CN102898489B - 具有抗癌活性的蝴蝶霉素类似物及合成方法 - Google Patents
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Abstract
在具有抗癌活性的蝴蝶霉素类似物及合成方法中,在N-6上位引入各种取代基合成蝴蝶霉素类似物,为获得具有更好生物活性和良好水溶性的蝴蝶霉素类似物提供了方法。
Description
技术领域
本发明涉及一类具有抗癌活性的化合物,特别是一种具有抗癌活性的N-6取代蝴蝶霉素类似物新化合物及制备方法。
背景技术
1985年,Doyle等发现蝴蝶霉素(Rebeccamycin)。它是从放线菌Saccharothrix Aerocoligenes的培养液中分离得到的一种微生物代谢物,其结构由吲哚[2,3-a]吡咯[3,4-c]咔唑核(简称为吲哚咔唑核)和β-葡萄糖两大部分构成,如下所示。
研究表明,蝴蝶霉素是一种新型的天然抗生素,是继喜树碱之后发现的对拓扑异构酶I(Topoisomerase I)具有一定的抑制作用、可以诱导真核状态的DNA的断裂从而产生较强抗肿瘤活性的物质。DNA结合实验显示,蝴蝶霉素与DNA作用时,吲哚并咔唑核嵌入DNA中,糖基部分能与凹槽作用增强DNA亲和力,而吡咯杂环部分能特异性识别DNA大小凹槽的碱基系列。
然而,由于蝴蝶霉素的水溶性较差导致无法对其做出进一步的药理评价。为了寻找生物活性更好的药物先导化合物,同时探究蝴蝶霉素类似物的构效关系(Structure ActivityRelationship),人们主要从三个方面对蝴蝶霉素的结构进行修饰和改造合成各种类似物,一是用其它基团特别是亲水性基团取代顶部酰胺基的氢原子;二是在吲哚并咔唑环的苯环上引入其它基团如卤素原子或羟基,或者将苯环改变为其它杂环,如吡啶环;三是用其它糖取代蝴蝶霉素的糖基部分。如下所示:
到目前为止,人们通过生物方法和化学方法,经全合成和半合成得到了大概300多种类似物,其中绝大部分是经过前两种修饰方法得到的,而且主要是为了改善蝴蝶霉素类似物水溶性,其中有一些类似物已用于临床研究。
目前,对于在蝴蝶霉素N-6位引入碱基、氨基酸和糖基等基团的蝴蝶霉素类似物尚未报道,鉴于碱基、氨基酸和糖等自身良好的水溶性和药物活性,我们在蝴蝶霉素N-6位氮原子引入碱基、氨基酸和糖基等,获得了具有更好生物活性和良好水溶性的蝴蝶霉素类似物。
发明内容
多年来,经过药物化学家对蝴蝶霉素的构效关系研究表明,吲哚咔唑核和糖基是蝴蝶霉素及其类似物活性表达所必需的结构部分,且糖苷键保持β构型时,药物具有更好的生物活性。同时发现,蝴蝶霉素结构中的两个氯原子对生物活性有负面作用,对N-6位的修饰以及糖上的4′-O-甲基对类似物的生物活性影响不大。目前,虽然有大量的蝴蝶霉素类似物被合成出来,但因这些类似物缺少理想的水溶性,最终都未能应用于临床治疗。
由于碱基、糖和氨基酸等在生物体内有着重要的生理功能,因而将不同种类的碱基、糖基和氨基酸等引入到蝴蝶霉素的N-6位,以期改善蝴蝶霉素类似物的水溶性,更重要的是希望增强其靶向特异性,从而改善其抗肿瘤的生物活性,通过药物活性筛选,寻找活性更好的药物先导化合物并完善其构效关系。本发明的技术解决方案是,具有抗癌活性的新型水溶性蝴蝶霉素类似物及合成方法,其特征在于化合物具有以下的结构:
其中:
取代基R3,R4为H,卤素,羟基等;
其中糖基选自以下化合物:
具有抗癌活性的新型水溶性蝴蝶霉素类似物的制备方法,其特征在于:
附图说明
图1为部分化合物分别在40μM和4μM浓度下,在白血病细胞(K562细胞)中的活性数据图。
图2为部分化合物分别在40μM和4μM浓度下,在乳腺癌细胞(MCF-7细胞)中的活性数据图。
具体实施方法
1.N-糖基蝴蝶霉素类似物I系列化合物的合成
我们选择以下六种糖基中间体为例,来说明N-糖基蝴蝶霉素类似物I系列化合物的合成。
我们从各种糖和氨基乙醇出发,按照以下合成路线,合成了六种糖基中间体,选择以下糖基中间体为例,来说明蝴蝶霉素类似物的合成:
1)N-Phth氨基乙醇的合成
向10mL圆底烧瓶中加入邻苯二甲酸酐(1mo1),然后在搅拌下将氨基乙醇(1eq)逐滴滴加入烧瓶中,反应放热。滴加完毕后,用油浴将温度升至100℃,反应约1h后结束。将溶液温度降至室温,溶液变成固体。向烧瓶中加入蒸馏水,缓慢升温,使固体溶解至完全,然后降温,结晶得到白色的固体N-Phth氨基乙醇,收率为80%。
2)糖基供体的合成
在圆底烧瓶中加入葡萄糖(1mmo1),乙酸酐(1mL)和水合硫酸铁(2mo1%),室温下搅拌,用TLC检测反应是否结束。反应完全后,经分离可以得到化合物1,用同样的方法可以得到化合物2和3,产率均为98%左右。
在圆底烧瓶中将2-氨基葡萄糖200mg溶解于3ml水中,加入192mg碳酸钾和1.4mg五水硫酸铜,搅拌溶解后加入6ml甲醇和TfN3的二氯甲烷溶液,然后再加入6ml甲醇,室温搅拌18h。反应结束后,旋干溶剂,加入吡啶和乙酸酐,在室温下搅拌过夜。反应结束后,柱层析分离,将得到的产品溶于DMF中,冰浴20分钟后加入醋酸肼搅拌反应,反应结束后,经洗涤,干燥,柱层析分离可以得到化合物4,收率为70%;用同样的方法得到化合物6,收率为99%。
在圆底烧瓶中加入4g鼠李烯糖溶解于30m1水中,升高反应温度至80℃,搅拌2h后,冷却至室温,加入4m1乙酸和2g叠氮化钠,室温下搅拌3h后,经萃取,干燥得到粗产品。将粗产品溶解于60m1二氯甲烷,并加入2.6g咪唑,在0℃缓慢向溶液中滴加溶有3.6g叔丁基二甲基氯硅烷(tert-Butyldimethylchlorosilane,TBDMS-C1)的二氯甲烷溶液,在零度条件下反应24h,经柱层析分离得到化合物5,收率为50%。
3)糖基中间体的合成
在氮气保护下,向烧瓶中加入1(5.12mmo1)和N-Phth氨基乙醇(6.17mmo1),加入20mL二氯甲烷,冰浴条件下搅拌10分钟,然后逐滴加入3.632mL BF3·Et2O溶液,继续冰浴反应1h。然后室温下反应过夜,经洗涤、干燥后,柱层析分离得到化合物7,收率为50%;同样的方法可以得到化合物8和9,收率分别为49%和64%。
在氮气保护和-20℃条件下,将30mg氢化钠溶于5ml四氢呋喃中,然后将溶有0.2g化合物4的四氢呋喃溶液逐滴加到氢化钠的四氢呋喃溶液中,滴加完毕后,搅拌1h。随着反应的进行,溶液颜色逐渐加深,温度缓慢升到0℃。最后将准备好的溶有0.16gN-Phth氨基乙醇三氟甲磺酸酯的四氢呋喃溶液再逐滴加入到前述反应液中。冰浴条件下反应过夜。反应结束后,减压蒸去四氢呋喃,然后加入二氯甲烷溶解,经洗涤,干燥,柱层析分离得化合物10,收率为30%;同样的方法可以得到化合物12,收率为65%。
将化合物5(0.36mmo1),氨基乙醇(0.69mmo1)和400mg粉状分子筛加入10ml干燥的二氯甲烷中,室温搅拌1h,然后将反应体系的温度降至-35℃,缓慢滴入0.55mmol三氟甲磺酸三甲基硅酯(TMSOTf),在-35℃条件下反应2h。最后使用三乙胺猝灭反应。然后经过滤,洗涤,柱层析纯化可以得到化合物11,收率为88%。
4)N-糖基蝴蝶霉素类似物I系列化合物的合成
采用吲哚啉糖苷化法,糖直接与底物经过三步反应即可得到化合物JDC-108。然后将化合物JDC-108在水中加入氢氧化钠回流,反应结束后,向溶液中滴加2mo1·L-1的稀盐酸,然后经过萃取和洗涤,经柱层析分离即可得到化合物13,收率为87%。
在烧瓶中分别加入化合物7-12(1mmo1)和甲胺的乙醇溶液(30mL),先室温下搅拌6h,再回流搅拌6h。TLC检测反应结束,减压蒸去溶剂,然后加入DMF溶液5mL,加入化合物13(1mmo1)加热到80℃反应4h,反应结束后,减压除去溶剂,得到粗产品。然后在吡啶催化下,与乙酸酐直接反应,TLC检测乙酰化完全后,减压出去吡啶和乙酸酐,柱层析分离得到乙酰化固体化合物,最后在室温下用甲醇钠进行脱保护即可得到化合物I-1,I-2,I-3,I-4,I-5,I-6,收率分别为85%左右。其中化合物I-4,I-5,I-6经过三苯基磷的还原及用0.01M HC1成盐,即可得到化合物I-7,I-8,I-9,收率分别为98%,97%,97%。
2N-氨基酸蝴蝶霉素类似物II系列化合物的合成
将底物1mmol化合物13和氨基酸(2eq)溶于5ml DMF中,加热到150℃反应1h,停止反应。反应结束后,减压除去DMF,经柱层析分离得到目标产物II-1,II-2,II-3,II-4,II-5,II-6,II-7,收率分别为90%,74%,79%,51%,38%,59%,72%。
3.N-碱基蝴蝶霉素类似物III系列化合物的合成
我们以在N-6位上引入腺嘌呤为例,来说明引入碱基的蝴蝶霉素类似物的合成。
在圆底烧瓶中加入2-氯乙胺盐酸盐1mol和邻苯二甲酸酐1mol以及冰乙酸,加热回流。反应结束后,经萃取洗涤,可得到化合物N-Phth-2-氯乙胺。然后在氢化钠的作用下与腺嘌呤反应,经甲胺醇溶液脱保护后可得到化合物14。
在50m1圆底烧瓶中加入化合物13和系列含氨基的碱基,以N,N-二甲基甲酰胺为溶剂,在100℃条件下反应,TLC检测反应,得到粗产品,柱层析分离得到系列化合物III,收率分别为92%,84%,83%,61%。
4.N-烷基及其它取代基蝴蝶霉素类似物IV系列化合物的合成
此类化合物的合成与N-氨基酸蝴蝶霉素类似物的合成方法类似,将底物1mmol化合物13和含氨基化合物(2eq)如氨基脲、苯肼等,溶于5ml DMF中,加热到100℃反应。反应结束后,减压除去DMF,经柱层析分离得到目标化合物IV系列,产率在69%~90%之间。
5.部分化合物初步测定的活性数据分析
在白血病细胞株K562和乳腺癌细胞MCF-7中用MTS测试方法测定了所合成的蒽环类抗生素简单结构类似物IV,V和VI系列的抗癌活性。白血病细胞株K562和乳腺癌细胞MCF-7(2000-10000)被接种至有RPMI-1640培养液的96孔板上培养24h。这些以指数形式增长的癌细胞,在37℃下(5%CO2,95%湿润空气)和不同浓度的化合物作用72h。72h之后,将四氮唑的盐[3-(4,5-dimethythiazol-2-y1)]-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium(MTS,最终浓度2mg/mL)和吩嗪甲基硫酸盐(DMS,最终浓度25μM)的混合物直接加入到含细胞的培养基中。在37℃下作用3h后,存活细胞率通过其对MTS作用的代谢物在490nm波长下的吸光率来测定。我们选择在40μM和4μM浓度条件下对此系列化合物进行了活性测试。
初步的生物活性测试表明,化合物I,II,III和IV系列在乳腺癌细胞(MCF-7细胞)和白血病细胞(K562细胞)中,对癌细胞具有较好的抑制作用。在40μM浓度条件下,化合物I-6,III-4,IV-4和IV-7在白血病细胞中有较好的生物活性,尤其是化合物I-6可以全部杀死白血病细胞(图1),而且乳腺癌细胞在化合物I-6的作用下,仅有10%左右的存活率(图2)。
化合物I-1 1H NMR(400MHz,DMSO-d6)δ2.96(t,1H,J=8.0Hz,),3.03(t,1H,J=8.4Hz),3.09-3.15(m,2H),3.52(d,1H,J=9.6Hz),3.57-3.65(m,2H),3.76-3.84(m,2H),3.91-3.96(m,3H),3.98-4.05(m,2H),4.11(d,1H,J=10.8Hz),4.23(d,1H,J=8.0Hz,),4.52(s,1H),5.05(d,3H,J=22.4Hz),5.45(s,1H),6.04(s,1H),6.27(d,1H,J=9.2Hz),6.60(s,1H),7.36(dd,2H,J=6.8Hz,J=12.8Hz,Ar-H),7.57(dd,2H,J=8.4Hz,J=17.2Hz,Ar-H),7.73(d,1H,J=8.0Hz),7.97(d,1H,J=8.8Hz,Ar-H),8.47(s,1H),9.08(d,1H,J=8.0Hz,Ar-H),9.16(d,1H,J=8.4Hz,Ar-H),11.73(s,1H,Nindole-H)ppm 13C NMR(100MHz,DMSO-d6)δ169.9,169.9,142.7,141.3,130.1,128.7,127.5,127.3,124.7,121.7,121.4,121.1,120.1,120.3,119.0,118.7,117.5,112.8,112.3,103.5,84.9,79.6,79.4,77.4,77.1,76.8,73.8,73.6,70.4,67.8,66.1,61.4,58.6,37.7 ppm.
化合物I-21H NMR(400MHz,DMSO-d6)δ3.31-3.52(3H,m),3.49-3.66(4H,m),3.76-3.84(2H,m),3.75-3.81(2H,m),3.81-4.06(5H,m),4.12(1H,d,J=8.8Hz,),4.53(1H,s),4.64(1H,s),4.73-4.74(2H,m),4.81(2H,m),5.07(1H,s),5.39(1H,s),5.80(1H,s),6.30(1H,d,J=8.8Hz,H-1′),6.38(1H,s),7.35-7.41(2H,m,Ar-H),7.58(2H,dd,J=8.4Hz,J=15.6Hz,Ar-H),7.74(1H,d,J=8.0Hz,Ar-H),7.99(1H,d,J=8.8Hz,Ar-H),8.46(1H,s),9.10(1H,d,J=8.0Hz,Ar-H),9.18(1H,d,J=8.0Hz,Ar-H),11.72(1H,s,Nindole-H)ppm.13C NMR(100MHz,DMSO-d6)δ169.9,169.8,142.7,141.3,130.1,128.7,127.5,127.3,124.8,121.7,121.4,121.1,120.2,118.9,118.6,117.5,112.8,112.3,99.9,84.9,79.3,76.8,74.5,73.6,72.4,71.2,70.6,70.4,67.8,67.1,63.7,61.4,60.6,58.6,37.4 ppm.
化合物I-3 1H NMR(400MHz,DMSO-d6)δ3.26-3.63(6H,m),3.78-3.89(3H,m)3.94-4.04(5H,m),4.18(1H,d,J=10.8Hz),4.18(1H,d,J=6.8Hz,H-1″),5.04(1H,brs),5.36(1H,brs),5.80(1H,brs),6.28(1H,d,J=8.8Hz,H-1′),6.40(1H,s),7.35-7.41(2H,m,Ar-H),7.58(2H,dd,J=8.4Hz,J=17.2Hz,Ar-H),7.74(1H,d,J=8.0Hz,Ar-H),7.99(1H,d,J=8.4Hz,Ar-H),8.46(1H,s),9.10(1H,d,J=8.0Hz,Ar-H),9.18(1H,d,J=8.0Hz,Ar-H),11.72(1H,s,Nindole-H)ppm.13CNMR(100MHz,DMSO-d6)δ169.9,169.8,142.7,141.3,130.1,128.7,127.5,127.3,124.8,121.7,121.4,121.1,120.8,120.3,118.9,118.6,117.5,112.7,112.3,104.1,84.9,79.3,76.8,75.7,73.8,73.6,72.4,70.9,70.4,68.4,67.9,66.0,61.4,60.6,58.6,37.8ppm.
化合物I-4 1H NMR(400MHz,DMSO-d6)δ3.02-3.16(5H,m),3.26-3.66(9H,m),3.78(1H,d,J=9.6Hz),3.86-4.05(5H,m),4.08-4.12(2H,m),4.37(1H,d,J=8.0Hz),6.27(1H,d,J=8.8Hz,H-1′),7.32-7.38(2H,m,Ar-H),7.53-7.59(2H,m,Ar-H),7.71(1H,d,J=8.0Hz,Ar-H),7.96(1H,d,J=8.4Hz,Ar-H),8.44(1H,s),9.09(1H,d,J=8.0Hz,Ar-H),9.17(1H,d,J=8.0Hz,Ar-H),11.62(1H,s,Nindole-H)ppm.13C NMR(100MHz,DMSO-d6)δ168.9,168.8,141.7,140.4,129.2,126.6,126.4,123.9,120.9,120.6,120.1,119.9,119.5,118.1,117.8,116.7,111.7,100.2,83.9,78.4,76.5,76.0,74.1,72.7,69.5,67.0,66.1,65.2,62.6,60.2,57.8,36.7ppm.
化合物I-5 1H NMR(400MHz,DMSO-d6)δ3.15(1H,d,J=3.6Hz),3.29-3.37(2H,m),3.42-3.46(2H,m),3.53-3.59(3H,m),3.78-3.82(1H,m),3.89-4.01(5H,m),4.08(2H,d,J=9.2Hz),4.29(1H,d,J=7.6Hz),4.65(1H,s),4.69(1H,d,J=4.8Hz),4.95(1H,d,J=5.2Hz),5.21(2H,s),5.49(1H,d,J=4.0Hz),6.09(1H,s),6.28(1H,d,J=8.8Hz,H-1′),7.33-7.38(2H,m,Ar-H),7.53-7.60(2H,m,Ar-H),7.71(1H,d,J=8.4Hz,Ar-H),7.96(1H,d,J=8.4Hz,Ar-H),9.09(1H,d,J=8.0IIz,Ar-H),9.17(1H,d,J=8.0Hz,Ar-H),11.65(1H,s,Nindole-H)ppm.13C NMR(100MHz,DMSO-d6)δ169.8,169.7,142.6,141.3,130.1,128.6,127.5,127.3,124.8,121.8,121.4,121.1,120.8,120.4,118.9,118.7,117.5,112.6,112.3,101.6,84.8,79.1,76.9,75.6,73.8,71.8,67.9,67.8,66.0,64.6,62.6,60.4,36.7 ppm.
化合物I-6 1H NMR(400MHz,DMSO-d6)δ1.06(1H,d,J=6.0Hz),1.49(1H,ddd,J=3.2Hz,J=12.8Hz,J=25.6Hz),1.89(1H,dd,J=4.4Hz,J=12.4Hz),2.91(1H,q,J=6.8Hz),3.51-3.58(4II,m),3.73-3.75(1H,m),3.82-3.91(3H,m),3.95-4.02(3H,m),4.08(1H,dd,J=3.2Hz,J=11.2Hz),4.88(1H,d,J=5.6Hz),5.10(1H,d,J=4.8Hz),5.36(1H,d,J=4.8Hz),5.44(1H,d,J=6.4Hz),5.99(1H,s),6.28(1H,d,J=8.4Hz,H-1′),7.34-7.39(2H,m,Ar-H),7.54-7.60(2H,m,Ar-H),7.71(1H,d,J=8.4Hz,Ar-H),7.96(1H,d,J=8.4Hz,Ar-H),9.10(1H,d,J=8.0Hz,Ar-H),9.17(1H,d,J=8.0Hz,Ar-H),11.67(1H,s,Nindole-H)ppm.13C NMR(100MHz,DMSO-d6)δ168.9,141.7,140.4,131.2,129.2,127.8,126.6,126.4,123.9,120.9,120.6,120.2,119.9,119.4,118.1,117.7,116.6,111.7,94.8,84.0,78.2,76.2,74.8,72.6,71.8,67.7,67.1,62.9,59.4,57.8,55.4,36.6,34.5,30.2,29.1,17.2ppm.
化合物I-71H NMR(400MHz,CD3OD)δ2.77(1H,dd,J=8.8Hz,J=10.4Hz),3.24-3.29(2H,m),3.49-3.65(3H,m),3.74-3.89(5H,m),3.91-4.09(3H,m),4.26-4.31(2H,m),4.64(1H,d,J=8.4Hz),6.20(1H,d,J=8.8Hz,H-1′),7.19-7.29(2H,m,Ar-H),7.42-7.53(2H,m,Ar-H),7.62(1H,d,J=8.0Hz,Ar-H),7.77(1H,d,J=8.4Hz,Ar-H),8.84(1H,d,J=8.0Hz,Ar-H),9.02(1H,d,J=8.0Hz,Ar-H),11.39(1H,s,Nindole-H)ppm.13C NMR(100MHz,CD3OD)δ170.1,170.0,142.4,141.3,130.0,128.4,126.8,124.6,124.4,121.6,121.5,120.5,120.0,119.8,119.2,118.0,117.7,111.5,110.6,100.2,98.6,85.1,79.2,77.0,76.9,73.5,72.4,70.2,67.9,67.2,60.7,58.7,56.1,37.0ppm.
化合物I-8 1H NMR(400MHz,CD3OD)δ3.02-3.07(1H,m),3.49-3.65(4H,m),3.68-3.74(3H,m),3.78-3.92(5H,m),4.03-4.09(3H,m),4.26-4.31(2H,m),4.59(1H,d,J=8.4Hz),6.20(1H,d,J=8.8Hz,H-1′),7.20-7.28(2H,m,Ar-H),7.44-7.53(2H,m,Ar-H),7.63(1H,d,J=8.0Hz,Ar-H),7.78(1H,d,J=8.4Hz,Ar-H),8.85(1H,d,J=8.0Hz,Ar-H),9.02(1H,d,J=8.0Hz,Ar-H),11.39(1H,s,Nindolc-H)ppm.13C NMR(100MHz,CD3OD)δ170.1,170.0,142.4,141.3,130.0,128.4,126.8,124.6,124.4,121.7,121.6,120.5,120.0,119.9,119.3,118.0,117.8,111.5,110.6,100.2,99.0,85.1,79.2,77.0,75.6,73.5,69.7,68.0,67.6,67.4,67.1,60.5,58.7,53.5,37.0,25.0ppm.
化合物I-9 1H NMR(400MHz,CD3OD)δ1.10(1H,d,J=6.0Hz),1.70(1H,ddd,J=3.2Hz,J=12.8Hz,J=25.6Hz),2.02(1H,dd,J=4.4Hz,J=12.4Hz),3.00(1H,t,J=9.6Hz),3.15-3.22(2H,m),3.48-3.55(2H,m),3.62-3.65(1H,m),3.74-3.84(3H,m),3.94(1H,t,J=9.2Hz),4.02-4.07(2H,m),4.26-4.31(2H,m),4.88(1H,d,J=2.4Hz),6.20(1H,d,J=8.8Hz,H-1′),7.23-7.27(2H,m,Ar-H),7.42-7.51(2H,m,Ar-H),7.58(1H,d,J=8.0Hz,Ar-H),7.76(1H,d,J=8.4Hz,Ar-H),8.87(1H,d,J=8.0Hz,Ar-H),9.04(1H,d,J=8.0Hz,Ar-H),11.36(1H,s,Nindole-H)ppm.13C NMR(100MHz,CD3OD)δ168.9,141.4,140.4,129.1,127.5,125.8,123.8,123.5,120.8,120.7,119.5,119.1118.9,118.2,117.1,116.9,110.6,109.7,94.1,84.2,78.3,76.1,72.6,71.8,67.4,67.1,62.8,57.8,48.9,35.7,32.6,15.4 ppm.
化合物II-1 1H NMR(400MHz,DMSO-d6)δ11.74(s,1H,Nindole-H),9.18(d,J=8.0Hz,1H,Ar-H),9.09(d,J=8.0Hz,1H,Ar-H),8.47(br.s,1H),7.97(d,J=6.4Hz,1H,Ar-H),7.76(d,J=8.4Hz,1H,Ar-H),7.57(t,J=7.6Hz,1H,Ar-H),7.51(t,J=7.6Hz,1H,Ar-H),7.29-7.39(m,2H,Ar-H),6.87(br.s,1H),6.27(d,J=8.8Hz,1H,H-1′),5.67(br.s,1H),5.22(br.s,1H),4.13-4.16(m,1H,H-6′a),4.01-4.06(m,3H,NCH2COOH,H-4′),3.89-3.92(m,1H,H-5′),3.75-3.78(m,1H,H-6′b),3.59-3.63(m,1H,H-3′),3.51-3.55(m,1H,H-2′)ppm.13C NMR(100MHz,DMSO-d6)δ170.3,170.2,160.9,142.6,141.3,129.9,128.6,127.3,127.1,124.8,124.7,121.8,121.5,121.0,120.9,120.7,119.4,118.8,117.4,112.7,112.3,84.9,79.6,76.7,73.5,67.7,58.6,49.0 ppm.
化合物II-2 1H NMR(400MHz,DMSO-d6)δ11.72(s,1H,Nindole-H),9.20(d,J=8.0Hz,1H,Ar-H),9.11(d,J=8.0Hz,1H,Ar-H),8.48(br.s,1H),7.97(d,J=8.8Hz,1H,Ar-H),7.77(d,J=8.4Hz,1H,Ar-H),7.57(t,J=7.6Hz,1H,Ar-H),7.51(t,J=7.6Hz,1H,Ar-H),7.30-7.38(m,2H,Ar-H),6.86(br.s,2H),6.27(d,J=8.8Hz,1H,H-1′),5.20(br.s,1H),4.64(q,J1=7.2Hz,J2=14.8Hz,1H,NCHCOOH),4.14-4.17(m,1H,H-6′a),4.02-4.07(m,1H,H-4′),3.90-3.92(m,1H,H-5′),3.75-3.78(m,1H,H-6′b),3.60-3.65(m,1H,H-3′),3.51-3.56(m,1H,H-2′)ppm.13CNMR(100MHz,DMSO-d6)δ170.4,160.5,142.6,141.3,129.9,128.6,127.3,127.1,124.9,124.8,121.8,121.5,121.0,120.9,120.6,119.3,118.7,117.3,112.7,112.2,84.9,79.6,76.7,73.5,67.7,58.6,50.4,16.8ppm.
化合物II-3 1H NMR(400MHz,CD3OD)δ9.21(d,J=8.0Hz,1H,Ar-H),9.08(d,J=8.0Hz,1H,Ar-H),7.79(d,J=8.4Hz,1H,Ar-H),7.77(d,J=8.4Hz,1H,Ar-H),7.54(t,J=7.6Hz,1H,Ar-H),7.46(t,J=7.6Hz,1H,Ar-H),7.25-7.34(m,4H,Ar-H),7.10(t,J=7.6Hz,2H,Ar-H),6.99(t,J=7.6Hz,1H,Ar-H),6.17(d,J=8.8Hz,1H,H-1′),5.11-5.13(m,1H,NCHCOOH),4.21-4.27(m,2H,H-3′,H-5′),3.96-4.02(m,1H,H-6′),3.59-3.83(m,4H,H-2′,H-3′,PhCH2)ppm.13C NMR(100MHz,CD3OD)δ170.1,169.9,142.3,139.3,129.9,128.6,128.3,127.8,126.5,125.7,124.9,124.7,122.0,121.9,120.5,120.3,119.8,119.1,118.6,117.8,111.4,110.4,85.0,79.1,77.0,73.2,67.8,58.6,55.8,35.4ppm.
化合物II-4 1H NMR(400 MHz,DMSO-d6)δ12.15(s,1H,NH),11.70(s,1H,Nindole-H),11.70(s,1H),9.17(d,J=8.0Hz,1H,Ar-H),9.07(d,J=8.0Hz,1H,Ar-H),7.95(d,J=8.4Hz,1H,Ar-H),7.71(d,J=8.4Hz,1H,Ar-H),7.56(t,J=7.6Hz,1H,Ar-H),7.49(t,J=7.6Hz,1H,Ar-H),7.27-7.39(m.3H,Ar-H),6.71(br.s,1H),6.52(br.s,1H),6.24(d,J=8.4Hz,1H,H-1′),5.95(br.s,1H),5.38(br.s,1H),4.99(br.s,1H),4.52(m,1H,NCHCOOH),4.09-4.12(m,1H,H-6′a),3.99-4.04(m,3H,H-4′).3.90-3.93(m,1H,H-5′),3.78-3.81(m,1H,H-6′b),3.45-3.60(m,4H,H-2′,H-3′,CH2HCOOH)ppM.13C NMR(100MHz,DMSO-d6)δ170.4,142.6,141.2,134.8,129.9,128.6,127.3,127.1,124.9,124.8,121.8,121.5,120.9,120.6,119.3,118.7,117.2,112.6,112.2,84.9,79.3,76.8,73.4,67.8,58.6,55.3,49.0,22.0,19.3ppm.
化合物II-5 1H NMR(400MHz,DMSO-d6)δ11.70(s,1H,Nindole-H),9.18(d,J=8.4Hz,1H,Ar-H),9.10(d,J=8.0Hz,1H,Ar-H),8.48(br.s,1H),7.96(d,J=8.8Hz,1H,Ar-H),7.73(d,J=8.4Hz,1H,Ar-H),7.50-7.59(m,2H,Ar-H),7.31-7.36(m,2H,Ar-H),6.58(br.s,1H),6.26(d,J=8.8Hz,1H,H-1′),6.07(br.s,1H),5.47(br.s,1H),5.06(br.s,1H),4.52(d,J=8.0Hz,1H,NCHCOOH),4.25(q,J1=7.6Hz,J2=10.4Hz,1H,HOCH2CHCOOH),4.10-4.13(m,1H,H-6′a),3.91-4.04(m.2H,H-4,H-5′,HOCH2CHCOOH),3.78-3.81(m,1H,H-6′b),3.50-3.66(m,2H,H-2′,H-3′)ppm.13C NMR(100MHz,DMSO-d6)δ170.6,170.3,161.27,142.6,141.2,130.0,128.6,127.3,127.1,124.9,124.8,121.8,121.5,120.9,120.8,120.6,119.3,118.7,117.2,112.7,112.2,84.9,79.5,76.7,73.5,67.7,60.5,58.6,56.5ppm.
化合物II-6 1H NMR(400MHz,CD3OD)δ9.30(d,J=8.0Hz,1H,Ar-H),9.08(d,J=8.0Hz,1H,Ar-H),7.82(d,J=8.8Hz,1H,Ar-H),7.67(d,J=7.6 Hz,1H,Ar-H),7.53-7.57(m,1H,Ar-H),7.44-7.48(m,1H,Ar-H),7.29-7.35(m,1H,Ar-H),7.23-7.27(m,1H,Ar-H),6.20(d,J=9.2Hz,1H,H-1′),4.86(t,J=8.0 Hz,1H,NCHCOOH),4.25-4.30(m,2H,H-4′,H-6′a),3.99-4.06(m,1H,H-5′,H-6′b),3.83-3.90(m,1H,H-2′),3.74-3.79(m,1H,H-3′),2.69-2.75(m,1H,CH2CH2COOH),2.26-2.34(m,1H,CH2CH2COOH)ppm.13C NMR(100MHz,CD3OD)δ180.7,176.1,170.3,142.4,141.3,129.9,128.4,126.4,125.1,124.7,122.0,120.8,120.2,119.8,119.3,118.9,117.9,111.3,110.4,85.1,79.1,77.0,73.3,67.8,58.6,54.7,35.5,26.9,20.3ppm.
化合物II-7 1H NMR(400MHz,DMSO-d6)δ11.63(s,1H,Nindole-H),9.10(d,J=8.4Hz,1H,Ar-H),8.99(d,J=8.0Hz,1H,Ar-H),8.43(br.s,1H),7.90(d,J=8.8 Hz,1H,Ar-H),7.66(d,J=8.0Hz,1H,Ar-H),7.51(t,J=7.6Hz,1H,Ar-H),7.44(t,J=7.6Hz,1H,Ar-H),7.22-7.31(m,2H,Ar-H),6.94(d,J=8.0 Hz,2H,Ar-H),6.61(br.s,1H),6.48(d,J=8.4Hz,2H,Ar-H),6.19(d,J=8.8Hz,1H,H-1′),5.02(br.s,1H),4.67(br.s,1H,NCHCOOH),4.04-4.08(m,1H,H-6′a),3.93-3.98(m,1H,H-4′),3.83-3.86(m,1H,H-5′),3.70-3.73(m,1H,H-6′b),3.39-3.55(m,4H,H-2′,H-3′,PhCH2)ppm.13C NMR(100MHz,DMSO-d6)δ170.6,155.7,142.6,141.2,131.1,130.6,129.9,129.7,128.5,127.3,127.1,124.8,121.7,121.5,120.9,120.6,119.2,118.6,117.1,115.5,115.0,112.6,112.2,84.9,79.4,76.7,73.4,67.7,58.6,57.5,49.0 ppm.
化合物III-1 1H NMR(400MHz,δ3.53-3.76(2H,m),3.77(1H,d,J=9.6Hz),3.93(1H,d,J=9.6Hz),4.01-4.06(1H,m),4.13-4.19(m,3H),4.53(2H,t,J=5.2Hz),6.29(d,J=9.2Hz,1H,H-1′),7.12(2H,s,-NH2),7.33-7.37(2H,m,Ar-H),7.66(dd,2H,J=10.4Hz,J=8.4HzAr-H),7.75(d,1H,J=8.4Hz,Ar-H),7.91(1H,s,H-8′)7.98(1H,d,J=8.8Hz,Ar-H),8.18(1H,s,H-2′),8.97(d,1H,J=8.0Hz,Ar-H),9.04(1H,d,J=8.0Hz,Ar-H),11.70(1H,s,Nindole-H)ppm.13C NMR(100MHz,DMSO-d6).169.6,169.5,156.3,152.7,150.2,142.6,141.3,130.2,128.6,127.5,127.3,124.7,121.7,121.3,121.0,120.8,120.2,119.0,118.9,117.5,112.7,112.3,84.8,79.4,76.7,73.7,72.4,70.4,67.8,.63.2,60.6,58.6ppm.
化合物III-2 1H NMR(400MHz,)δ3.80(1H,d,J=10.4Hz),3.88-4.10(7H,m),5.52(1H,d,J=7.2Hz,H-5′),6.30(1H,d,J=8.8Hz,H-1′),6.86(1H,s),7.00(1H,s),7.36(2H,s,Ar-H),7.54-7.60(3H,m),7.70(1H,d,J=8.4Hz,Ar-H),7.98(1H,d,J=8.8Hz,Ar-H),9.05(1H,d,J=8.0Hz,Ar-H),9.12(1H,d,J=8.0Hz,Ar-H),11.68(1H,s,Nindole-H)ppm.13C NMR(100MHz,DMSO-d6)169.7,169.6,166.4,156.4,146.3,142.6,141.3,130.1,128.7,127.5,127.3,124.8,121.8,121.4,121.1,120.8,120.4,118.9,118.7,117.5,112.6,112.3,93.9,84.5,79.1,77.0,73.5,67.9,58.7,56.4,49.0,48.0 ppm.
化合物III-3 1H NMR(400MHz,)δ3.46-3.59(2H,m),3.76(1H,d,J=10.0Hz),3.86-3.92(1H,m),4.00(1H,t,J=9.2Hz),4.09-4.20(3H,m),6.24(1H,d,J=8.8Hz,H-1′),7.24-7.29(2H,m,Ar-H),7.52(2H,t,J=7.2Hz,Ar-H),7.70(1H,d,J=8.0Hz,Ar-H),7.91(1H,d,J=8.4Hz,Ar-H),8.46(1H,s,H-6′),8.97(1H,d,J=8.0Hz,Ar-H),9.04(1H,d,J=7.6Hz,Ar-H),11.91(1H,s,Nindole-H)ppm.13C NMR(100MHz,DMSO-d6)170.0,169.9,142.5,141.3,130.1,128.7,127.5,127.3,124.7,121.7,121.3,121.0,120.8,120.2,118.9,118.6,117.6,112.7,112.2,84.9,79.4,76.8,73.5,67.8,58.6ppm.
化合物III-4 1H NMR(400MHz,)δ3.57-3.61(2H,m),3.28-3.81(1H,m),3.93-4.02(3H,m),4.08-4.11(3H,m),4.50(2H,t,J=5.2 Hz),6.27(1H,d,J=8.8 Hz,H-1′),7.35-7.40(2H,m,Ar-H),7.55-7.61(2H,m,Ar-H),7.72(1H,d,J=8.0Hz,Ar-H),7.88(1H,d,J=3.2 Hz,H-6′),7.98(1H,d,J=8.8 Hz,Ar-H),9.07(1H,d,J=8.0Hz,Ar-H),9.14(1H,d,J=7.6Hz,Ar-H)ppm.13C NMR(100MHz,DMSO-d6)169.8,169.7,160.3,155.3,143.8,142.7,141.3,141.2,140.2,140.0,132.0,128.7,127.6,127.4,124.7,121.6,121.4,121.1,120.9,120.2,119.0,118.6,117.4,112.7,112.3,84.8,79.1,76.7,73.4,67.8,64.1,58.6 ppm.
化合物IV-1 1H NMR(400MHz,)δ3.43(1H,d,J=7.2Hz),3.50(1H,t),3.61(1H,s),3.80(1H,d,J=10.8Hz)),6.25(1H,d,J=8.0Hz,H-1′),7.38(2H,d,J=4.8Hz,Ar-H),7.56-7.62(2H,m,Ar-H),7.68(1H,d,J=7.6Hz,Ar-H),7.93(1H,d,J=9.2Hz,Ar-H),9.02(1H,d,J=7.6Hz,Ar-H),9.09(1H,d,J=6.8Hz,Ar-H)ppm.13C NMR(100MHz,DMSO-d6 .168.3,168.1,160.8,159.9,142.7,141.3,130.3,128.9,127.6,127.4,124.7,121.7,121.4,121.2,121.1,119.0,117.5,112.8,112.5,84.9,76.7,73.7,67.9,49.0 ppm.
化合物IV-2 1H NMR(400MHz,)δ3.81(1H,d,J=10.8Hz),3.94-4.09(2H,m),4.12(6H,s),6.27(1H,d,J=8.0Hz,H-1′),7.33-7.37(2H,d,Ar-H),7.53-7.60(2H,m,Ar-H),7.72(1H,d,J=8.0Hz,Ar-H),7.97(1H,d,J=8.8Hz,Ar-H),9.10(1H,d,J=8.0Hz,Ar-H),9.17(1H,d,J=7.6Hz,Ar-H),11.6(1H,s)ppm.13C NMR(100MHz,DMSO-d6)170.0,169.9,142.8,141.4,130.1,128.7,127.5,127.3,121.7,121.4,121.2,121.1,120.3,118.9,118.8,117.5,112.8,112.4,84.8,79.5,76.7,73.6,67.7,55.9 ppm.
化合物IV-3 1H NMR(400MHz,)δ3.59(1H,t,J=4.8Hz),3.86(1H,d,J=10.0Hz),4.01(1H,t,J=10.0Hz),4.12(2H,d,J=9.2Hz),4.94(1H,d,J=4.4Hz),5.17(d,1H,J=3.2Hz),5.42(d,1H,J=2.8Hz,),6.06(1H,s),7.38(2H,t,J=7.2Hz,Ar-H),7.50(1H,d,J=6.4Hz,Ar-H),7.60(6H,t,J=8.4Hz,Ar-H),7.75(1H,d,J=8.0Hz,Ar-H),8.01(1H,d,J=8.4Hz Ar-H),9.12(1H,d,J=8.0Hz,Ar-H),9.19(1H,d,J=8.0Hz,Ar-H),11.76(1H,s,Nindole-H)ppm.13C NMR(100MHz,DMSO-d6 169.1,169.0,162.8,142.8,141.3,132.9,130.4,129.3,129.0,128.2,127.7,127.5,124.9,121.8,124.4,121.2,121.0,119.1,118.5,117.6,112.7,112.4,84.9,79.0,77.0,73.5,67.7,62.5,58.7 ppm.
化合物IV-4 1H NMR(400MHz,)δ3.54(1H,t,J=9.2Hz),3.81(1H,d,J=4.0Hz),4.01(2H,d,J=6.4Hz),4.07(1H,d,J=11.2Hz),6.29(1H,d,J=8.8Hz),6.81(3H,m,Ar-H),7.20(2H,t,J=8.0Hz,Ar-H),7.37(m,2H,Ar-H),7.58(2H,m,Ar-H),7.71(1H,d,J=8.0Hz,Ar-H),7.98(1H,d,J=8.4Hz,Ar-H),9.04(1H,d,J=8.0Hz,Ar-H),9.11(1H,d,J=8.0Hz,Ar-H)ppm.13C NMR(100MHz,DMSO-d6)168.7,168.6,147.8,142.7,141.2,130.3,129.6,127.9,127.7,124.7,121.6,121.3,121.1,120.2,119.2,118.0,117.6,116.3,112.6,112.4,84.8,78.9,76.7,73.4,70.9,67.9,58.6 ppm.
化合物IV-5 1H NMR(400MHz,)δ3.54-3.59(1H,m),3.64-3.66(1H,m),3.82(1H,d,J=10.4Hz),3.97-4.14(2H m),4.13(d,1H,J=11.2Hz),6.24(1H,s),6.34(1H,d,J=8.8Hz,H-1′),6.87(1H,s),7.37-7.42(2H,m,Ar-H),7.61(2H,dd,J=8.4Hz,J=16.4Hz Ar-H),7.76-7.78(3H,m),8.03(1H,d,J=8.4Hz,Ar-H),8.78(2H,d,J=1.6Hz,J=1.2Hz),9.13(1H,d,J=8.0Hz,Ar-H),9.13(1H,d,J=7.6Hz,Ar-H),11.81(1H,s,Nindole-H)ppm.13C NMR(100MHz,DMSO-d6).168.1,168.0,151.9,150.8,142.8,141.4,140.5,139.7,130.5,129.1,128.5,127.8,127.6,125.3,124.8,121.7,121.3,121.2,121.1,120.0,119.2,118.4,117.7,112.8,112.5,84.9,79.2,76.9,73.6,67.9,58.7ppm.
化合物IV-6 1H NMR(400MHz,)δ3.57-3.64(3H,m,),3.83(1H,d,J=10.4Hz),3.97-4.06(m,2H),4.12(1H,d,J=9.6Hz),5.05(1H,d,J=5.2Hz),5.34(1H,d,J=5.2Hz),5.65(1H,s,J=5.2Hz),6.33(1H,s),6.35(1H,d,J=8.8Hz,H-1′),7.37-7.42(2H,m,Ar-H),7.61(2H,dd,J=8.4Hz,J=16.4Hz,Ar-H),7.74(1H,d,J=8.0Hz,Ar-H),7.99-8.05(3H,m),8.87(2H,d,J=5.2Hz),9.05(1H,d,J=8.0Hz,Ar-H),9.12(1H,d,J=7.6Hz,Ar-H),11.81(1H,s,Nindole-H)ppm.13C NMR(100MHz,DMSO-d6 167.5,167.4,165.2,151.1,149.7,142.8,141.4,139.3,130.5,129.1,127.8,127.6,124.6,122.0,121.6,121.3,121.1,119.2,118.3,117.7,116.6,112.9,112.5,84.9,79.2,76.8,73.6,68.0,58.7 ppm.
化合物IV-7 1HNMR(400MHz,)δ2.46-2.70(2H,m),2.52-2.60(2H,m),3.29-3.36(4H,m),3.51-3.62(2H,m),3.82-4.10(7H,m),4.93(1H,d,J=5.2Hz),5.17(1H,d,J=5.2Hz),5.42(1H,d,J=4.4Hz),6.04(1H,t,J=5.2Hz),6.30(d,J=8.4Hz,1H,H-1′),7.35-7.40(2H,m,Ar-H),7.55-7.60(m,2H,Ar-H),7.70(1H,d,J=8.4Hz,Ar-H),7.97(2H,m,Ar-H),9.10(1H,d,J=8.0Hz,Ar-H),9.17(1H,d,J=7.6Hz,Ar-H),11.69(1H,s Nindole-H)ppm.13C NMR(100 MHz,DMSO-d6)170.0,161.6,142.5,141.1,129.9,128.5,127.8,127.6,124.7,121.6,121.3,121.0,120.2,119.0,118.6,117.5,112.5,112.1,84.8,78.8,76.7,74.4,73.3,71.0,72.4,67.9,58.6,55.7,53.4,52.3,45.3,60.6,58.6,37.8 ppm.
化合物IV-8 1HNMR(400MHz,)δ2.0(3H,s),(2H,m),3.16(2H,s),3.52(1H,t,J=8Hz),3.61(1H,t,J=8.8Hz),3.82-4.10(7H,m3.78(d,1H,J=5.2Hz),3.88-3.93(3H,m),4.03(1H,t,J=9.6Hz),4.05-4.44(3H,m),6.31(1H,d,J=11.6Hz,H-1′),7.34-7.39(2H,m,Ar-H),7.54-7.69(2H,m,Ar-H),7.83(1H,d,J=8.4Hz,Ar-H),7.98(d,1H,J=8.4Hz,Ar-H),9.10(1H,d,J=8.0Hz,Ar-H),9.17(1H,d,J=7.6Hz,Ar-H),11.69(1H,s,Nindole-H)ppm.13C NMR(100MHz,DMSO-d6 170.0,169.9,168.6,142.7,141.4,130.1,128.7,127.5,127.3,124.7,121.7,121.4,121.1,120.8,120.3,118.9,118.6,117.5,112.8,112.4,84.9,79.5,76.7,73.6,67.8,58.6,56.4,55.9,53.2,49.0,41.3,21.6 ppm.
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