.58(m,2H,2'-H),1.50–1.38(m,4H,3'-H and4'-H),1.00(d,J=6.9Hz,3H,10-Me),0.96(d,J=6.7Hz,3H,14-Me);ESI-MS:m/z831.6[M+Na]+(calcd.832.4)。
将3a制备方法中的阿魏酸变为2-甲基肉桂酸,同法可制得3h:
17-(6-(2-甲基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3h),为紫色固体(33.0%);mp98-100℃;1H NMR(600MHz,CDCl3)δ9.18(s,1H,1-CONH),7.91(d,J=15.4Hz,1H,9’-H),7.49(d,J=7.7Hz,1H,15’-H),7.27(s,1H,19-H),7.23(d,J=6.5Hz,1H,12’-H),7.18(d,J=7.4Hz,2H,13’-H and14’-H),6.95(d,J=11.1Hz,1H,3-H),6.58(t,J=11.6Hz,1H,4-H),6.32–6.26(m,2H,17-NH and8’-H),5.89(d,J=9.5Hz,1H,5-H),5.86(t,J=10.5Hz,1H,9-H),5.74(s,1H,7’CO-NH),5.19(s,1H,7-H),4.92(br s,2H,7-CONH2),4.31(d,J=9.8Hz,1H,6-H),3.59–3.53(m,2H,11-H and12-H),3.47–3.43(m,2H,6’-H),3.42–3.38(m,2H,1’-H),3.35(s,3H,12-OMe),3.26(s,3H,6-OMe),2.76–2.71(m,1H,10-H),2.67(d,J=13.6Hz,1H,15-H),2.43(s,3H,11’-Me),2.42–2.38(m,1H,15-H),2.02(s,3H,2-Me),1.79(s,3H,8-Me),1.79–1.76(m,2H,13-H),1.74–1.71(m,1H,14-H),1.71–1.67(m,2H,5'-H),1.63–1.58(m,2H,2'-H),1.49–1.40(m,4H,3'-H and4'-H),1.00(d,J=6.9Hz,3H,10-Me),0.96(d,J=6.7Hz,3H,14-Me);ESI-MS:m/z811.7[M+Na]+(calcd.812.0)。
将3a制备方法中的阿魏酸变为3-甲基肉桂酸,同法可制得3i:
17-(6-(3-甲基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3i),为紫色固体(13.4%);mp121-123℃;1H NMR(600MHz,CDCl3)δ9.18(s,1H,1-CONH),7.60(d,J=15.6Hz,1H,9’-H),7.31(s,1H,15’-H),7.30(s,1H,14’-H),7.28(s,1H,19-H),7.24(d,J=7.9Hz,1H,13’-H),7.16(d,J=7.6Hz,1H,11’-H),6.95(d,J=12.1Hz,1H,3-H),6.58(t,J=11.6Hz,1H,4-H),6.37(d,J=15.5Hz,1H,8’-H),6.28(s,1H,17-NH),5.90(d,J=9.4Hz,1H,5-H),5.86(t,J=10.6Hz,1H,9-H),5.67(s,1H,7’CO-NH),5.19(s,1H,7-H),4.81(br s,2H,7-CONH2),4.31(d,J=9.9Hz,1H,6-H),3.59–3.53(m,2H,11-H and12-H),3.47–3.43(m,2H,6’-H),3.42–3.38(m,J=5.9Hz,2H,1’-H),3.36(s,3H,12-OMe),3.27(s,3H,6-OMe),2.77–2.72(m,1H,10-H),2.68(d,J=14.0Hz,1H,15-H),2.44–2.40(m,1H,15-H),2.36(s,3H,12’-Me),2.02(s,3H,2-Me),1.80(s,3H,8-Me),1.79–1.77(m,2H,13-H),1.74–1.66(m,3H,14-H and5'-H),1.64–1.58(m,2H,2'-H),1.49–1.39(m,4H,3'-H and4'-H),1.00(d,J=6.9Hz,3H,10-Me),0.97(d,J=6.7Hz,3H,14-Me);ESI-MS:m/z811.7[M+Na]+(calcd.812.0)。
将3a制备方法中的阿魏酸变为4-甲基肉桂酸,同法可制得3j:
17-(6-(4-甲基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3j),为紫色固体(6.7%);mp108-111℃;1H NMR(600MHz,CDCl3)δ9.18(s,1H,1-CONH),7.59(d,J=15.5Hz,1H,9’-H),7.39(d,J=7.9Hz,2H,11’and15’-H),7.28(s,1H,19-H),7.17(d,J=7.8Hz,2H,12’and14’-H),6.95(d,J=11.6Hz,1H,3-H),6.58(t,J=11.5Hz,1H,4-H),6.34(d,J=15.6Hz,1H,8’-H),6.28(s,1H,17-NH),5.90(d,J=9.7Hz,1H,5-H),5.86(t,J=10.5Hz,1H,9-H),5.64(s,1H,7’CO-NH),5.19(s,1H,7-H),4.79(br s,2H,7-CONH2),4.31(d,J=9.9Hz,1H,6-H),3.59–3.53(m,2H,11-H and12-H),3.48–3.43(m,2H,6’-H),3.42–3.38(m,2H,1’-H),3.35(s,3H,12-OMe),3.27(s,3H,6-OMe),2.76–2.72(m,1H,10-H),2.67(d,J=14.1Hz,1H,15-H),2.45–2.38(m,1H,15-H),2.36(s,3H,13’-Me),2.02(s,3H,2-Me),1.80(s,3H,8-Me),1.79–1.77(m,2H,13-H),1.74–1.70(m,1H,14-H),1.70–1.67(m,2H,5’-H),1.63–1.57(m,2H,2’-H),1.48–1.39(m,4H,3’-H and4’-H),1.00(d,J=6.9Hz,3H,10-Me),0.96(d,J=6.6Hz,3H,14-Me);ESI-MS:m/z811.6[M+Na]+(calcd.812.0)。
将3a制备方法中的阿魏酸变为2-硝基肉桂酸,同法可制得3k:
17-(6-(2-硝基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3k),为紫色固体(11.1%);mp114-115℃;1H NMR(600MHz,CDCl3)δ9.16(s,1H,1-CONH),7.98(d,J=8.0Hz,1H,14’-H),7.93(d,J=15.6Hz,1H,9’-H),7.62–7.56(m,2H,11’-H and13’-H),7.51–7.45(m,1H,12’-H),7.24(s,1H,19-H),6.93(d,J=11.5Hz,1H,3-H),6.56(t,J=11.3Hz,1H,4-H),6.34(d,J=15.6Hz,1H,8’-H),6.28(s,1H,17-NH),6.09(s,1H,7’CO-NH),5.88(s,1H,5-H),5.86–5.81(m,1H,9-H),5.16(s,1H,7-H),4.94(br s,2H,7-CONH2),4.29(d,J=9.9Hz,1H,6-H),3.58–3.51(m,2H,11-H and12-H),3.46–3.41(m,2H,6’-H),3.40–3.35(m,2H,1’-H),3.34(s,3H,12-OMe),3.24(s,3H,6-OMe),2.75–2.68(m,1H,10-H),2.64(d,J=13.4Hz,1H,15-H),2.43–2.36(m,1H,15-H),2.00(s,3H,2-Me),1.77(s,3H,8-Me),1.77–1.75(m,2H,13-H),1.72–1.69(m,1H,14-H),1.69–1.65(m,2H,5'-H),1.61–1.56(m,2H,2'-H),1.47–1.37(m,4H,3'-H and4'-H),0.97(d,J=6.9Hz,3H,10-Me),0.94(d,J=6.7Hz,3H,14-Me);ESI-MS:m/z842.6[M+Na]+(calcd.842.9).
将3a制备方法中的阿魏酸变为3-硝基肉桂酸,同法可制得3l:
17-(6-(3-硝基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3l),为紫色固体(11.8%);mp116-118℃;1H NMR(600MHz,CDCl3)δ9.17(s,1H,1-CONH),8.35(s,1H,11’-H),8.16(d,J=8.2Hz,1H,13’-H),7.76(d,J=7.6Hz,1H,15’-H),7.66(d,J=15.6Hz,1H,9’-H),7.54(t,J=7.9Hz,1H,14’-H),7.24(s,1H,19-H),6.94(d,J=11.7Hz,1H,3-H),6.59–6.53(m,2H,4-H and8’-H),6.28(s,1H,17-NH),6.07(s,1H,7’CO-NH),5.89–5.82(m,2H,5-H and9-H),5.17(s,1H,7-H),4.94(br s,2H,7-CONH2),4.30(d,J=9.9Hz,1H,6-H),3.58–3.51(m,2H,11-H and12-H),3.46–3.39(m,4H,6’-H and1’-H),3.34(s,3H,12-OMe),3.25(s,3H,6-OMe),2.75–2.69(m,1H,10-H),2.65(d,J=13.7Hz,1H,15-H),2.43–2.35(m,1H,15-H),2.00(s,3H,2-Me),1.78(s,3H,8-Me),1.77–1.75(m,2H,13-H),1.72–1.70(m,1H,14-H),1.69–1.65(m,2H,5'-H),1.63–1.58(m,2H,2'-H),1.47–1.39(m,4H,3'-H and4'-H),0.98(d,J=6.9Hz,3H,10-Me),0.95(d,J=6.6Hz,3H,14-Me);ESI-MS:m/z842.6[M+Na]+(calcd.842.9)。
将3a制备方法中的阿魏酸变为2-甲氧基肉桂酸,同法可制得3m:
17-(6-(2-甲氧基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3m),为紫色固体(18.6%);mp121-123℃;1H NMR(600MHz,CDCl3)δ9.18(s,1H,1-CONH),7.85(d,J=15.8Hz,1H,9’-H),7.46(d,J=7.5Hz,1H,15’-H),7.30(t,J=7.2Hz,1H,13’-H),7.27(s,1H,19-H),6.97–6.92(m,2H,3-H and14’-H),6.90(d,J=8.3Hz,1H,12’-H),6.58(t,J=11.3Hz,1H,4-H),6.52(d,J=15.8Hz,1H,8’-H),6.28(s,1H,17-NH),5.90(d,J=9.5Hz,1H,5-H),5.86(t,J=10.5Hz,1H,9-H),5.72(s,1H,7’CO-NH),5.18(s,1H,7-H),4.84(br s,2H,7-CONH2),4.30(d,J=9.8Hz,1H,6-H),3.87(s,3H,11’-OMe),3.59–3.52(m,2H,11-H and12-H),3.48–3.42(m,2H,6’-H),3.42–3.37(m,2H,1’-H),3.35(s,3H,12-OMe),3.26(s,3H,6-OMe),2.76–2.71(m,1H,10-H),2.67(d,J=13.5Hz,1H,15-H),2.44–2.38(m,1H,15-H),2.02(s,3H,2-Me),1.80(s,3H,8-Me),1.79–1.76(m,2H,13-H),1.74–1.70(m,1H,14-H),1.70–1.65(m,2H,5'-H),1.63–1.57(m,2H,2'-H),1.49–1.38(m,4H,3'-H and4'-H),1.00(d,J=6.9Hz,3H,10-Me),0.96(d,J=6.7Hz,3H,14-Me);ESI-MS:m/z827.7[M+Na]+(calcd.828.0)。
将3a制备方法中的阿魏酸变为4-甲氧基肉桂酸,同法可制得3n:
17-(6-(4-甲氧基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3n),为紫色固体(12.1%);mp119-122℃;1H NMR(600MHz,CDCl3)δ9.18(s,1H,1-CONH),7.58(d,J=15.5Hz,1H,9’-H),7.45(d,J=8.6Hz,2H,11’-H and15’-H),7.28(s,1H,19-H),6.96(d,J=11.1Hz,1H,3-H),6.89(d,J=8.7Hz,2H,12’-H and14’-H),6.58(t,J=11.4Hz,1H,4-H),6.28(s,1H,17-NH),6.25(d,J=15.4Hz,1H,8’-H),5.91(d,J=9.3Hz,1H,5-H),5.86(t,J=10.4Hz,1H,9-H),5.57(s,1H,7’CO-NH),5.19(s,1H,7-H),4.87–4.59(m,2H,7-CONH2),4.31(d,J=9.7Hz,1H,6-H),3.83(s,3H,13’-OMe),3.59–3.54(m,2H,11-H and12-H),3.48–3.43(m,2H,6’-H),3.42–3.37(m,2H,1’-H),3.36(s,3H,12-OMe),3.27(s,3H,6-OMe),2.76–2.72(m,1H,10-H),2.68(d,J=13.8Hz,1H,15-H),2.44–2.38(m,1H,15-H),2.03(s,3H,2-Me),1.80(s,3H,8-Me),1.80–1.77(m,2H,13-H),1.74–1.71(m,1H,14-H),1.71–1.67(m,2H,5’-H),1.62–1.58(m,2H,2’-H),1.48–1.40(m,4H,3’-H and4’-H),1.00(d,J=6.9Hz,3H,10-Me),0.97(d,J=6.7Hz,3H,14-Me);ESI-MS:m/z827.6[M+Na]+(calcd.828.0)。
将3a制备方法中的阿魏酸变为3-羟基4-甲氧基肉桂酸,同法可制得3o:
17-(6-(3-羟基-4-甲氧基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3o),为紫色固体(18.8%);mp124-126℃;1H NMR(600MHz,CDCl3)δ9.18(s,1H,1-CONH),7.52(d,J=15.5Hz,1H,9’-H),7.27(s,1H,19-H),7.10(d,J=1.8Hz,1H,11’-H),7.00–6.97(m,1H,15’-H),6.95(d,J=10.9Hz,1H,3-H),6.82(d,J=8.3Hz,1H,14’-H),6.58(t,J=11.4Hz,1H,4-H),6.28(s,1H,17-NH),6.23(d,J=15.5Hz,1H,8’-H),5.90(d,J=9.4Hz,1H,5-H),5.86(t,J=10.5Hz,1H,9-H),5.70(s,1H,7’CO-NH),5.19(s,1H,7-H),4.79(br s,2H,7-CONH2),4.31(d,J=9.8Hz,1H,6-H),3.90(s,3H,13’-OMe),3.59–3.52(m,2H,11-H and12-H),3.47–3.41(m,2H,6’-H),3.41–3.36(m,2H,1’-H),3.35(s,3H,12-OMe),3.26(s,3H,6-OMe),2.78–2.70(m,1H,10-H),2.67(d,J=13.9Hz,1H,15-H),2.44–2.37(m,1H,15-H),2.02(s,3H,2-Me),1.79(s,3H,8-Me),1.79–1.76(m,2H,13-H),1.75–1.70(m,1H,14-H),1.70–1.67(m,2H,5'-H),1.62–1.56(m,2H,2'-H),1.47–1.39(m,4H,3'-H and4'-H),1.00(d,J=6.9Hz,3H,10-Me),0.96(d,J=6.6Hz,3H,14-Me);ESI-MS:m/z843.7[M+Na]+(calcd.844.0)。
将3a制备方法中的阿魏酸变为2,3-二甲氧基肉桂酸,同法可制得3p:
17-(6-(2,3-二甲氧基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3p),为紫色固体(10.8%);mp95-98℃;1H NMR(600MHz,CDCl3)δ9.18(s,1H,1-CONH),7.86(d,J=15.8Hz,1H,9’-H),7.27(s,1H,19-H),7.10(d,J=7.9Hz,1H,15’-H),7.04(t,J=8.0Hz,1H,14’-H),6.95(d,J=11.9Hz,1H,3-H),6.91(d,J=7.8Hz,1H,13’-H),6.58(t,J=11.4Hz,1H,4-H),6.47(d,J=15.8Hz,1H,8’-H),6.28(s,1H,17-NH),5.90(d,J=9.8Hz,1H,5-H),5.86(t,J=10.5Hz,1H,9-H),5.69(s,1H,7’CO-NH),5.19(s,1H,7-H),4.81(br s,2H,7-CONH2),4.31(d,J=9.9Hz,1H,6-H),3.87(s,3H,12’-OMe),3.85(s,3H,11’-OMe),3.59–3.54(m,2H,11-H and12-H),3.48–3.43(m,2H,6’-H),3.43–3.38(m,2H,1’-H),3.36(s,3H,12-OMe),3.27(s,3H,6-OMe),2.76–2.71(m,1H,10-H),2.67(d,J=14.1Hz,1H,15-H),2.45–2.38(m,1H,15-H),2.02(s,3H,2-Me),1.80(s,3H,8-Me),1.79–1.77(m,2H,13-H),1.74–1.71(m,1H,14-H),1.71–1.67(m,2H,5’-H),1.64–1.58(m,2H,2’-H),1.49–1.40(m,4H,3’-H and4’-H),1.00(d,J=6.9Hz,3H,10-Me),0.96(d,J=6.8Hz,3H,14-Me);ESI-MS:m/z857.5[M+Na]+(calcd.858.0)。
将3a制备方法中的阿魏酸变为2,5-二甲氧基肉桂酸,同法可制得3q:
17-(6-(2,5-二甲氧基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3q),为紫色固体(11.4%);mp124-126℃;1H NMR(600MHz,CDCl3)δ9.18(s,1H,1-CONH),7.81(d,J=15.8Hz,1H,9’-H),7.27(s,1H,19-H),7.01(d,J=2.8Hz,1H,12’-H),6.95(d,J=11.4Hz,1H,3-H),6.87–6.82(m,2H,13’-H and15’-H),6.58(t,J=11.3Hz,1H,4-H),6.50(d,J=15.8Hz,1H,8’-H),6.28(br s,1H,17-NH),5.91(d,J=9.5Hz,1H,5-H),5.86(t,J=10.6Hz,1H,9-H),5.65(s,1H,7’CO-NH),5.19(s,1H,7-H),4.78(s,2H,7-CONH2),4.31(d,J=9.8Hz,1H,6-H),3.83(s,3H,14’-OMe),3.78(s,3H,11’-OMe),3.59–3.54(m,2H,11-H and12-H),3.48–3.43(m,2H,6’-H),3.42–3.37(m,2H,1’-H),3.36(s,3H,12-OMe),3.27(s,3H,6-OMe),2.76–2.72(m,1H,10-H),2.67(d,J=13.8Hz,1H,15-H),2.46–2.38(m,1H,15-H),2.03(s,3H,2-Me),1.80(d,J=0.9Hz,3H,8-Me),1.79–1.78(m,2H,13-H),1.74–1.71(m,1H,14-H),1.71–1.67(m,2H,5’-H),1.62–1.59(m,2H,2’-H),1.47–1.41(m,4H,3’-H and4’-H),1.00(d,J=6.9Hz,3H,10-Me),0.97(d,J=6.7Hz,3H,14-Me);ESI-MS:m/z857.5[M+Na]+(calcd.858.0)。
将3a制备方法中的阿魏酸变为3,5-二甲氧基肉桂酸,同法可制得3r:
17-(6-(3,5-二甲氧基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3r),为紫色固体(10.4%);mp132-135℃;1H NMR(600MHz,CDCl3)δ9.18(s,1H,1-CONH),7.54(d,J=15.5Hz,1H,9’-H),7.28(s,1H,19-H),6.95(d,J=11.5Hz,1H,3-H),6.64(d,J=2.1Hz,2H,11’-Hand15’-H),6.59(t,J=11.4Hz,1H,4-H),6.46(s,1H,13’-H),6.35(d,J=15.5Hz,1H,8’-H),6.29(s,1H,17-NH),5.91(d,J=9.3Hz,1H,5-H),5.86(t,J=10.6Hz,1H,9-H),5.66(s,1H,7’CO-NH),5.19(s,1H,7-H),4.81(br s,2H,7-CONH2),4.31(d,J=9.8Hz,1H,6-H),3.80(s,6H,12’-OMe and14’-OMe),3.59–3.53(m,2H,11-H and12-H),3.49–3.43(m,2H,6’-H),3.42–3.37(m,2H,1’-H),3.36(s,3H,12-OMe),3.27(s,3H,6-OMe),2.77–2.71(m,1H,10-H),2.67(d,J=13.6Hz,1H,15-H),2.45–2.39(m,1H,15-H),2.02(s,3H,2-Me),1.80(s,3H,8-Me),1.79–1.78(m,2H,13-H),1.72–1.67(m,3H,14-H and5’-H),1.62–1.58(m,2H,2’-H),1.46–1.40(m,4H,3’-H and4’-H),1.00(d,J=6.9Hz,3H,10-Me),0.96(d,J=6.6Hz,3H,14-Me);ESI-MS:m/z857.5[M+Na]+(calcd.858.0)。
将3a制备方法中的阿魏酸变为2,3,4-三甲氧基肉桂酸,同法可制得3s:
17-(6-(2,3,4-三甲氧基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3s),为紫色固体(6.5%);mp118-120℃;1H NMR(600MHz,CDCl3)δ9.19(s,1H,1-CONH),7.74(d,J=15.7Hz,1H,9’-H),7.27(s,1H,19-H),7.20(d,J=8.7Hz,1H,15’-H),6.95(d,J=11.4Hz,1H,3-H),6.67(d,J=8.7Hz,1H,14’-H),6.58(t,J=11.3Hz,1H,4-H),6.42(d,J=15.7Hz,1H,8’-H),6.29(s,1H,17-NH),5.90(d,J=9.5Hz,1H,5-H),5.86(t,J=10.6Hz,1H,9-H),5.64(s,1H,7’CO-NH),5.19(s,1H,7-H),4.81(br s,2H,7-CONH2),4.31(d,J=9.7Hz,1H,6-H),3.90(s,3H,12’-OMe),3.88(s,3H,13’-OMe),3.87(s,3H,11’-OMe),3.60–3.54(m,2H,11-H and12-H),3.48–3.43(m,2H,6’-H),3.42–3.37(m,2H,1’-H),3.36(s,3H,12-OMe),3.27(s,3H,6-OMe),2.77–2.71(m,1H,10-H),2.67(d,J=13.3Hz,1H,15-H),2.46–2.37(m,1H,15-H),2.02(s,3H,2-Me),1.81–1.77(m,5H,8-Me and13-H),1.76–1.71(m,1H,14-H),1.71–1.67(m,2H,5'-H),1.64–1.56(m,2H,2'-H),1.48–1.39(m,4H,3'-H and4'-H),1.00(d,J=6.9Hz,3H,10-Me),0.97(d,J=6.6Hz,3H,14-Me);ESI-MS:m/z887.5[M+Na]+(calcd.888.0)。
将3a制备方法中的阿魏酸变为4-三氟甲基肉桂酸,同法可制得3t:
17-(6-(4-三氟甲基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3t),为紫色固体(15.2%);mp128-131℃;1H NMR(600MHz,CDCl3)δ9.18(s,1H,1-CONH),7.65(d,J=15.8Hz,1H,9’-H),7.61(q,J=8.5Hz,4H,11’-H and12’-H and14’-H and15’-H),7.28(s,1H,19-H),6.95(d,J=11.1Hz,1H,3-H),6.58(t,J=11.4Hz,1H,4-H),6.47(d,J=15.6Hz,1H,8’-H),6.30(s,1H,17-NH),5.89(d,J=9.9Hz,1H,5-H),5.86(t,J=10.5Hz,1H,9-H),5.79(s,1H,7’CO-NH),5.19(s,1H,7-H),4.84(br s,2H,7-CONH2),4.31(d,J=9.8Hz,1H,6-H),3.60–3.53(m,2H,11-H and12-H),3.47–3.39(m,4H,6’-H and1’-H),3.35(s,3H,12-OMe),3.27(s,3H,6-OMe),2.76–2.70(m,1H,10-H),2.68(d,J=14.1Hz,1H,15-H),2.44–2.37(m,1H,15-H),2.02(s,3H,2-Me),1.80(s,3H,8-Me),1.79–1.77(m,2H,13-H),1.74–1.65(m,3H,14-H and5'-H),1.64–1.58(m,2H,2'-H),1.50–1.39(m,4H,3'-H and4'-H),1.00(d,J=6.9Hz,3H,10-Me),0.96(d,J=6.6Hz,3H,14-Me);ESI-MS:m/z865.7[M+Na]+(calcd.865.9)。
将3a制备方法中的阿魏酸变为4-三氟甲氧基肉桂酸,同法可制得3u:
17-(6-(4-三氟甲氧基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3u),为紫色固体(18.5%);mp128-130℃;1H NMR(600MHz,CDCl3)δ9.18(s,1H,1-CONH),7.61(d,J=15.5Hz,1H,9’-H),7.52(d,J=8.5Hz,2H,11’-H and15’-H),7.27(s,1H,19-H),7.21(d,J=8.3Hz,2H,12’-H and14’-H),6.95(d,J=11.8Hz,1H,3-H),6.58(t,J=11.4Hz,1H,4-H),6.36(d,J=15.5Hz,1H,8’-H),6.29(s,1H,17-NH),5.89(d,J=9.4Hz,1H,5-H),5.86(t,J=10.5Hz,1H,9-H),5.74(s,1H,7’CO-NH),5.19(s,1H,7-H),4.86(br s,2H,7-CONH2),4.31(d,J=9.9Hz,1H,6-H),3.60–3.51(m,2H,11-H and12-H),3.47–3.37(m,4H,6’-H and1’-H),3.35(s,3H,12-OMe),3.27(s,3H,6-OMe),2.77–2.70(m,1H,10-H),2.67(d,J=13.9Hz,1H,15-H),2.45–2.37(m,1H,15-H),2.02(s,3H,2-Me),1.79(s,3H,8-Me),1.79–1.76(m,2H,13-H),1.75–1.65(m,3H,14-H and5'-H),1.64–1.56(m,2H,2'-H),1.49–1.38(m,4H,3'-H and4'-H),1.00(d,J=6.9Hz,3H,10-Me),0.96(d,J=6.6Hz,3H,14-Me);ESI-MS:m/z881.6[M+Na]+(calcd.881.9)。
将3a制备方法中的阿魏酸变为4-二甲氨基肉桂酸,同法可制得3v:
17-(6-(4-二甲氨基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3v),为紫色固体(8.7%);mp126-127℃;1H NMR(600MHz,CDCl3)δ9.19(s,1H,1-CONH),7.56(d,J=15.4Hz,1H,9’-H),7.43(d,J=8.1Hz,2H,11’-H and15’-H),7.28(s,1H,19-H),6.96(d,J=12.2Hz,1H,3-H),6.83(s,2H,12’-H and14’-H),6.58(t,J=11.4Hz,1H,4-H),6.29(s,1H,17-NH),6.21(d,J=15.4Hz,1H,8’-H),5.91(d,J=9.7Hz,1H,5-H),5.86(t,J=10.6Hz,1H,9-H),5.56(s,1H,7’CO-NH),5.19(s,1H,7-H),4.31(d,J=9.9Hz,1H,6-H),3.59–3.53(m,2H,11-H and12-H),3.48–3.43
(m,2H,6’-H),3.41–3.37(m,2H,1’-H),3.36(s,3H,12-OMe),3.27(s,3H,6-OMe),3.02(s,6H,13’-N-Me and-N-Me),2.77–2.71(m,1H,10-H),2.67(d,J=13.5Hz,1H,15-H),2.44–2.39(m,1H,15-H),2.03(s,3H,2-Me),1.80(s,3H,8-Me),1.79–1.77(m,2H,13-H),1.75–1.71(m,1H,14-H),1.71–1.67(m,2H,5'-H),1.61–1.58(m,2H,2'-H),1.48–1.39(m,J=11.6Hz,4H,3'-Hand4'-H),1.00(d,J=6.9Hz,3H,10-Me),0.97(d,J=6.7Hz,3H,14-Me);ESI-MS:m/z840.8[M+Na]+(calcd.841.0).
实施例2:格尔德霉素衍生物体外抗肿瘤细胞活性筛选试验
测试方法:
用MTT法对所有化合物的抗肿瘤活性进行评价。取对数生长期的肿瘤细胞以一定密度接种于96孔细胞培养板中,细胞置37℃,5%CO2的培养箱中培养24h,加入不同浓度的化合物,继续培养72h后,每孔加10μL浓度为5mg/mL MTT溶液,37℃孵育4小时,弃去培养基,然后每孔加100μL DMSO溶解,用酶标仪测定OD值(测定波长570nm)。
肿瘤细胞增殖的抑制率按以下公式计算:
抑制率=(阴性对照组OD值–实验组OD值)/(阴性对照组OD值–空白组OD值)×100%
IC50表示样品对肿瘤细胞的抑制率为50%时的浓度。
测试材料:
人乳腺癌细胞MDA-MB-231、人肺癌细胞A549、人宫颈癌细胞HeLa、人前列腺癌PC3、人胃癌细胞BGC-823、和人结肠癌细胞SW480、人表皮癌A431、人肝癌细胞HepG2、人正常肝细胞HL7702和人正常脐静脉上皮细胞HUVEC细胞;购于ATCC。
测试结果:见表1。
表1GA衍生物3a-3v,17-AAG和GA(10μM)对人乳腺癌细胞MDA-MB-231的抑制率
表2部分GA衍生物对人乳腺癌细胞MDA-MB-231的活性
由表1可以看出,化合物3a~3v在10μM时对乳腺癌细胞MDA-MB-231呈现较强的抑制活性。
进一步的,我们选取代表性的化合物3a~3f测定其对乳腺癌细胞MDA-MB-231的IC50值(表2)。结果表明,化合物3a和3f对MDA-MB-231的活性最强(分别为0.27μM和0.19μM),优于阳性药17-AAG。
再进一步的,选取活性较好的化合物3f作为研究对象,筛选其对于其他7株癌细胞株和2株正常细胞的体外抑制活性。
结果表明,化合物3f除了对MDA-MB-231表现出较强抑制作用外,对于其他癌细胞A549、PC-3、HeLa、A431、BGC-823、SW480和HepG2均表现出卓越的抑制活性(表3)。其次,化合物3f对人正常脐静脉上皮细胞HUVEC和人正常肝细胞毒性HL7702毒性较小。综上所述,化合物3f对多种组织类型包括乳腺,生殖和呼吸系统来源的肿瘤细胞具有显著的抑制作用,具有较好的成药性。
表3化合物3f对8株癌细胞和2株正常细胞的活性
实施例3:预防和治疗乳腺癌的注射剂
注射剂配方见表4。
表4治疗乳腺癌注射剂配方
制备方法:
按配方量将卵磷脂用注射用水稀释使成混悬状态,再加入3f的二甲基亚砜溶液,迅速握旋使药物均用分散,活性成分含量为2mg/mL。
Claims (10)
2.如权利要求1所述的17-(6-(取代肉桂酰氨基)己二胺)-17-去甲氧基格尔德霉素衍生物,其特征在于:
R为2-氯、3-氯、4-氯、2-溴、3-溴、4-溴、2-碘、3-碘、4-碘、2-氨基、3-氨基、4-氨基、2-氰基、3-氰基、4-氰基、2-甲基、3-甲基、4-甲基、3,4-二甲基、2-乙基、3-乙基、4-乙基、2-硝基、3-硝基、4-硝基、2-羟基、3-羟基、4-羟基、3,4-二羟基、2,3,4-三羟基、3,4,5-三羟基、2-甲氧基、3-甲氧基、4-甲氧基、2-乙氧基、3-乙氧基、4-乙氧基、4-羟基-3-甲氧基、3-羟基-4-甲氧基、2,3-二甲氧基、2,5-二甲氧基、3,4-二甲氧基、3,5-二甲氧基、2,3,4-三甲氧基、3,4,5-三甲氧基、3,4,5-三乙氧基、4-三氟甲基、4-三氟甲氧基或4-二甲氨基。
3.如权利要求2所述的17-(6-(取代肉桂酰氨基)己二胺)-17-去甲氧基格尔德霉素衍生物,其特征在于:
R为3-氯、2-甲基、3-甲基、4-甲基、2-硝基、3-硝基、3-羟基、4-羟基、3,4-二羟基、2-甲氧基、4-甲氧基、4-羟基-3-甲氧基、3-羟基-4-甲氧基、2,3-二甲氧基、2,5-二甲氧基、3,4-二甲氧基、3,5-二甲氧基、2,3,4-三甲氧基、3,4,5-三甲氧基、4-三氟甲基、4-三氟甲氧基或4-二甲氨基。
4.如权利要求3所述的17-(6-(取代肉桂酰氨基)己二胺)-17-去甲氧基格尔德霉素衍生物,其特征在于:
R为2-甲氧基、4-甲氧基、4-羟基-3-甲氧基、3-羟基-4-甲氧基、3-羟基、4-羟基、3,4-二羟基、2,3-二甲氧基、2,5-二甲氧基、3,4-二甲氧基、2,3,4-三甲氧基或3,4,5-三甲氧基。
5.如权利要求4所述的17-(6-(取代肉桂酰氨基)己二胺)-17-去甲氧基格尔德霉素衍生物,其特征在于:
所述格尔德霉素衍生物是:17-(6-(4-羟基-3-甲氧基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3a)、17-(6-(4-羟基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3b)、17-(6-(3-羟基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3c)、17-(6-(3,4-二羟基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3d)、17-(6-(3,4-二甲氧基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3e)、或17-(6-(3,4,5-三甲氧基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3f)。
6.如权利要求5所述的17-(6-(取代肉桂酰氨基)己二胺)-17-去甲氧基格尔德霉素衍生物,其特征在于:
所述的格尔德霉素衍生物是:17-(6-(4-羟基-3-甲氧基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3a)、17-(6-(3,4-二甲氧基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3e)、或17-(6-(3,4,5-三甲氧基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3f)。
7.权利要求1所述17-(6-(取代肉桂酰氨基)己二胺)-17-去甲氧基格尔德霉素衍生物在制备抗肿瘤药物中的应用。
8.如权利要求7所述的应用,其特征在于:所述17-(6-(取代肉桂酰氨基)己二胺)-17-去甲氧基格尔德霉素衍生物是:17-(6-(4-羟基-3-甲氧基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3a)或17-(6-(3,4,5-三甲氧基肉桂酰胺基)己二胺)-17-去甲氧基格尔德霉素(3f);所述抗肿瘤药物是抗人乳腺癌细胞MDA-MB-231、人肺癌细胞A549、人宫颈癌细胞HeLa、人前列腺癌PC3、人胃癌细胞BGC-823、人结肠癌细胞SW480、人表皮癌A431或/和人肝癌细胞HepG2的药物。
9.一种抗肿瘤药物组合物,其特征在于:所述药物组合物含有权利要求1所述的17-(6-(取代肉桂酰氨基)己二胺)-17-去甲氧基格尔德霉素衍生物和药学上可接受的载体。
10.一种用于预防和治疗乳腺癌的制剂,其特征在于:所述制剂含有治疗有效量的权利要求6所述的17-(6-(取代肉桂酰氨基)己二胺)-17-去甲氧基格尔德霉素衍生物和药学上可接受的载体。
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WO2008038964A1 (en) * | 2006-09-29 | 2008-04-03 | Korea Research Institute Of Bioscience And Biotechnology | Geldanamycin derivatives, pharmaceutically acceptable salt thereof, preparation method thereof and agent for the prevention and treatment of tumor containing the same as an active ingredient |
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WO2008038964A1 (en) * | 2006-09-29 | 2008-04-03 | Korea Research Institute Of Bioscience And Biotechnology | Geldanamycin derivatives, pharmaceutically acceptable salt thereof, preparation method thereof and agent for the prevention and treatment of tumor containing the same as an active ingredient |
CN101220068A (zh) * | 2008-01-18 | 2008-07-16 | 中国医学科学院医药生物技术研究所 | 一组格尔德霉素衍生物及其制备方法 |
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