CN106995481A - Rakicidin A衍生物,其药物组合物及其用途 - Google Patents
Rakicidin A衍生物,其药物组合物及其用途 Download PDFInfo
- Publication number
- CN106995481A CN106995481A CN201610044635.0A CN201610044635A CN106995481A CN 106995481 A CN106995481 A CN 106995481A CN 201610044635 A CN201610044635 A CN 201610044635A CN 106995481 A CN106995481 A CN 106995481A
- Authority
- CN
- China
- Prior art keywords
- cancer
- compound
- nmr
- synthesis
- cdcl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0205—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Crystallography & Structural Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及Rakicidin A衍生物,其药物组合物及其用途,特别是式(I)所示的Rakcidin A衍生物,用于治疗癌症疾病,含有治疗有效量的Rakicidin A衍生物(I)及药学上可接受的载体的药物组合物或与其他抗癌药物的组合物,Rakicidin A衍生物在药物中的应用,特别是在制备治疗癌症药物中的应用。
Description
技术领域
本发明属于药物技术领域,具体地说,涉及Rakicidin A衍生物,其药物组合物,及其在制备抗癌或辅助抗癌药物中的应用。
背景技术
在超过95%的慢性粒细胞白血病(CML)患者中,费城染色体的易位产生了Bcr-Abl癌基因。相应的,伊马替尼作为一种选择性的Bcr-Abl酪氨酸激酶抑制剂现在被用于CML的一线治疗,并在临床中取得了巨大的成功。但是,依马替尼的耐药性已成为临床应用中一个重要的问题。例如,有报道,在新诊断的慢性期CML患者中3-4%是伊马替尼耐药的。在加速期中,耐药比例高达40-50%,而在急变期患者中,耐药性可超过80%。为了克服伊马替尼获得耐药性,近期越来越多的酪氨酸激酶抑制剂被研发出来,并用于CML的二线治疗,例如nilotinib,dasatinib以及bosutinib。但是这些新药对于携带T315I突变的患者无效。因此,人们依然在寻找克服伊马替尼耐药性的治疗方法,但目前结果并不尽如人意。为了迎接这种挑战,许多其他作用机制的新化合物亟待被研发。
在包括CML的许多癌症中,具有一类表现出干细胞性质的细胞。这些被称为癌症干细胞的细胞癌症产生耐药,复发及转移的主要原因。对于CML来说,Bcr-Abl酪氨酸激酶抑制剂那一治疗CML干细胞,而这些细胞将导致临床治疗中出现伊马替尼耐药性。而且,酪氨酸激酶抑制剂的使用将促使骨髓中的CML干细胞的归巢和生存。有报道称,一些小分子具有选择性抑制CML干细胞的活性,但是研发特异性抗癌症干细胞治疗药物的努力还没有产生预期的效果。
据报道,天然产物rakicidin A可以显著性的诱导实体瘤中的低氧选择细胞毒性,并且可以诱导酪氨酸激酶抑制剂耐药性的CML干细胞样细胞死亡。rakicidin A首先从Micromonospora sp.提取物中分离获得,随后包括rakicidin A,B,C及D等一系列脂肽类化合物被鉴定出来。总体来说,rakicidin类化合物具有一种独特的4-氨基-2,4-戊二烯酮结构,并且,该结构在在如microtermolide A,vinylamycin及BE-43547A1等天然产物中也被发现。
Rakicidin类化合物由于其机构和生物活性特点,在合成和药物研究方面都引起了人们的兴趣。最近,我们预测了rakicidin A的五个未知的手性中心的构型为2S,3S,14S,15S和16R。这些预测随后通过对rakicidin A进行合成及表征并通过对rakicidin A天然产物的降解实验获得证实。在Rakicidin A的合成中人们发现,Rakicidin A具有合成难度高,化合物不稳定等缺点。本发明在已有发现的基础上,合成了Rakicidin A的衍生物,该衍生物具有治疗癌症的作用。
发明内容
本发明提供了一种Rakicidin A衍生物(I),其药物组合物及其在制备治疗癌症药物中的应用。
为了实现本发明的上述目的,本发明提供如下的技术方案:
一种如下式(I)的化合物,
其中式(I)中,
n等于11或12;
2号,3号,14号,15号,16号碳原子的绝对构型为R或S。
上述的化合物,优选为化合物1a、1a’、1b、1c、1d、1e。
上述的化合物在制备治疗癌症或治疗癌症的辅助药物中的药物中的用途,其中癌症为白血病、乳腺癌、前列腺癌、鼻咽癌、大肠癌、肺癌、肝癌、食道癌、胃癌、肠道癌、肾癌、口腔癌、何杰金淋巴癌、胰腺癌、直肠结肠癌、子官颈癌、非何杰金淋巴癌、神经胶质瘤、黑瘤、膀胱癌、卵巢癌、甲状腺癌或卡波西肉瘤。
本发明还提供了一种用于治疗癌症的药物组合物,其中含有有效量的式(I)的Rakicidin A衍生物和药学上可接受的载体或与其他抗癌药物的组合物。
具体实施方式
为了理解本发明,下面以实施例进一步说明本发明,但不意于限制本发明的保护范围。
化合物的制备路线如下:
实施例1:化合物2a的合成
中间体化合物6a的合成:
氩气保护下,将醛5a(约50.0mmol)的二氯甲烷溶液(50mL)冷却至-78℃,缓慢加入新配制好的TiCl4溶液(50.0mL,1M in DCM),低温搅拌10分钟后,将化合物4a(50mmol)的二氯甲烷溶液(30mL)用注射器缓慢加入到反应体系中。滴加完毕后,保持低温继续搅拌3小时反应完全。加入饱和NH4Cl(100mL)淬灭反应。混合液静置、分液,水相用二氯甲烷(2×100mL)萃取。合并的有机相用无水硫酸钠干燥,抽滤除去无水硫酸钠,减压旋干溶剂,粗品用柱层析(石油醚/乙酸乙酯=20/1)纯化得到化合物6a(13.5g,73%)为白色固体。[α]20 D=-63.1(c=1.0,CHCl3);νmax(KBr):3533,3072,2962,1690,1457,1387,1121,1056,915cm-1;1H NMR(400MHz,CDCl3)δ5.81-5.70(1H,m),5.05-4.99(2H,m),3.89(1H,dd,J=7.7,5.0Hz),3.66-3.57(1H,m),3.49(2H,q,J=13.8Hz),3.33-3.22(1H,m),2.24(1H,d,J=10.0Hz),2.23-2.14(2H,m),2.11-2.00(2H,m),1.96-1.82(3H,m),1.73-1.64(1H,m),1.42-1.31(2H,m),1.18(3H,s),1.14(3H,d,J=6.6Hz),0.96(3H,s),0.89(3H,d,J=6.9Hz);13CNMR(100MHz,CDCl3)δ175.5,137.0,116.5,78.1,65.6,53.3,48.4,47.9,44.7,43.3,38.5,38.5,35.3,33.1,26.5,20.9,20.0,14.3,12.2;HRMS(ESI)理论值:C19H32NO4S+[M+H]+:370.2047,测量值:370.2051。
中间体化合物7a的合成
氩气保护下,将化合物6a(9.50g,25.7mmol,in 60mL THF)缓慢的滴入到预先用冰水浴冷却的氢化锂铝(1.46g,38.6mmol)的四氢呋喃溶液(50mL)中。滴加完毕以后,撤掉冰水浴缓慢升至室温,继续搅拌3小时原料反应完全。用一次性注射器小心的加入1.46mL的水淬灭反应,然后依次加入1.46mL 15%NaOH溶液和2.92mL水。搅拌10分钟后,往反应液中加入约300g的无水硫酸镁固体,剧烈摇晃,使生成的铝盐均匀的附在硫酸镁表面,用砂板漏斗抽滤掉硫酸镁固体,反复用乙酸乙酯洗涤硫酸镁上附着的产品,合并滤液后浓缩旋干,粗品用柱层析(10~20%乙酸乙酯/石油醚)纯化得到化合物44(2.92g,72%)为无色油状液体。[α]20 D=-29.7(c=1.0,CHCl3);νmax(KBr):3334,3076,2967,1641,1460,1031,984,804cm-1;1H NMR(400MHz,CDCl3)δ5.82-5.71(m,1H),5.04-4.97(m,2H),4.12-3.70(m,2H),3.68-3.55(m,2H),3.44(d,J=9.2Hz,1H),2.15-1.97(m,2H),1.85-1.73(m,1H),1.72-1.62(m,1H),0.84(d,J=6.7Hz,3H),0.76(d,J=6.8Hz,3H);13C NMR(100MHz,CDCl3)δ137.5,116.1,79.3,68.4,38.7,37.3,35.2,13.5,12.0;HRMS(ESI):calculated for C9H19O2 +[M+H]+:159.1380,found,159.1372。
中间体化合物8a的合成
氩气保护下,将Grubbs二代催化剂在25℃下加入到7a(17.0g,108mmol)和11-甲基十二-1-烯(110g,600mmol)的二氯甲烷溶液(50mL)中,搅拌10h后,减压旋干,粗品用柱层析(石油醚/乙酸乙酯=99∶1)纯化得到棕色油状物。
得到的棕色油状物用300mL乙醇溶解,加入10%Pd/C(2.60g)。用氢气置换三次。氢气环境下,反应在20℃搅拌20h。所得反应液过滤,浓缩旋干,粗品用柱层析(石油醚/乙酸乙酯=9/1)纯化得到化合物8a(12.9g,38%两步)为无色油状液体。[α]20 D=-9.6(c=1.0,CHCl3);νmax(KBr):3339,2924,2856,1462,1028,977,803,720cm-1;1H NMR(400MHz,CDCl3)δ3.73-3.70(m,2H),3.46(d,J=8.6Hz,1H),3.16(s,1H),2.57(s,1H),1.90-1.78(m,1H),1.67-1.57(m,1H),1.56-1.46(m,1H),1.35-1.21(band,20H),1.16-1.12(m,2H),0.86(d,J=6.6Hz,9H),0.80(d,J=6.9Hz,3H);13C NMR(100MHz,CDCl3)δ80.5,68.9,39.2,37.5,35.3,34.2,30.1,30.0,29.8,28.1,27.6,27.5,22.8,13.7,12.4;HRMS(ESI):calculatedfor C20H43O2 +[M+H]+:315.3258,found,315.3255.
中间体化合物9a的合成
氩气保护环境下,将酸片段3a(1.67g,4.33mmol)和双醇化合物8a(1.07g,3.41mmol)溶解在干燥的二氯甲烷中,室温下,依次加入EDCI(2.61g,13.6mmol)和DMAP(540mg,4.43mmol),然后反应在室温下继续搅拌6小时后,TLC检测反应完全。加入100mL水淬灭反应,搅拌5分钟后,混合液静置、分液,水相用二氯甲烷(3×80mL)萃取,合并后的有机相用无水硫酸钠干燥,抽滤去除硫酸钠固体,滤液浓缩旋干,得到的粗品用柱层析(3~8%乙酸乙酯/石油醚)纯化得到化合物9a(1.60g,70%)为无色油状液体。[α]20 D=+1.6(c=1.0,CHCl3);νmax(KBr):3528,3450,2954,2854,1762,1725,1501,1464,1266,1136,855,745cm-1;1H NMR(400MHz,CDCl3)δ5.28(d,J=9.8Hz,1H),4.80(s,1H),4.74(d,J=9.8Hz,1H),4.33(dd,J=10.7,3.7Hz,1H),4.18(dd,J=10.7,6.1,Hz,1H),3.73(s,3H),3.36-3.25(m,2H),1.97-1.87(m,1H),1.78(s,1H),1.64-1.47(m,2H),1.42(s,9H),1.35-1.20(br,22H),0.93-0.82(m,21H),0.62-0.55(m,6H);13C NMR(100MHz,CDCl3)δ171.2,170.2,155.6,80.2,75.8,72.4,68.9,57.5,52.5,39.2,36.3,34.8,34.5,30.1,29.8,28.4,28.1,27.6,27.5,22.8,14.2,12.2,6.7,4.6;HRMS(ESI)calculated for:C36H71NO8SiNa+[M+Na]+:696.4841,found,696.4849.
中间体化合物10a的合成
氩气保护状态下,将化合物9a(3.94g,5.84mmol)溶解在重蒸过的干燥四氢呋喃(60mL)中,反应体系冷却至-40℃,用一次性注射器沿瓶壁慢慢滴加LiHMDS(12.0mL,12.0mmol,1M in THF),然后反应在-40℃状态下继续搅拌50分钟后,加入饱和NaHCO3(80mL)淬灭反应,搅拌5分钟后,自然升至室温。混合液静置、分液,水相用乙酸乙酯(3×100mL)萃取,合并后的有机相用无水硫酸钠干燥半小时,抽滤去除硫酸钠固体,滤液浓缩旋干,粗品用柱层析(4~8%乙酸乙酯/石油醚)纯化得到化合物10a(2.32g,59%)为无色油状液体。回收的原料可以继续重复此反应步骤。[α]20 D=-32.6(c=1.0,CHCl3);νmax(KBr):3539,3449,2954,2925,2854,1762,1726,1498,1366,1135,980,854,744cm-1;1H NMR(400MHz,CDCl3)δ5.25(d,J=9.8Hz,1H),4.87(d,J=2.0Hz,1H),4.84(dd,J=9.6,2.0Hz,1H),4.71(dd,J=9.8,1.8Hz,1H),3.74(s,3H),3.58-3.38(m,2H),2.49(br_s,1H),1.88-1.78(m,1H),1.76-1.65(m,1H),1.53-1.45(m,1H),1.43(s,9H),1.33-1.20(m,22H),0.98-0.84(m,21H),0.66-0.59(m,6H);13C NMR(100MHz,CDCl3)δ171.6,171.0,155.8,80.5,80.4,71.8,64.5,57.5,52.5,39.2,37.3,34.3,34.0,30.1,29.9,29.8,28.4,28.1,27.6,22.8,14.4,13.0,6.8,4.8;HRMS(ESI)calculated for:C36H71NO8SiNa+[M+Na]+:696.4841,found,696.4848.
中间体化合物12a的合成
氩气保护下,将化合物10a(2.34g,3.47mmol)溶解在干燥的二氯甲烷(80mL)溶液中,室温下,加入戴斯-马丁氧化剂(1.77g,4.17mmol),然后反应在室温下继续搅拌2小时后,TLC检测反应完全。加入饱和碳酸氢钠(50mL)淬灭反应,然后加入过量的饱和硫代硫酸钠水溶液(20mL)还原掉过过量的戴斯-马丁氧化剂,搅拌10分钟后,混合液静置、分液,水相用二氯甲烷(3×100mL)萃取,合并后的有机相用无水硫酸钠干燥半小时,抽滤去除硫酸钠,滤液浓缩旋干,得到粗品不用进一步纯化直接用作下一步反应。
将上一步得得到的粗品油状物溶解在叔丁醇(100mL)中,加入2-甲基-2-丁烯(37.0mL,350mmol),室温搅拌状态下加入NaH2PO4(2.91g,24.3mmol)和NaClO2(2.80g,31.0mmol)的水溶液(15mL),反应液的颜色由无色变为黄棕色为正常现象,随后颜色会变浅,该反应在室温下搅拌过夜反应完全(大于5小时即可),加入饱和NaHCO3(200mL)搅拌10分钟淬灭反应,用正己烷(3×100mL)萃取混合液,合并后的有机相用无水硫酸钠干燥半小时,抽滤去除硫酸钠,滤液浓缩旋干,得到的粗品用柱层析(1~3%甲醇/二氯甲烷)纯化得到无色油状液体。在氩气保护下,将上述油状液体和化合物11a(831mg,4.05mmol)溶解在干燥的二氯甲烷溶液中,室温下,依次加入EDCI(1.03g,5.40mmol),HOBt(547mg,4.05mmol),最后加入DIPEA(0.950mL,5.40mmol),反应在室温下继续搅拌4小时后,TLC检测原料反应完全。加入1%的HCl(100mL,aq)搅拌2分钟后淬灭反应,混合液静置、分液,水相用二氯甲烷(3×80mL)萃取,合并后的有机相用无水硫酸钠干燥,抽滤去除硫酸钠固体,滤液浓缩旋干,得到的粗品用柱层析(8~15%乙酸乙酯/石油醚)纯化得到化合物12a(1.60g,68%)为无色油状液体。[α]20 D=-48.6(c=1.0,CHCl3);νmax(KBr):3443,3338,2956,2926,2855,1744,1718,1673,1465,1305,1096,1017,838,780cm-1;1H NMR(400MHz,CDCl3)δ6.33(d,J=8.0Hz,1H),5.25(d,J=9.8Hz,1H),5.16(dd,J=9.5,1.6Hz,1H),4.99(d,J=1.5Hz,1H),4.69(dd,J=9.8,1.7Hz,1H),4.01(m,1H),3.74(s,3H),3.71-3.63(m,4H),2.32(m,1H),1.88-1.68(br,2H),1.52-1.44(m,1H),1.45(s,9H),1.24(m,20H),1.14(m,2H),1.09(d,J=6.9Hz,3H),0.93(t,J=7.9Hz,9H),0.89-0.82(m,18H),0.66-0.55(m,6H),0.06(s,3H),0.05(s,3H);13C NMR(100MHz,CDCl3)δ174.0,171.7,168.4,156.6,80.8,79.5,71.2,62.5,57.6,53.0,52.6,44.1,39.2,34.0,33.4,30.1,29.9,29.8,28.5,28.1,27.6,26.0,22.8,18.3,14.1,12.6,6.8,4.7,-5.3,-5.4;HRMS(ESI)calculated for:C45H90N2O10Si2Na+[M+Na]+:897.6026,found,897.6029.
中间体化合物14a的合成
氩气保护下,将化合物12a(1.60g,1.83mmol)溶解在干燥的二氯甲烷(25mL)中,室温下,加入戴斯-马丁氧化剂(1.01g,2.38mmol),然后反应在室温下继续搅拌1.5小时后,TLC检测原料反应完全,加入饱和碳酸氢钠(40mL)淬灭反应,然后加入硫代硫酸钠(20mL)还原掉过量的戴斯-马丁氧化剂,搅拌10分钟后,混合液静置、分液,无机相用二氯甲烷(3×100rnL)萃取,合并后的有机相用无水硫酸钠干燥半小时,抽滤去除硫酸钠,滤液浓缩旋干,得到的粗品用快速柱层析(8~12%乙酸乙酯/石油醚)纯化得到无色油状液体。将无水氯化锂盛在单口圆底烧瓶中,加入溶解有化合物13(644mg,1.99mmol)的乙腈(4mL)溶液,密封,氩气气球正压保护,将体系冷却至-10℃,搅拌5分钟后加入DBU(304mg,1.99mmol),再搅拌10分钟,加入溶解有上述油状液体(1.34g,1.53mmol)的二氯甲烷溶液(20mL),反应保持低温搅拌15分钟,TLC检测醛反应完全。加入100mL水淬灭反应,用二氯甲烷(3×70mL)萃取,合并后的有机相后用无水硫酸钠干燥半小时,抽滤去除硫酸钠,减压蒸馏旋干除去溶剂,得到的粗品用柱层析(10~20%乙酸乙酯/石油醚)纯化得到化合物14a(830mg,52%)为无色油状液体。[α]20 D=-47.4(c=1.0,CHCl3);νmax(KBr):3444,3327,2952,2927,1744,1668,1638,1500,1467,1305,1064,977,841cm-1;1H NMR(400MHz,CDCl3)δ6.93(d,J=8.2Hz,0.77H),6.89(d,J=8.2Hz,0.23H),6.86-6.76(m,1H),6.55(d,J=15.2Hz,0.77H),6.34(d,J=15.2Hz,0.23H),5.22(d,J=9.5Hz,1H),5.06-4.99(br,1H),4.95(s,0.77H),4.85(s,0.23H),4.73-4.57(br,1H),4.54-4.45(m,1H),4.21(d,J=18.0Hz,0.23H),4.13-3.98(m,1.54H),3.22(d,J=18.0Hz,0.23H),3.78-3.65(br,6H),3.12(s,2.31H),2.97(s,0.69H),2.38(m,1H),1.79(s,1H),1.75(br,1H),1.54-1.38(br,19H),1.35-1.17(br,20H),1.14-1.02(br,3H),0.92(t,J=7.9Hz,9H),0.87-0.80(br,18H),0.61(m,6H),0.06(br,6H);HRMS(ESI):calculated for C54H103N3O12Si2Na+[M+Na]+:1064.6972,found,1064.6970.
化合物2a的合成
氩气保护下,将化合物14a(0.730g,0.700mmol)溶解在二氯甲烷中(7mL),加入三乙基硅烷(0.670mL,4.20mmol),冰水浴冷却状态下,用一次性注射器缓慢滴加三氟乙酸(4.5mL),维持温度搅拌半小时后,自然升至室温,继续搅拌3小时。加入甲苯(7mL)稀释反应液,减压蒸馏小心旋干除去溶剂,再次加入少量甲苯(3mL)共沸带掉残留的三氟乙酸。粗产品用20倍硅胶快速柱层析(8~20%甲醇/二氯甲烷)得到白色的固体。将该白色固体溶解在干燥的四氢呋喃(20mL)中备用。在氩气保护状态下,在两口圆底烧瓶中盛有溶解在THF(800mL)中的HATU(3.99g,10.5mmol)和DIPEA(3.67mL,21.0mmol),油浴维持体系温度在30℃,将上一步得到的四氢呋喃溶液用自动进样器慢慢滴加到此反应体系中,滴加过程约持续8小时,滴加完毕后反应继续搅拌过夜。减压蒸馏除去溶剂,用甲醇/乙酸乙酯(v/v=2∶1,300mL)稀释,砂板漏斗铺一层薄薄的硅藻土,抽滤除去不溶物,滤液旋干,得到的粗品用乙酸乙酯(300mL)再次溶解,乙酸乙酯相分别依次用1%的HCl(aq,80mL),饱和NaHCO3(60mL),饱和食盐水(60mL)洗涤。分液后的有机相用无水硫酸钠干燥半小时,砂板漏斗抽滤除去硫酸钠,减压蒸馏旋干,得到的粗品用柱层析(1~4%甲醇/二氯甲烷)纯化得到化合物2a(268mg,60%两步反应产率)为白色固体。[α]20 D=-125.0(c=1.0,DMSO);νmax(KBr):3380,3296,2924,2853,1746,1715,1693,1673,1651,1464,977,845cm-1;1H NMR(400MHz,DMSO-d6)δ8.40(d,J=9.9Hz,1H),7.81(d,J=9.0Hz,1H),6.75(dd,J=14.9,2.6Hz,1H),6.00(d,J=5.4Hz,1H),5.96(dd,J=15.0,1.9Hz,1H),5.13(d,J=10.7Hz,1H),4.91(t,J=5.6Hz,1H),4.87(dd,J=9.9,1.9Hz,1H),4.51-4.39(br,3H),3.69(d,J=18.2Hz,1H),3.59(s,3H),3.39-3.35(m,1H),2.95(s,3H),2.87-2.80(m,1H),1.73-1.64(m,1H),1.55-1.45(m,1H),1.40-1.10(br,22H),1.02(d,J=7.0Hz,3H),0.94(d,J=6.8Hz,3H),0.85(d,J=6.6Hz,6H);13C NMR(100MHz,DMSO-d6)δ173.0,171.7,168.3,168.0,165.7,143.7,118.5,78.1,71.6,63.1,54.8,52.1,51.9,51.2,41.4,38.5,36.5,33.7,33.0,29.4,29.2,29.1,29.1,27.4,27.0,26.8,22.6,15.9,13.2;HRMS(ESI)calculated for:C33H57N3O9Na+[M+Na]+:662.3987,found,662.3992.
实施例2:化合物2b的合成
中间体化合物6b的合成
与上述化合物6a的合成步骤相同。柱层析(石油醚/乙酸乙酯=20/1)纯化。产率:73%,白色固体。[α]20 D=+63.1(c=1.0,CHCl3);νmax(KBr):3533,3072,2962,1690,1457,1387,1121,1056,915cm-1;1H NMR(400MHz,CDCl3)δ5.81-5.70(1H,m),5.05-4.99(2H,m),3.89(1H,dd,J=7.7,5.0Hz),3.66-3.57(1H,m),3.49(2H,q,J=13.8Hz),3.33-3.22(1H,m),2.24(1H,d,J=10.0Hz),2.23-2.14(2H,m),2.11-2.00(2H,m),1.96-1.82(3H,m),1.73-1.64(1H,m),1.42-1.31(2H,m),1.18(3H,s),1.14(3H,d,J=6.6Hz),0.96(3H,s),0.89(3H,d,J=6.9Hz);13C NMR(100MHz,CDCl3)δ175.5,137.0,116.5,78.1,65.6,53.3,48.4,47.9,44.7,43.3,38.5,38.5,35.3,33.1,26.5,20.9,20.0,14.3,12.2;HRMS(ESI)calculatedfor C19H32NO4S+[M+H]+:370.2047,found 370.2051.
中间体化合物7b的合成
与上述化合物7a的合成步骤相同。柱层析(石油醚/乙酸乙酯=4∶1)纯化得到化合物7b(15.0g,72%)为无色油状液体。[α]20 D=+31.3(c=1.0,CHCl3);νmax(KBr):3339,3076,1641,1469,1029,984,804cm-1;1H NMR(400MHz,CDCl3)δ5.82-5.71(1H,m),5.04-4.97(2H,m),4.12-3.70(2H,m),3.68-3.55(2H,m),3.44(1H,d,J=9.2Hz),2.15-1.97(2H,m),1.85-1.73(1H,m),1.72-1.62(1H,m),0.84(3H,d,J=6.7Hz),0.76(3H,d,J=6.8Hz);13CNMR(100MHz,CDCl3)δ137.5,116.1,79.3,68.4,38.7,37.3,35.2,13.5,12.0;HRMS(ESI)calculated for C9H19NO2 +[M+H]+:159.1380,found 159.1378.
中间体化合物8b的合成
与上述化合物8a的合成步骤相同。用柱层析(石油醚/乙酸乙酯=9/1)纯化得到化合物8b(12.9g,38%两步)为无色油状液体。[α]20 D=+9.3(c=1.0,CHCl3);νmax(KBr):3340,2924,2856,1462,1268,1029,977,721cm-1;1H NMR(400MHz,CDCl3)δ3.73-3.62(2H,m),3.47(1H,d,J=8.5Hz),3.15-2.42(2H,br),1.85(1H,s),1.61(1H,s),1.51(1H,s),1.40-1.20(20H,band),1.19-1.10(2H,br),0.89-0.83(9H,m),0.81(3H,d,J=6.0Hz);13CNMR(100MHz,CDCl3)δ80.5,69.0,39.2,37.5,35.3,34.2,30.1,30.0,29.8,28.1,27.6,27.5,22.8,13.7,12.4;HRMS(ESI)calculated for C20H43O2 +[M+H]+:315.3258,found315.3257.
中间体化合物9b的合成
与上述化合物9a的合成步骤相同。柱层析(石油醚/乙酸乙酯=20∶1)纯化得到化合物9b(7.50g,71%)为无色油状液体。[α]20 D=-1.3(c=1.0,CHCl3);νmax(KBr):3532,3450,2955,2925,2879,1762,1725,1501,1464,1367,1344,1263,1209,1168,1063,1008,987,855cm-1;1H NMR(400MHz,CDCl3)δ5.28(1H,d,J=9.8Hz),4.80(1H,s),4.74(1H,d,J=9.8Hz),4.33(1H,dd,J=10.8,3.7Hz),4.19(1H,dd,J=10.7,6.1,Hz),3.74(3H,s),3.36-3.25(2H,m),1.97-1.87(1H,m),1.72(1H,d,J=5.5,Hz),1.64-1.47(2H,m),1.43(9H,s),1.35-1.20(22H,br),0.97-0.80(21H,m),0.65-0.52(6H,m);13C NMR(100MHz,CDCl3)δ171.2,170.2,155.6,80.2,75.8,72.3,68.9,57.5,52.5,39.2,36.3,34.8,34.5,30.1,29.8,28.4,28.1,27.6,27.5,22.8,14.2,12.2,6.7,4.6;HRMS(ESI)calculated forC36H71NO8SiNa+[M+Na]+:696.4841,found 696.4845.
中间体化合物10b的合成
与上述化合物10a的合成步骤相同。用柱层析法(石油醚/乙酸乙酯=20∶1)纯化得化合物10b(4.27g,58%)为无色油状液体。[α]20 D=+16.8(c=1.0,CHCl3);νmax(KBr):3448,2961,2926,2879,2855,1762,1726,1499,1463,1367,1166,1097,1021,862,802,745cm-1;1H NMR(400MHz,CDCl3)δ5.24(1H,d,J=9.8Hz),4.87(1H,d,J=2.0Hz),4.84(1H,dd,J=9.6,2.0Hz),4.71(1H,dd,J=9.8,2.0Hz),3.74(3H,s),3.58-3.38(2H,m),2.46(1H,br),1.86-1.78(1H,m),1.77-1.66(1H,m),1.55-1.47(1H,m),1.44(9H,s),1.34-1.10(22H,m),1.01-0.82(21H,m),0.70-0.57(6H,m);13C NMR(100MHz,CDCl3)δ171.6,171.0,155.8,80.5,80.3,71.8,64.5,57.5,52.5,39.2,37.3,34.3,34.0,30.1,29.9,29.8,28.4,28.1,27.6,22.8,14.4,13.0,6.8,4.8;HRMS(ESI)calculated for C36H71NO8SiNa+[M+Na]+:696.4841,found 696.4845.
中间体化合物12b的合成
与上述化合物12a的合成步骤相同。用柱层析法(石油醚/乙酸乙酯=9/1)纯化后得化合物12b(4.19g,64%三步)为无色油状液体。[α]20 D=+20.5(c=1.0,CHCl3);νmax(KBr):3443,3346,2953,2927,2880,2856,1744,1722,1502,1465,1414,1367,1261,1166,1097,1021,802cm-1;1H NMR(400MHz,CDCl3)δ6.31(1H,d,J=8.0Hz),5.24(1H,d,J=9.8Hz),5.16(1H,dd,J=9.5,1.9Hz),4.99(1H,d,J=1.7Hz),4.69(1H,dd,J=9.8,1.8Hz),4.01(1H,m),3.80-3.63(4H,m),3.74(3H,s),2.32(1H,m),1.79-1.69(1H,M),1.55-1.45(1H,m),1.45(9H,s),1.35-1.19(21H,m),1.17-1.12(2H,m),1.09(3H,d,J=6.9Hz),0.93(9H,m),0.90-0.82(18H,m),0.66-0.55(6H,m),0.06(3H,s),0.05(3H,s);13C NMR(100MHz,CDCl3)δ173.9,171.7,168.3,156.6,80.8,79.5,71.2,62.5,57.6,52.9,52.6,44.1,39.2,34.0,33.4,30.1,30.0,29.8,28.5,28.1,27.6,26.0,22.8,18.3,14.1,12.6,6.8,4.7,-5.3,-5.6;HRMS(ESI)calculated for C45H90N2O10Si2Na+[M+Na]+:897.6026,found897.6026.
化合物2b的合成:
20℃条件下,向12b(4.20g,4.80mmol)的二氯甲烷溶液(60mL)中加入DessMartin试剂(2.65g,6.24mmol)。搅拌1h后,加入饱和无水碳酸氢钠溶液(100mL)和饱和无水硫代硫酸钠溶液(30mL)淬灭。反应混合物继续搅拌10分钟,二氯甲烷(3×100mL)萃取。合并的有机相用无水硫酸钠干燥,浓缩。粗品用柱层析法(石油醚/乙酸乙酯=8/1)纯化后得到无色油状液体,直接用于下一步。
-10℃条件下,向化合物13(1.60mg,4.95mmol)的乙腈溶液(15mL)中依次加入无水氯化锂(252mg,5.94mmol)和DBU(0.74mL,4.95mmol),搅拌10分钟。然后将上步所得醛的二氯甲烷溶液(40mL)加入到反应液中。继续搅拌10分钟后,加入100ml水淬灭。水相用二氯甲烷(3×100mL)萃取。合并的有机相用无水硫酸钠干燥,浓缩。粗品用柱层析法(石油醚/乙酸乙酯=8/1)纯化后得化合物14b为无色油状液体。
0℃条件下,向14b(0.730g,0.700mmol)的二氯甲烷溶液(12mL)中依次加入三乙基硅烷(1.10mL,6.90mmol)和三氟醋酸(8mL)。搅拌4h后,加入10ml甲苯稀释,浓缩。所得白色固体溶解在20ml四氢呋喃溶液中,30℃条件下,将此混合溶液缓慢地加入到HATU(6.55g,17.3mmol)和DIPEA(6.00mL,34.5mmol)的四氢呋喃溶液(1100mL)中,搅拌10h。将溶剂旋干,用甲醇和乙酸乙酯(v/ν=2∶1,500mL)稀释,过滤,浓缩。剩余物用乙酸乙酯(500mL)溶解,依次用1%HCl(3×50mL),饱和无水碳酸氢钠溶液(60mL)和食盐水(3×50mL)洗涤。有机相用无水硫酸钠干燥,减压浓缩。粗品用柱层析法纯化(二氯甲烷/甲醇=30/1)后得化合物2b(426mg,26%四步)为白色固体。[α]20 D=+108.5(c=1.0,DMSO);νmax(KBr):3576,3389,2923,2853,1740,1694,1674,1536,1464,1403,1271,1109,974,845cm-1;1H NMR(400MHz,DMSO-d6)δ8.40(1H,d,J=9.9Hz),7.81(1H,d,J=8.9Hz),6.74(1H,d,J=15.0Hz),5.99(1H,d,J=5.4Hz),5.96(1H,dd,J=15.0Hz),5.12(1H,d,J=10.5Hz),4.99-4.83(2H,m),4.51-4.39(3H,br),3.68(1H,d,J=18.2Hz),3.58(3H,s),3.37-3.34(1H,m),2.96(3H,s),2.90-2.78(1H,m),1.73-1.64(1H,m),1.55-1.45(1H,m),1.40-1.18(23H,br),1.01(3H,d,J=6.7Hz),0.93(3H,d,J=6.6Hz),0.84(6H,d,J=6.5Hz);13C NMR(100MHz,DMSO-d6)δ172.9,171.6,168.3,167.9,165.7,143.6,118.5,78.0,71.5,63.1,54.8,52.1,51.9,51.2,41.4,38.5,36.5,33.6,33.0,29.3,29.2,29.1,27.4,27.0,26.8,22.5,15.9,13.2;HRMS(ESI)calculated for C33H57N3O9Na+[M+Na]+:662.3987,found 662.3990.
实施例3:化合物2c的合成
中间体化合物6c的合成:
与上述化合物6a的合成步骤相同。快速柱色谱洗脱:石油醚/乙酸乙酯=20/1;产率:72%;白色固体;[α]20 D=-48.7(c=1.0,CHCl3);νmax(KBr):3513,3071,2962,1660,1458,916cm-1;1H NMR(400MHz,CDCl3)δ5.83-5.73(1H,m),5.08-5.00(2H,m),3.90(1H,dd,J=7.5,5.1Hz),3.49(2H,q,J=13.8Hz),3.46-3.40(1H,m),3.38-3.31(1H,m),2.71(1H,d,J=10.2Hz),2.37(1H,m),2.17-2.04(2H,m),1.97-1.83(4H,m),1.65-1.55(1H,m),1.43-1.31(2H,m),1.27(3H,d,J=6.7Hz),1.17(3H,s),0.97(3H,s),0.96(3H,d,J=6.6Hz);13CNMR(100MHz,CDCl3)δ176.2,137.0,116.4,80.0,65.5,53.2,48.4,47.8,44.7,42.1,38.6,36.6,35.4,33.0,26.5,20.8,20.0,16.2,15.0;HRMS(ESI)calculated for C19H32NO4S+[M+H]+:370.2047,found370.2041.
中间体化合物7c的合成:
与上述化合物7a的合成步骤相同。快速柱色谱洗脱:石油醚/乙酸乙酯=4/1;产率:70%;无色油状液体;[α]20 D=-16.6(c=0.5,CHCl3);νmax(KBr):3333,3075,1642,1461,984,805cm-1;1H NMR(400MHz,CDCl3)δ5.88-5.75(1H,m),5.07-4.99(2H,m),3.84-3.74(1H,m),3.66-3.55(1H,m),3.42-3.32(1H,m),3.22(1H,s),3.01(1H,d,J=3.8Hz),2.39-2.26(1H,m),2.00-1.83(2H,m),1.82-1.71(1H,m),0.93(3H,d,J=6.9Hz),0.92(3H,d,J=6.8Hz);13C NMR(100MHz,CDCl3)δ137.8,116.2,81.8,67.6,36.7,35.9,35.1,16.8,14.3;HRMS(ESI)calculated for C9H19NO2 +[M+H]+:159.1380,found 159.1378.
中间体化合物8c的合成:
与上述化合物8a的合成步骤相同。快速柱色谱洗脱:石油醚/乙酸乙酯=9/1;产率:33%两步;无色油状液体;[α]20 D=-18.3(c=1.0,CHCl3);νmax(KBr):3364,2953,2852,1463,1071,980,720cm-1;1H NMR(400MHz,CDCl3)δ3.75(1H,dd,J=10.7,3.4Hz),3.61(2H,dd,J=10.8,7.2Hz),3.35(1H,dd,J=7.7,4.0Hz),2.95(1H,s),1.94-1.80(1H,m),1.67-1.57(1H,m),1.56-1.44(2H,m),1.42-1.34(1H,m),1.20-1.07(20H,band),0.93(3H,d,J=6.9Hz),0.86(3H,d,J=6.4Hz),0.84(6H,d,J=6.4Hz);13C NMR(100MHz,CDCl3)δ82.4,68.1,39.2,36.8,35.7,30.2,30.1,29.8,29.6,28.1,27.6,22.8,16.9,14.2;HRMS(ESI)calculated for C20H42O2Na+[M+Na]+:337.3077,found 337.3078.
中间体化合物9c的合成:
与上述化合物9a的合成步骤相同。快速柱色谱洗脱:石油醚/乙酸乙酯=9/1;产率:70%;无色油状液体;[α]20 D=0(c=0.8,CHCl3);νmax(KBr):3500,2955,2853,1761,1725,1500,1259,1135,989,744cm-1;1H NMR(400MHz,CDCl3)δ5.26(1H,d,J=9.8Hz),4.79(1H,s),4.73(1H,d,J=9.8Hz),4.32(1H,dd,J=10.8,4.0Hz),4.19-4.10(1H,m),3.73(3H,s),3.25-3.18(1H,m),2.02-1.95(1H,m),1.64-1.54(1H,m),1.52-1.45(1H,m),1.41(9H,s),1.32-1.10(20H,br),0.96-0.88(18H,m),0.84(6H,d,J=6.6Hz),0.68-0.52(6H,m);13CNMR(100MHz,CDCl3)δ171.2,170.2,155.6,80.2,77.9,72.3,68.3,57.4,52.5,39.2,35.3,30.1,30.0,29.8,29.8,28.3,28.1,27.5,27.4,22.8,15.9,14.8,6.7,4.6;HRMS(ESI)calculated for C36H71NO8SiNa+[M+Na]+:696.4841,found 696.4844.
中间体化合物10c的合成:
与上述化合物10a的合成步骤相同。快速柱色谱洗脱:石油醚/乙酸乙酯=9/1;产率:50%;无色油状液体;[α]20 D=-21.6(c=1.0,CHCl3);νmax(KBr):3449,2925,2878,1762,1725,1463,1381,1259,1062,855cm-1;1H NMR(400MHz,CDCl3)δ5.23(1H,d,J=9.6Hz),4.89(1H,d,J=1.8Hz),4.79(1H,dd,J=9.2,3.2Hz),4.71(1H,dd,J=9.6,1.8Hz),3.74(3H,s),3.59-3.40(2H,m),2.44(1H,dd,J=8.0,5.5Hz),1.88-1.78(1H,m),1.77-1.71(1H,m),1.59-1.46(1H,m),1.44(9H,s),1.33-1.15(22H,m),1.01-0.91(12H,m),0.89(3H,d,J=6.8Hz),0.85(6H,d,J=6.6Hz),0.68-0.58(6H,m);13C NMR(100MHz,CDCl3)δ171.5,170.8,155.8,82.2,80.3,71.8,64.4,57.5,52.5,39.2,36.9,34.0,30.1,29.8,29.7,28.4,28.1,27.5,27.5,22.7,17.0,14.6,6.8,4.7;HRMS(ESI)calculated for C36H71NO8SiNa+[M+Na]+:696.4841,found 696.4844.
中间体化合物12c的合成:
与上述化合物12b的合成步骤相同。快速柱色谱洗脱:石油醚/乙酸乙酯=9/1;产率:59%三步;无色油状液体;[α]20 D=-15.5(c=1.0,CHCl3);νmax(KBr):3440,2953,2879,1745,1720,1657,1464,1252,1006,986,838,777cm-1;1H NMR(400MHz,CDCl3)δ6.25(1H,d,J=8.0Hz),5.22(1H,d,J=9.8Hz),5.08(1H,dd,J=9.3,2.3Hz),4.96(1H,d,J=1.6Hz),4.64(1H,dd,J=9.7,1.6Hz),3.98(1H,m),3.72(3H,s),3.76-3.55(4H,m),3.40-2.31(1H,m),1.80-1.69(1H,br),1.52-1.43(1H,m),1.43(9H,s),1.23(20H,m),1.15-1.05(5H,m),0.92-0.82(28H,m),0.63-0.54(6H,m),0.03(3H,s),0.02(3H,s);13C NMR(100MHz,CDCl3)δ173.8,171.6,168.4,156.5,80.8,80.7,71.3,62.4,57.6,52.9,52.6,39.1,30.1,30.0,29.8,29.8,28.4,28.0,27.5,27.3,25.9,22.7,16.8,13.9,6.7,4.6,4.6,-5.4,-5.4;HRMS(ESI)calculated for C45H90N2O10Si2Na+[M+Na]+:897.6026,found897.6028.
化合物2c的合成:
与上述化合物2b的合成步骤相同。快速柱色谱洗脱:二氯甲烷/甲醇=30/1;产率:23%四步;白色固体;[α]20 D=-31.4(c=1.0,5%MeOH in CH2Cl2);νmax(KBr):3413,2925,2854,1741,1649,1619,1464,1273,979,852cm-1;1H NMR(400MHz,DMSO-d6)δ8.47(1H,d,J=9.6Hz),7.84(1H,d,J=9.0Hz),6.74(1H,dd,J=14.9,2.5Hz),6.03(1H,d,J=4.8Hz),5.95(1H,dd,J=15.0,1.7Hz),5.11(1H,d,J=10.8Hz),4.91-4.85(2H,m),4.53-4.37(3H,m),3.68(1H,d,J=18.2Hz),3.57(3H,s),3.37-3.34(1H,m),2.94(3H,s),2.91-2.83(1H,m),1.78-1.65(1H,m),1.54-1.44(1H,m),1.48-1.10(23H,br),1.01(3H,d,J=6.9Hz),0.90(3H,d,J=6.9Hz),0.84(6H,d,J=6.6Hz);13C NMR(100MHz,DMSO-d6)δ173.0,171.7,168.5,168.0,165.7,143.7,118.5,77.7,71.5,63.1,54.8,52.1,51.9,51.2,41.0,38.5,36.5,33.8,33.0,29.4,29.1,29.1,27.4,27.2,26.9,22.6,16.3,15.8;HRMS(ESI)calculatedfor C33H57N3O9Na+[M+Na]+:662.3987,found 662.3990.
实施例4:化合物2a’的合成
中间体化合物8a’的合成:
与上述化合物8a的合成步骤相同。快速柱色谱洗脱:石油醚/乙酸乙酯=9/1;产率:39%两步;无色油状液体;[α]20 D=-8.5(c=1.0,CHCl3);νmax(KBr):3343,2923,2853,1464,1380,1286,1028,976cm-1;1H NMR(400MHz,CDCl3)δ3.71(1H,dd,J=10.7,3.4Hz),3.63(1H,dd,J=10.5,8.0Hz),3.46(1H,dd,J=8.9,2.4Hz),3.19(1H,brs),2.60(1H,brs),1.91-1.79(1H,m),1.65-1.55(1H,m),1.54-1.45(1H,m),1.38-1.20(22H,band),1.18-1.10(2H,m),0.86(3H,d,J=6.8Hz),0.85(6H,d,J=6.4Hz),0.80(3H,d,J=6.9Hz);13C NMR(100MHz,CDCl3)δ80.5,70.0,39.2,37.5,35.3,34.2,30.1,30.0,29.9,29.8 28.1,27.6,27.5,22.8,13.7,12.4;HRMS(ESI)calculated for C21H45O2 +[M+H]+:329.3414,found329.3416.
中间体化合物10a′的合成:
与上述化合物10a的合成步骤相同。快速柱色谱洗脱:石油醚/乙酸乙酯=9/1;产率:55%;无色油状液体;[α]20 D=-18.6(c=1.0,CHCl3);νmax(KBr):3449,2925,2879,1761,1725,1501,1464,1344,1267,1136,1062,986,855cm-1;1H NMR(400MHz,CDCl3)δ5.24(1H,d,J=9.8Hz),4.87(1H,d,J=2.3Hz),4.84(1H,dd,J=9.6,2.3Hz),4.71(1H,dd,J=9.8,2.1Hz),3.73(3H,s),3.58-3.41(2H,m),2.45(1H,brs),1.86-1.79(1H,m),1.75-1.66(1H,m),1.52-1.44(1H,m),1.42(9H,s),1.35-1.20(24H,m),0.95-0.83(21H,m),0.66-0.59(6H,m);13C NMR(100MHz,CDCl3)δ171.5,170.9,155.7,80.4,80.3,71.8,64.5,57.5,52.5,39.2,37.3,34.2,33.9,31.7,30.1,29.8,29.8,28.3,28.1,27.5,22.8,14.4,14.2,13.0,6.8,4.8;HRMS(ESI)calculated for C37H73NO8SiNa+[M+Na]+:710.4998,found710.5000.
中间体化合物12a′的合成:
与上述化合物12a的合成步骤相同。快速柱色谱洗脱:石油醚/乙酸乙酯=9/1;产率:60%三步;无色油状液体;[α]20 D=-43.2(c=1.0,CHCl3);νmax(KBr):3443,3342,2952,2926,2855,1743,1723,1502,1466,1366,1253,1168,1132,988,839cm-1;1H NMR(400MHz,CDCl3)δ6.31(1H,d,J=8.0Hz),5.25(1H,d,J=9.8Hz),5.16(1H,dd,J=9.5,2.0Hz),4.99(1H,d,J=1.7Hz),4.69(1H,dd,J=9.8,1.8Hz),4.05-3.97(1H,m),3.73(3H,s),3.75-3.63(4H,m),2.33(1H,m),1.81-1.65(2H,br),1.52-1.45(1H,m),1.45(9H,s),1.25(22H,m),1.18-1.12(2H,m),1.09(3H,d,J=6.9Hz),0.93(9H,t,J=7.9Hz),0.89-0.84(18H,m),0.65-0.57(6H,m),0.06(3H,s),0.05(3H,s);13C NMR(100MHz,CDCl3)δ173.9,171.7,168.3,156.6,80.8,79.5,71.2,62.5,57.6,52.9,52.6,44.1,39.2,34.0,33.4,30.1,28.4,28.1,27.6,26.0,22.8,18.3,14.1,12.5,6.8,4.7,-5.3,-5.4;HRMS(ESI)calculated forC46H92N2O10Si2Na+[M+Na]+:911.6183,found 911.6185.
化合物2a′的合成:
与上述化合物2b的合成步骤相同。快速柱色谱洗脱:二氯甲烷/甲醇=30/1;产率:25%四步;白色固体;[α]20 D=-98.7(c=1.0,10%MeOH in CHCl3);νmax(KBr):3312,2923,2852,1734,1691,1602,1536,1493,1405,1366,1270,1078,970,844cm-1;1H NMR(400MHz,DMSO-d6)δ8.37(1H,d,J=10.0Hz),7.79(1H,d,J=9.0Hz),6.74(1H,dd,J=14.9,2.5Hz),5.98(1H,d,J=4.4Hz),5.96(1H,d,J=12.0Hz),5.12(1H,d,J=10.6Hz),4.88(1H,t,J=4.4Hz),4.86(1H,d,J=9.0Hz),4.47-4.37(3H,br),3.68(1H,d,J=18.2Hz),3.58(3H,s),3.39-3.35(1H,m),2.94(3H,s),2.87-2.78(1H,m),1.70-1.63(1H,m),1.55-1.45(1H,m),1.36-1.12(24H,br),1.01(3H,d,J=6.9Hz),0.93(3H,d,J=6.8Hz),0.84(6H,d,J=6.6Hz);13C NMR(100MHz,DMSO-d6)δ173.0,171.7,168.4,168.0,165.7,143.7,118.5,78.1,71.6,63.1,54.8,52.0,51.9,51.2,41.4,38.5,36.5,33.4,29.4,29.1,27.4,27.0,22.6,16.0,13.2;HRMS(ESI)calculated for C34H59N3O9Na+[M+Na]+:676.4144,found 676.4148.
实施例5:化合物2d的合成
中间体化合物9d的合成:
与上述化合物9a的合成步骤相同。快速柱色谱洗脱:石油醚/乙酸乙酯=9/1;产率:75%;无色油状液体;[α]20 D=-1.5(c=1.0,CHCl3);νmax(KBr):3531,3450,2955,2925,2879,2854,1761,1724,1501,1464,1361,1343,1271,1209,1168,1136,1063,1005,854cm-1;1H NMR(400MHz,CDCl3)δ5.27(1H,d,J=10.1Hz),4.78(1H,s),4.74(1H,d,J=9.9Hz),4.31(1H,dd,J=10.7,5.9Hz),4.23(1H,dd,J=10.8,3.6Hz),3.73(3H,s),3.33-3.26(1H,m),1.96-1.85(1H,m),1.76(1H,s),1.62-1.48(2H,m),1.42(9H,s),1.35-1.22(22H,br),0.94-0.82(21H,m),0.62-0.54(6H,m);13C NMR(100MHz,CDCl3)δ171.1,170.3,155.7,80.2,75.6,72.3,68.9,57.4,52.5,39.2,36.4,34.7,34.5,32.0,30.1,29.8,29.5,28.3,28.1,27.5,27.5,22.8,14.2,12.2,6.7,4.6;HRMS(ESI)calculated for C36H71NO8SiNa+[M+Na]+:696.4841,found 696.4845.
化合物10d的合成:
与上述化合物10b的合成步骤相同。快速柱色谱洗脱:石油醚/乙酸乙酯=9/1;产率:52%;无色油状液体;[α]20 D=-13.0(c=0.8,CHCl3);νmax(KBr):3455,2956,2926,2879,2855,1761,1723,1502,1464,1367,1271,1209,1169,1064,1007,985,854cm-1;1HNMR(400MHz,CDCl3)δ5.29(1H,d,J=9.7Hz),4.86(1H,dd,J=9.8,2.2Hz),4.79(1H,d,J=1.7Hz),4.71(1H,dd,J=9.8,1.8Hz),3.74(3H,s),3.58-3.40(2H,m),2.40-2.20(1H,brs),1.89-1.81(1H,m),1.75-1.65(1H,s),1.54-1.45(1H,m),1.42(9H,s),1.25-1.10(22H,m),1.02-0.82(21H,m),0.68-0.57(6H,m);13C NMR(100MHz,CDCl3)δ171.5,171.2,155.7,80.4,80.1,72.1,64.2,57.5,52.5,39.2,37.0,34.2,33.9,30.1,29.8,29.8,28.4,28.1,27.6,27.5,22.8,14.3,13.0,6.8,4.9;HRMS(ESI)calculated for C36H71NO8SiNa+[M+Na]+:696.4841.found 696.4843.
中间体化合物12d的合成:
与上述化合物12b的合成步骤相同。快速柱色谱洗脱:石油醚/乙酸乙酯=9/1;产率:48%三步;无色油状液体;[α]20 D=+5.4(c=1.0,CHCl3);νmax(KBr):3442,3312,2953,2926,2879,2855,2737,1760,1722,1656,1503,1465,1366,1341,1255,1168,1063,1007,922,839cm-1;1H NMR(400MHz,CDCl3)δ6.31(1H,d,J=7.3Hz),5.64(1H,d,J=9.7Hz),4.95(1H,dd,J=8.0,4.0Hz),4.73(1H,d,J=2.3Hz),4.69(1H,dd,J=9.7,2.4Hz),3.96-3.90(1H,m),3.87-3.82(1H,m),3.74(3H,s),3.73-3.60(4H,m),3.10(1H,s),2.80-2.70(1H,m),1.85-1.81(m,1H),1.53-1.48(1H,m),1.42(9H,s),1.24(20H,m),1.14(2H,m),1.11(3H,d,J=8.9Hz),0.93(9H,t,J7.9Hz),0.89-0.84(18H,m),0.66-0.56(6H,m),0.07(3H,s),0.06(3H,s);13C NMR(100MHz,CDCl3)δ173.2,171.5,169.7,155.7,80.6,80.5,72.2,62.7,62.5,57.4,52.5,52.4,43.9,39.2,34.8,33.4,30.1,29.7,28.4,28.1,27.6,26.9,26.0,22.8,18.3,15.0,14.6,6.8,5.0,-5.4;HRMS(ESI)calculated for C45H90N2O10Si2Na+[M+Na]+:897.6026,found 897.6032.
化合物2d的合成
与上述化合物2b的合成步骤相同。快速柱色谱洗脱二氯甲烷/甲醇=30/1;yield:30%for four steps;white solid;[α]20 D=+5.4(c=1.0,5%MeOH in CHCl3);νmax(KBr):3423,3105,2960,2925,2854,1737,1728,1681,1660,1602,1525,1464,1405,1368,1337,1263,1100,1023,836cm-1;1H NMR(400MHz,DMSO-d6)δ8.79(1H,d,J=9.8Hz),7.13(1H,d,J=9.2Hz),6.53-6.44(2H,m),6.03(1H,dd,J=15.6,1.6Hz),5.03(1H,dd,J=9.7,1.6Hz),4.95(1H,t,J=5.9Hz),4.87(1H,dd,J=8.9,3.9Hz),4.78(1H,dd,J=4.9,2.5Hz),4.74-4.64(1H,m),4.19(1H,d,J=17.1Hz),3.71(1H,d,J=17.1Hz),3.64(3H,s),3.47-3.39(1H,m),2.96(3H,s),2.84-2.74(1H,m),1.56-1.43(2H,m),1.30-1.14(22H,m),1.09(3H,d,J=7.2Hz),0.83(6H,d,J=6.6Hz),0.63(3H,d,J=6.6Hz);13C NMR(100MHz,DMSO-d6)δ171.8,171.0,169.7,169.5,167.1,140.6,122.3,79.7,70.3,63.0,54.4,52.0,51.6,38.5,35.6,35.0,29.4,29.1,27.4,26.8,25.8,22.6,15.1,13.4;HRMS(ESI)calculatedfor C33H57N3O9Na+[M+Na]+:662.3987,found 662.3992.
实施例6化合物2e的合成
化合物9e的合成:
与上述化合物9a的合成步骤相同。快速柱色谱洗脱:石油醚/乙酸乙酯=10/1;产率:83%;无色油状液体;[α]20 D=+3.2(c=1.0,CHCl3);νmax(KBr):3450,2956,2925,2879,2854,1761,1724,1499,1464,1387,1368,1266,1206,1167,1136,1063,1005,855cm-1;1HNMR(400MHz,CDCl3)δ5.28(1H,d,J=9.8Hz),4.79(1H,d,J=1.5Hz),4.75(1H,d,J=9.8Hz),4.32(1H,dd,J=10.8,5.9Hz),4.23(1H,dd,J=10.8,3.7Hz),3.74(3H,s),3.34-3.27(1H,m),1.97-1.86(1H,m),1.73(1H,s),1.64-1.56(1H,m),1.56-1.47(1H,m),1.43(9H,s),1.25(22H,br),0.98-0.81(21H,m),0.64-0.54(6H,m);13C NMR(100MHz,CDCl3)δl71.2,170.4,155.8,80.3,75.7,72.4,69.0,57.5,52.6,39.3,36.5,34.8,34.6,30.2,29.9,28.4,28.2,27.6,27.6,22.9,14.3,12.2,6.8,4.7;HRMS(ESI)calculated forC36H71NO8SiNa+[M+Na]+:696.4841,found 696.4845.
化合物10e的合成:
与上述化合物10a的合成步骤相同。快速柱色谱洗脱:石油醚/乙酸乙酯=10/1;产率:65.6%;无色油状液体;[α]20 D=+12.0(c=0.5,CHCl3);νmax(KBr):3454,2954,2926,2879,2855,1761,1723,1498,1462,1367,1257,1210,1167,1136,1062,988,855cm-1;1H NMR(400MHz,CDCl3)δ5.30(1H,d,J=9.7Hz),4.87(1H,dd,J=9.8,2.3Hz),4.80(1H,d,J=1.8Hz),4.72(1H,dd,J=9.8,1.9Hz),3.75(3H,s),3.58-3.50(1H,m),3.48-3.42(1H,m),2.36-2.29(1H,m),1.90-1.81(1H,m),1.78-1.69(1H,brs),1.56-1.46(1H,m),1.43(9H,s),1.25-1.10(21H,m),1.02-0.82(21H,m),0.68-0.59(6H,m);13C NMR(100MHz,CDCl3)δ171.6,171.3,155.7,80.5,80.1,72.2,64.3,57.6,52.6,39.3,37.1,34.3,34.0,30.2,29.9,28.4,28.2,27.6,27.6,22.9,14.4,13.1,6.9,4.9;HRMS(ESI)calculated for C36H71NO8SiNa+[M+Na]+:696.4841,found 696.4843.
化合物12e的合成:
与上述化合物12a的合成步骤相同。快速柱色谱洗脱:石油醚/乙酸乙酯=8/1;产率:59.4%三步;无色油状液体;[α]20 D=-6.0(c=1.0,CHCl3);νmax(KBr):3451,3315,2953,2926,2879,2855,1761,1721,1652,1502,1464,1366,1341,1254,1168,1139,1063,1006,983,839cm-1;1H NMR(400MHz,CDCl3)δ6.31(1H,d,J=7.3Hz),5.64(1H,d,J=9.7Hz),4.95(1H,t,J=5.7Hz),4.73(1H,d,J=2.4Hz),4.69(1H,dd,J=9.7,2.4Hz),3.99-3.91(1H,m),3.89-3.81(1H,m),3.73(3H,s),3.73-3.62(4H,m),3.14-3.08(1H,m),2.81-2.69(1H,m),1.87-1.77(1H,m),1.54-1.47(1H,m),1.41(9H,s),1.24(20H,m),1.14(2H,m),1.11(d,J=10.1Hz,3H),0.97-0.81(18H,m),0.66-0.57(6H,m),0.07(3H,s),0.06(3H,s);13CNMR(100MHz,CDCl3)δ173.3,171.6,169.7,155.8,80.6,80.5,72.3,62.7,62.6,57.4,52.6,52.4,44.0,39.3,34.8,33.4,30.1,29.9,29.9,28.4,28.2,27.6,27.0,26.0,22.9,18.4,15.1,14.7,6.9,5.1,-5.3.HRMS(ESI)calculated for C45H90N2O10Si2Na+[M+Na]+:897.6026,found 897.6028.
化合物2e的合成:
与上述化合物2b的合成步骤相同。快速柱色谱洗脱:二氯甲烷/甲醇=25/1;产率:31.2%四步;白色固体;[α]20 D=-10.8(c=0.25,DMSO);νmax(KBr):3419,2926,2855,1741,1660,1536,1464,1404,1367,1269,1221,1147,1112,1044,977,838cm-1;1H NMR(400MHz,DMSO-d6)δ8.78(1H,d,J=9.6Hz),7.13(1H,d,J=9.2Hz),6.53-6.44(2H,d,J=17.9Hz),6.04(1H,d,J=15.5Hz),5.04(1H,d,J=9.7Hz),4.94(1H,t,J=5.3Hz),4.88(1H,d,J=5.9Hz),4.78(1H,s),4.75-4.63(1H,m),4.21(1H,d,J=17.0Hz),3.71(1H,d,J=17.0Hz),3.64(3H,s),3.48-3.41(1H,m),2.97(3H,s),2.84-2.75(1H,m),1.60-1.45(2H,m),1.36-1.14(22H,m),1.09(3H,d,J=6.4Hz),0.84(6H,d,J=6.3Hz),0.64(3H,d,J=5.7Hz);13CNMR(100MHz,DMSO-d6)δ171.9,171.1,169.8,169.6,167.2,140.7,122.3,79.8,70.4,63.1,54.4,52.1,38.6,35.7,35.1,29.4,29.1,27.5,26.9,26.6,25.9,22.6,15.2,13.4;HRMS(ESI)calculated for C33H57N3O9Na+[M+Naa+:662.3987,found 662.3990.
实施例7化合物1a的合成:
0℃条件下,向2a(83mg,0.130mmol)的四氢呋喃溶液(4.5mL)中加入三乙胺(36μL,0.260mmol)和甲磺酰氯(15μL,0.195mmol)。搅拌30分钟后加入水(0.1mL)淬灭,无水硫酸钠干燥,过滤,浓缩。所得粗品用10ml四氢呋喃溶解。20℃条件下,向溶液中加入DBU(195mg,1.30mmol)。搅拌2h后,加入1%HCl(15mL)淬灭。水相用乙酸乙酯(3×35mL)萃取。合并的有机相用食盐水(10mL)洗,无水硫酸钠干燥,浓缩。粗品用柱层析法(二氯甲烷/甲醇=20∶1)纯化后得到1a(48mg,60%for two steps)为白色固体。[α]20 D=-132.8(c=0.1,DMSO);νmax(KBr):3385,2924,2854,1727,1696,1652,1523,1464,1274,1109,977cm-1;1H NMR(400MHz,DMSO-d6)δ8.93(1H,s),8.38(1H,d,J=9.7Hz),6.85(1H,d,J=14.9Hz),6.20(1H,d,J=14.9Hz),6.03(1H,d,J=5.1Hz),5.42,(1H,s),5.35(1H,s),5.10(1H,d,J=10.4Hz),4.84(1H,d,J=9.7Hz),4.48(1H,d,J=18.9Hz),4.44(1H,s),3.71(1H,d,J=18.3Hz),3.56(3H,s),2.97(3H,s),2.96-2.86(1H,m),1.74-1.65(1H,m),1.53-1.42(1H,m),1.36-1.08(22H,br),1.04(3H,d,J=6.6Hz),0.94(3H,d,J=6.7Hz),0.83(6H,d,J=6.6Hz);13C NMR(100MHz,DMSO-d6)δ172.4,171.6,168.2,168.0,166.0,138.6,137.7,118.6,116.8,78.5,71.4,54.9,52.4,51.6,41.7,38.5,36.6,33.7,32.8,29.3,29.2,29.1,27.4,26.9,26.8,22.5,15.1,13.1;HRMS(ESI)calculated for:C33H55N3O8Na+[M+Na]+:644.3881,found644.3887.
实施例8化合物1a′的合成:
与上述化合物1a的合成步骤相同。快速柱色谱洗脱:二氯甲烷/甲醇=20/1;产率:33%两步;白色固体;[α]20 D=-93.3(c=0.2,DMSO);νmax(KBr):3466,3381,2923,2852,1741,1698,1672,1614,1524,1256,1213,1109,978,862cm-1;1H NMR(400MHz,DMSO-d6)δ8.93(1H,s),8.40(1H,d,J=9.6Hz),6.85(1H,d,J=15.0Hz),6.21(1H,d,J=14.7Hz),6.04(1H,d,J=5.1Hz),5.43(1H,s),5.35(1H,s),5.11(1H,d,J=9.9Hz),4.85(1H,d,J=8.8Hz),4.48(1H,d,J=18.1Hz),4.46(1H,d,J=8.8Hz),3.72(1H,d,J=18.1Hz),3.57(3H,s),2.97(3H,s),2.97-2.81(1H,m),1.74-1.66(1H,m),1.53-1.46(1H,m),1.38-1.05(24H,m),1.04(3H,d,J=6.4Hz),0.95(3H,d,J=6.5Hz),0.84(6H,d,J=6.4Hz).;13C NMR(100MHz,DMSO-d6)δ172.4,171.6,168.2,168.0,166.0,138.6,137.7,118.6,116.8,78.6,71.5,54.9,52.4,51.9,41.7,38.5,29.2,26.9,22.5;HRMS(ESI)calculated forC34H57N3O8Na+[M+Na]+:658.4038,found 658.4042.
实施例9化合物1b的合成:
与上述化合物1a的合成步骤相同。快速柱色谱洗脱:二氯甲烷/甲醇=20/1;产率:38%两步;白色固体;[α]20 D=+76.6(c=0.5,DMSO);νmax(KBr):3286,3103,2923,2853,1744,1722,1693,1672,1613,1526,1465,1376,1255,1213,1112,975,864cm-1;1H NMR(400MHz,DMSO-d6)δ8.91(1H,s),8.38(1H,d,J=9.8Hz),6.85(1H,d,J=15.0Hz),6.21(1H,d,J=15.0Hz),6.02(1H,d,J=5.5Hz),5.43,(1H,s),5.35(1H,s),5.11(1H,d,J=10.3Hz),4.85(1H,dd,J=9.8,1.7Hz),4.47(1H,d,J=18.2Hz),4.45(1H,s),3.72(1H,d,J=18.0Hz),3.57(3H,s),2.97(3H,s),2.96-2.86(1H,m),1.74-1.65(1H,m),1.53-1.42(1H,m),1.38-1.08(22H,br),1.04(3H,d,J=6.9Hz),0.95(3H,d,J=6.8Hz),0.84(6H,d,J=6.6Hz);13C NMR(100MHz,DMSO-d6)δ172.4,171.6,168.2,168.0,166.0,138.6,137.7,118.6,116.8,78.5,71.4,54.9,52.4,51.5,41.7,38.5,36.6,33.7,32.8,29.3,29.2,29.1,29.0,27.4,26.9,26.8,22.5,15.1,13.1;HRMS(ESI)calculated for:C33H55N3O8Na+[M+Na]+:644.3881,found 644.3885.
实施例10化合物1c的合成:
与上述化合物1a的合成步骤相同。快速柱色谱洗脱:二氯甲烷/甲醇=20/1;产率:51%两步;白色固体;[α]20 D=-48.0(c=0.1,DMSO);νmax(KBr):3281,3056,2925,2853,1730,1665,1611,1533,1464,1329,1180,1106,973cm-1;1H NMR(400MHz,DMSO-d6)δ8.89(1H,s),8.39(1H,d,J=9.8Hz),6.85(1H,d,J=14.9Hz),6.20(1H,d,J=14.9Hz),6.04(1H,d,J=5.2Hz),5.42,(1H,s),5.35(1H,s),5.08(1H,d,J=10.2Hz),4.85(1H,d,J=9.7Hz),4.52-4.42(2H,m),3.71(1H,d,J=18.2Hz),3.57(3H,s),3.11-2.91(1H,m),2.97(3H,s),1.81-1.70(1H,m),1.54-1.44(1H,m),1.33-1.09(22H,br),1.05(3H,d,J=6.7Hz),0.90(3H,d,J=6.9Hz),0.84(6H,d,J=6.6Hz);13C NMR(100MHz,DMSO-d6)δ172.4,171.6,168.4,168.0,166.0,138.6,137.7,118.6,116.8,80.1,71.4,54.8,52.4,51.8,41.3,38.5,36.6,33.8,29.3,29.3,29.2,29.1,28.8,27.4,27.0,26.8,22.5,16.1,15.0;HRMS(ESI)calculated for:C33H55N3O8Na+[M+Na]+:644.3881,found 644.3887.
实施例11化合物1d的合成:
与上述化合物1a的合成步骤相同。快速柱色谱洗脱:二氯甲烷/甲醇=20/1;产率:36%两步;白色固体;[α]20 D=-16.7(c=0.1,DMSO);νmax(KBr):3260,2923,2853,1741,1696,1613,1518,1464,1378,1262,1213,1143,1110,976,847cm-1;1H NMR(400MHz,DMSO-d6)δ8.70(1H,d,J=9.4Hz),8.39(1H,s),6.81(1H,d,J=15.4Hz),6.30(1H,s),6.04(1H,d,J=15.4Hz),5.45(1H,s),5.43(1H,s),5.00-4.88(2H,m),4.64(1H,d,J=4.3Hz),4.15(1H,d,J=17.6Hz),3.86(1H,d,J=17.6Hz),3.63(3H,s),2.95(3H,s),2.87-2.79(1H,m),1.60-1.54(1H,m),1.52-1.44(1H,m),1.32-1.12(22H,m),1.06(3H,d,J=7.2Hz),0.84(6H,d,J=6.6Hz),0.73(3H,d,J=6.6Hz);13C NMR(100MHz,DMSO-d6)δ171.7,171.3,169.3,169.0,166.8,138.0,137.6,120.7,116.0,78.8,69.8,54.1,52.6,51.9,43.0,38.9,38.5,35.6,34.8,32.2,29.5,27.4,26.8,26.1,22.5,22.1,14.5;HRMS(ESI)calculated forC33H55N3O8Na+[M+Na]+:644.3881,found644.3885.
实施例12化合物1e的合成:
与上述化合物1a的合成步骤相同。快速柱色谱洗脱:二氯甲烷/甲醇=30/1;产率:40.3%两步;白色固体;[α]20 D=+13.4(c=0.2,DMSO);νmax(KBr):3251,2925,2854,1741,1695,1662,1612,1517,1464,1398,1262,1213,1107,1018,978,804cm-1;1H NMR(400MHz,DMSO-d6)δ8.79(1H,d,J=9.6Hz),8.40(1H,s),6.81(1H,d,J=15.5Hz),6.35(1H,s),6.06(1H,d,J=15.5Hz),5.46(1H,s),5.42(1H,s),5.03-4.90(2H,m),4.64(1H,br),4.16(1H,d,J=17.6Hz),3.85(1H,d,J=17.6Hz),3.63(3H,s),2.95(3H,s),2.89-2.80(1H,m),1.61-1.53(1H,m),1.55-1.44(1H,m),1.40-1.34(1H,m),1.26-1.18(22H,m),1.12(3H,d,J=7.1Hz),0.84(6H,d,J=6.6Hz),0.73(3H,d,J=6.6Hz);13C NMR(100MHz,DMSO-d6)δ171.7,171.2,169.4,169.0,166.7,138.0,137.6,120.7,116.0,78.8,69.8,54.1,52.5,51.9,43.1,38.5,35.6,34.8,32.2,29.3,29.2,29.0,28.9,27.4,26.8,26.1,22.5,14.5,14.4;HRMS(ESI)calculated for C33H55N3O8Na+[M+Na]+:644.3881,found 644.3883.
实施例13:Rakicidin A衍生物的药理作用
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Rakicidin A衍生物,每一测试浓度5孔,置37℃、5%CO2饱和湿度条件下培养72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1Rakicidin A衍生物对各种癌细胞的抑制活性(IC50,μM)
其中K562、K562/G+分别表示慢性粒细胞白血病和耐伊马替尼慢性粒细胞白血病细胞株。
活性测试结果表明,筛选的化合物对受试细胞显示出抑制活性。因此测试化合物具有用于治疗癌症用途。
本发明的化合物、用途和方法已经通过具体的实施例进行了描述。本领域技术人员可以借鉴本发明的内容适当改变原料、工艺条件等环节来实现相应的其它目的,其相关改变都没有脱离本发明的内容,所有类似的替换和改动对于本领域技术人员来说是显而易见的,都被视为包括在本发明的范围之内。
Claims (3)
1.一种如下式(I)的化合物,
其中式(I)中,
n等于11或12;
2号,3号,14号,15号,16号碳原子的绝对构型为R或S。
2.根据权利要求1所述的化合物,优选为化合物1a、1a’、1b、1c、1d、1e。
3.权利要求1-2任一项所述的化合物在制备治疗癌症或治疗癌症的辅助药物中的药物中的用途,其中癌症为白血病、乳腺癌、前列腺癌、鼻咽癌、大肠癌、肺癌、肝癌、食道癌、胃癌、肠道癌、肾癌、口腔癌、何杰金淋巴癌、胰腺癌、直肠结肠癌、子官颈癌、非何杰金淋巴癌、神经胶质瘤、黑瘤、膀胱癌、卵巢癌、甲状腺癌或卡波西肉瘤。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610044635.0A CN106995481A (zh) | 2016-01-25 | 2016-01-25 | Rakicidin A衍生物,其药物组合物及其用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610044635.0A CN106995481A (zh) | 2016-01-25 | 2016-01-25 | Rakicidin A衍生物,其药物组合物及其用途 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN106995481A true CN106995481A (zh) | 2017-08-01 |
Family
ID=59428916
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610044635.0A Pending CN106995481A (zh) | 2016-01-25 | 2016-01-25 | Rakicidin A衍生物,其药物组合物及其用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN106995481A (zh) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108530379A (zh) * | 2018-03-27 | 2018-09-14 | 福建省微生物研究所 | 一种天然Rakicidins类化合物Rakicidin G及其提取方法 |
CN109956993A (zh) * | 2017-12-26 | 2019-07-02 | 天津尚德药缘科技股份有限公司 | Rakicidin衍生物,制备方法及其在制备抗癌药物中的用途 |
CN110437313A (zh) * | 2019-08-12 | 2019-11-12 | 福建省微生物研究所 | 一种Rakicidins酯化衍生物及其制备方法与应用 |
CN110698537A (zh) * | 2019-08-12 | 2020-01-17 | 福建省微生物研究所 | 一种天然Rakicidins类化合物Rakicidin B1-2及其发酵提取方法 |
CN110698541A (zh) * | 2019-08-12 | 2020-01-17 | 福建省微生物研究所 | 一种天然Rakicidins类化合物Rakicidin J及其发酵提取方法 |
CN111494641A (zh) * | 2020-04-22 | 2020-08-07 | 南开大学 | 肿瘤微环境响应性的表面电荷可反转纳米药物递送载体 |
-
2016
- 2016-01-25 CN CN201610044635.0A patent/CN106995481A/zh active Pending
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109956993A (zh) * | 2017-12-26 | 2019-07-02 | 天津尚德药缘科技股份有限公司 | Rakicidin衍生物,制备方法及其在制备抗癌药物中的用途 |
CN109956993B (zh) * | 2017-12-26 | 2023-03-28 | 新沂尚德药缘药业有限公司 | Rakicidin衍生物,制备方法及其在制备抗癌药物中的用途 |
CN108530379A (zh) * | 2018-03-27 | 2018-09-14 | 福建省微生物研究所 | 一种天然Rakicidins类化合物Rakicidin G及其提取方法 |
CN108530379B (zh) * | 2018-03-27 | 2021-08-31 | 福建省微生物研究所 | 一种天然Rakicidins类化合物Rakicidin G及其提取方法 |
CN110437313A (zh) * | 2019-08-12 | 2019-11-12 | 福建省微生物研究所 | 一种Rakicidins酯化衍生物及其制备方法与应用 |
CN110698537A (zh) * | 2019-08-12 | 2020-01-17 | 福建省微生物研究所 | 一种天然Rakicidins类化合物Rakicidin B1-2及其发酵提取方法 |
CN110698541A (zh) * | 2019-08-12 | 2020-01-17 | 福建省微生物研究所 | 一种天然Rakicidins类化合物Rakicidin J及其发酵提取方法 |
CN110698541B (zh) * | 2019-08-12 | 2023-04-14 | 福建省微生物研究所 | 一种天然Rakicidins类化合物Rakicidin J及其发酵提取方法 |
CN110698537B (zh) * | 2019-08-12 | 2023-05-12 | 福建省微生物研究所 | 一种天然Rakicidins类化合物Rakicidin B1-2及其发酵提取方法 |
CN111494641A (zh) * | 2020-04-22 | 2020-08-07 | 南开大学 | 肿瘤微环境响应性的表面电荷可反转纳米药物递送载体 |
CN111494641B (zh) * | 2020-04-22 | 2021-08-03 | 南开大学 | 肿瘤微环境响应性的表面电荷可反转纳米药物递送载体 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN106995481A (zh) | Rakicidin A衍生物,其药物组合物及其用途 | |
CN107531743B (zh) | 鹅去氧胆酸衍生物 | |
CN101990399B (zh) | 用作治疗剂的二羟基苯甲酸内酯的合成 | |
CN106243182B (zh) | 甘草次酸-硫化氢供体试剂衍生物及其合成方法和应用 | |
CN106496183A (zh) | 咖啡酸酯连接的大环内酯衍生物及其制备方法 | |
CN109956993B (zh) | Rakicidin衍生物,制备方法及其在制备抗癌药物中的用途 | |
CN106543076A (zh) | 制备阿伐斯汀的方法 | |
CA3147078A1 (en) | (2-acetamidyl)thio-beta-d-galactopyranoside derivatives | |
CN104072578B (zh) | 天然产物Tubulysin U的制备方法 | |
CN108137644B (zh) | 一种具有抗肿瘤作用的化合物及其制备方法和应用 | |
WO2012139522A1 (zh) | 去氢木香烃内酯衍生物,其药物组合物及其制备方法和用途 | |
CN106916147A (zh) | 化合物及其制备方法和用途 | |
CN106146535A (zh) | 一种依维莫司的制备方法 | |
CN109053839A (zh) | 核苷修饰物3’-O-CH2N3-2’-O-Me-胞嘧啶核苷的新型制备方法 | |
JP4502338B2 (ja) | タキソイド化合物の製造法 | |
WO2022062401A1 (zh) | 一种泰格列净的制备方法 | |
CN102659657B (zh) | 一种蛋白酶抑制剂pf429242的合成方法 | |
CN108530515A (zh) | 天然产物be-43547环状母核的制备方法 | |
CN108440395A (zh) | 一种米力农杂质的制备方法 | |
KR100868116B1 (ko) | 도세탁셀·모노프로필렌글라이콜 내포화합물 및 이의제조방법 | |
CN104098594B (zh) | 生物素-鬼臼毒素酯化衍生物及其药物组合物和其制备方法与应用 | |
CN107056753A (zh) | 一种兰索拉唑粗品精制方法 | |
ES2287310T3 (es) | Derivados de c-2' metilados de paclitaxel para usar como agentes antitumorales. | |
CN116143758B (zh) | 一类氮杂黄酮类靶向蛋白嵌合体及其在制备抗肿瘤药物中的应用 | |
TWI744448B (zh) | 甘草酸及半乳糖醛酸甘草酸之製造方法與該製造方法中所使用之中間體 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20170801 |
|
WD01 | Invention patent application deemed withdrawn after publication |