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CN113372405B - 一种akba衍生物及其制备方法和应用 - Google Patents

一种akba衍生物及其制备方法和应用 Download PDF

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CN113372405B
CN113372405B CN202110527666.2A CN202110527666A CN113372405B CN 113372405 B CN113372405 B CN 113372405B CN 202110527666 A CN202110527666 A CN 202110527666A CN 113372405 B CN113372405 B CN 113372405B
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范培红
李长昊
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Abstract

本发明提供一种AKBA衍生物，其具有式Ⅰ或式Ⅱ所示的结构：
Figure DDA0003066446540000011
其中，R1选自：‑H或‑Ac；R2选自：环烷基、芳基、被至少一个甲基取代的芳基、C1～7直链或支链饱和烷基、
Figure DDA0003066446540000012
或

Description

一种AKBA衍生物及其制备方法和应用
技术领域
本发明涉及医药技术领域，具体涉及一种AKBA衍生物及其制备方法和应用。
背景技术
公开该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解，而不必然被视为承认或以任何形式暗示该信息构成已经成为本领域一般技术人员所公知的现有技术。
目前非传染性疾病是全球死亡的主要原因，其中肿瘤预计将成为21世纪全球死亡的主要原因。2018年，估计将有1810万新的癌症病例和960万癌症病例死亡。研究表明，肿瘤细胞的线粒体膜电位远大于正常细胞，随着人们对肿瘤细胞中线粒体的功能和结构变化的了解，化合物特异性地靶向至线粒体成为了药物开发的一个新的领域。
天然产物是发现抗肿瘤活性化合物的宝库。研究表明AKBA具有广谱的抗肿瘤活性，在体外和体内均能抑制癌细胞的生长，其作用机制涉及G0/G1细胞周期阻滞、诱导细胞凋亡、抑制自噬和增强耐药细胞敏感性等各个方面。但由于其本身水溶性较差，其抗肿瘤活性相比于上市抗肿瘤药物较弱，修饰AKBA以制备具有更好的潜在抗肿瘤活性的衍生物一直是相关领域研究热点。
发明内容
针对现有技术中存在的技术问题，本发明的目的是提供一种AKBA衍生物及其制备方法和应用，本发明中提供的AKBA衍生物相较于AKBA具有更强的抗肿瘤活性的同时对正常细胞的毒性降低，具有作为抗肿瘤药物的潜力。
本发明的设计思路：AKBA具有广谱的抗肿瘤活性，在体外和体内均能抑制癌细胞的生长，其作用机制涉及G0/G1细胞周期阻滞、诱导细胞凋亡、抑制自噬和增强耐药细胞敏感性等各个方面。本发明在设计AKBA衍生物时，主要以增强抗肿瘤活性及选择性为基本出发点为基本出发点，研究设计、合成了如下式所示的AKBA衍生物。
为了实现上述目的，本发明的技术方案如下所述：
在本发明的第一方面，提供一种AKBA衍生物，具有式Ⅰ或式Ⅱ所示的结构：
Figure BDA0003066446530000021
其中，R1选自：-H或-Ac；
R2选自：环烷基、芳基、被至少一个甲基取代的芳基、C1～7直链或支链饱和烷基、
Figure BDA0003066446530000022
n为1-10的整数。
在本发明的某些实施方式中，所述的AKBA衍生物，其具有式A、式K、式Br、式P、式DKB所示结构：
Figure BDA0003066446530000023
优选的，R2选自：三元环烷基、六元环烷基；苯基、
Figure BDA0003066446530000024
C5～7直链或支链饱和烷基；
优选的，n为1-10的整数，进一步优选为1，3，4，6，9；
进一步优选的，所述C5～7直链或支链饱和烷基选自：
Figure BDA0003066446530000031
优选的，所述AKBA衍生物选自下列化合物：
Figure BDA0003066446530000032
Figure BDA0003066446530000041
发明人在本发明的研究过程中研究了结构变化对于抗肿瘤活性以及对于正常细胞毒性的影响，结果发现：
1)A环(左面第一个环为A环，即存在酯基的环)引入不饱和酮时，脱羧基/羧基连接乙二胺，活性未明显提高；
2)乙二胺衍生物系列(式A，式K)化合物整体来看，3位酯基(R1)水解后活性有所下降；含3-位乙酰基的式A系列，取代基R2为三元环(A-1)时，抗肿瘤活性及选择性较好；3-位乙酰基水解的式K系列，对苯甲基取带较苯基活性明显提高；脂肪族酰基类，随着碳链(6-8)变长活性有所增强；
3)溴代产物(式Br系列)，碳链偏短或偏长都会导致活性下降，五碳/六碳活性较好，11个碳的化合物Br-5活性基本丧失；三苯基膦产物(式P系列)，碳链较长时(八碳以上)，显现较好活性，11碳的化合物P-5活性最优，对A549细胞杀伤提高了20倍；
4)化合物均对不同肿瘤细胞无明显选择性。AKBA对肿瘤细胞与正常细胞的细胞毒性无明显差异，所合成的化合物，除含三元环的取代基的A-1，三苯基磷衍生物P-5外，相比肿瘤细胞，一般对正常细胞有更强的细胞毒性。
在本发明的第二方面，提供了一种制备第一方面中所述的AKBA衍生物的方法，其包括：以AKBA为起始原料，使AKBA的C-24羧基进行酰胺化反应，得中间体化合物A-N-B，然后将中间体化合物与对应酰氯，生成式A衍生物并对其进行水解生成式K衍生物；将A-N-B与对应碳链的溴代羧酸生成中间体式Br衍生物，并将其与三苯基磷相连得到产物式P衍生物；对C-24羧基进行苄酯保护，随后进行氧化，脱羧得到式DKB衍生物。
在本发明提供的一些实施方式中，所述方法通过如下反应路线实现：
Figure BDA0003066446530000051
Figure BDA0003066446530000061
在本发明的一些实施方式中，中间体A-N-B及式Br-1～5酰胺化反应的缩合剂选自O-(7-氮杂苯并三唑-1-基)-N，N，N，N-四甲基脲六氟磷酸酯(HATU)，N,N-二异丙基乙胺(DIPEA)；
在本发明的一些实施方式中，式A-1～8酰胺化反应选取相应酰氯，加入三乙胺做催化剂，酯水解反应条件选取为室温条件下甲醇做溶剂加入氢氧化钠，成盐反应的溶剂选自甲苯、N,N-二甲基甲酰胺、正丁醇和乙腈中的一种或多种，优选为乙腈，优选的，成盐反应在80-85℃加热回流条件下进行。
应当知晓，在本发明的披露下，本领域技术人员能够在本发明的基础上进一步优化反应条件，比如在本领域更多的常用的试剂中选择替代溶剂，比如根据本发明公开的物质用量在常规的调整中进一步扩大或缩小比例以获得更高的收率或减少杂质的产生，当然，还应当理解的是，每步反应后，本领域技术人员可选择对产物进行纯化的操作以使得下一步反应更加精准，常规的纯化方法都可以作为选择或者经过常规实验后加以选择。
在本发明的第三方面，提供了一种药物组合物，其包含第一方面中所述的AKBA衍生物。
本发明所述“组合物”指包括治疗有效量的规定成分的药物产品，以及直接或间接地由规定量的规定成分的组合产生的任何产品。
在本发明的第四方面，提供了一种药物制剂，其包含第一方面中所述AKBA衍生物和至少一种药学上可接受的载体或辅料。
本发明的AKBA衍生物或含有它的药物组合物或药物制剂可以单位剂量形式给药。给药剂型可以是液体剂型、固体剂型。液体剂型可以是真溶液类、胶体类、微粒剂型、乳剂剂型、混旋剂型。其他剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、栓剂、冻干粉针剂、包合物等。
本发明的药物组合或药物制剂中还可以含有常用的载体，这些载体包括但不局限于：离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白如人血清蛋白、缓冲物质(如磷酸盐、甘油、山梨酯、山梨酸钾、饱和植物脂肪酸的部分甘油酯混合物、水、盐)或电解质、硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶态氧化硅、三硅酸镁、聚乙烯吡咯烷酮、纤维素物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜂蜡、羊毛酯等。载体在药物组合物或药物制剂中的含量可以是1wt％-98wt％，通常大约占到80wt％。为方便起见，防腐剂、缓冲剂等可直接溶于载体中。
所述药学上可接受的辅料，包括但不限于赋形剂，所述赋形剂可以为粘合剂、填充剂、润滑剂、崩解剂、缓冲剂、稳定剂、防腐剂等等。所述辅料指药物组合物或药物制剂中除有效成分之外的成分，其对受试者无毒，且与药物活性成分可稳定共存或采用适当手段后稳定共存。
口服片剂和胶囊可以含有粘合剂，比如糖浆、阿拉伯胶、山梨醇、黄芪胶或聚乙烯吡咯烷酮；可以含有填充剂，比如乳糖、蔗糖、玉米淀粉、磷酸钙、山梨醇、氨基乙酸；可以含有润滑剂，如硬脂酸镁，滑石，聚乙二醇，硅土；可以含有崩解剂，如马铃薯淀粉，或可接受的增润剂，如月桂醇钠硫酸盐。片剂可以用制药学上公知的方法包衣。
口服液可以制成水和油的悬浮液，溶液，乳浊液，糖浆，也可以制成干品，用前补充水或其它合适的媒质。这种液体制剂可以包含常规的添加剂，如悬浮剂、山梨醇、纤维素甲醚、葡萄糖糖浆、凝胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶、氢化的食用油脂、乳化剂、如卵磷脂、山梨聚糖单油酸盐、阿拉伯树胶；或非水载体(可能包含可食用油)，如杏仁油、油脂如甘油、乙二醇、或乙醇；防腐剂，如对羟基苯甲酸甲酯或丙酯，山梨酸。如需要可添加调味剂或着色剂。
对于胃肠外投药，液态剂型通常由化合物和一种消毒的载体制成。载体首选水。依照所选载体和药物浓度的不同，化合物既可溶于载体中也可制成悬浮溶液，在制成注射用溶液时先将化合物溶于水中，过滤消毒后装入封口瓶或安瓿中。
在本发明的第五方面，提供了一种靶向线粒体的药物载体，其包含第一方面中所述的AKBA衍生物。
在本发明的实施方式中，经验证本发明的AKBA衍生物可以利用肿瘤细胞膜电位差异在肿瘤细胞线粒体内选择性地积聚，因而具有很好的肿瘤细胞线粒体靶向性。
在本发明的第六方面，提供了一种递药系统，其包含第一方面中所述的AKBA衍生物或第五方面中所述的靶向线粒体的药物载体。本发明的AKBA衍生物因其良好的对肿瘤细胞线粒体的靶向性，使得其能够作为递药系统或递药系统中的主要成分，可选择地将更多具有活性的药物递送至肿瘤细胞的线粒体内，实现良好的肿瘤治疗作用。
在本发明的第七方面，提供了第一方面中所述的AKBA衍生物或第三方面中所述的药物组合物或第四方面中所述药物制剂或第五方面中所述的靶向线粒体的药物载体或第六方面中所述的递药系统在制备抗肿瘤药物中的应用。
在本发明的实施方式中，所述肿瘤为肺癌或前列腺癌。
本发明还提供了一种治疗肿瘤的方法，其包括向受试者施用治疗有效剂量的第一方面中所述的AKBA衍生物或第三方面中所述的药物组合物或第四方面中所述药物制剂或第五方面中所述的靶向线粒体的药物载体或第六方面中所述的递药系统，所述肿瘤尤其指肺癌和前列腺癌，特别是肺癌；所述受试者是指已经是治疗、观察或实验的对象的动物，优选指哺乳动物，最优选指人。所述“治疗有效量”是指包括本发明化合物在内的活性化合物或药剂的量，该量可引起研究者、兽医、医生或其他医疗人员所追求的组织系统、动物或人的生物学或医学响应，这包括减轻或部分减轻受治疗的疾病、综合征、病症或障碍的症状。必须认识到，本发明所述活性成分的最佳给药剂量和间隔是由其性质和诸如给药的形式、路径和部位以及所治疗的特定哺乳动物等外部条件决定的，而这一最佳给药剂量可用常规的技术确定。同时也必须认识到，最佳的疗程，即同时化合物在额定的时间内每日的剂量，可用本领域内公知的方法确定。
本发明具有以下有益效果：本发明的AKBA衍生物能够靶向肿瘤细胞线粒体，与AKBA相比，具有对于肿瘤细胞更强的抑制活性，对正常细胞的毒性作用降低，能够有效地抑制肺癌细胞和前列腺癌细胞。本发明的AKBA衍生物具有被开发为抗肿瘤新药的潜力。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。本发明所使用的试剂或原料均可通过常规途径购买获得，如无特殊说明，本发明所使用的试剂或原料均按照本领域常规方式使用或者按照产品说明书使用。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
实施例1化合物A/K-1制备
取化合物AKBA(4.92mmol，2.52g)溶于30mL DMF中，滴加DIPEA(24.6mmol，4.05mL)冰水浴，加入HATU(9.87mmol，3.75g)搅拌10分钟后加入N-boc-ethylenediamine(14.7mmol，2.56mL)氮气保护反应12小时，TLC检测反应基本完成，加入200mL水，100mL乙酸乙酯萃取三次后合并有机层，经饱和碳酸氢钠(100mL)、盐酸水溶液(1N,100mL)、饱和食盐水洗后，有机层经无水硫酸钠干燥过滤，旋蒸浓缩，硅胶柱色谱法(乙酸乙酯：石油醚1：7～1：2)分离得到白色粉末(A-N-B)2.25g，产率为69.9％。
将化合物A-N-B(0.11mmol，73mg)溶于无水CH2Cl2(2mL)缓慢滴加TFA(1.5mL)冰浴反应30分钟后，TLC检测反应完全，减压去除溶剂，加入无水CH2Cl2(2mL)并滴加TEA(0.2mL)，冰浴条件下加入环丙基甲酰氯(0.22mmol，23mg)氮气保护，反应2小时后，TLC检测反应完全。加入盐酸溶液(1N,15mL)，乙酸乙酯(2×15mL)萃取，将有机相依次经饱和碳酸氢钠(30mL)与饱和食盐水(30mL)洗涤并经无水硫酸钠干燥，减压去除溶剂，硅胶柱色谱法(乙酸乙酯：石油醚1：5～1：1)分离得到白色固体(A-1)61mg，产率为87.8％。
将化合物A-1(0.06mmol，37mg)溶于甲醇(1mL)中，加入氢氧化钠溶液(4M,1mL)室温搅拌12小时后，TLC检测反应基本完成加入盐酸溶液(1M)调至中性，减压除去甲醇，加入10mL水与乙酸乙酯(2×10mL)萃取，合并有机层并经无水硫酸钠干燥，减压去除溶剂，经硅胶柱色谱法(乙酸乙酯：石油醚1：5～1：1)分离得到白色固体(K-1)29mg，产率为84.3％。合成路线如下：
Figure BDA0003066446530000091
波谱数据：
A-N-B:white solid.1H NMR(600MHz,CDCl3):δ6.35(s,1H,-NH-),5.55(s,1H,H-12),5.32(t,J＝2.5Hz,1H,H-3),4.89(s,1H,-NH-),3.44-3.24(m,4H,-NH-CH 2-CH 2-NH-),2.53(m,1H,H-1a),2.41(s,1H,H-9),2.35(m,1H,H-2a),2.10(m,1H,H-16a),2.08(s,3H,-COCH 3),1.89-1.48(m,11H,overlapped),1.44(s,9H,-Boc),1.40-1.36(m,2H),1.35(s,3H,H-27),1.25-1.21(m,2H),1.19(s,3H,H-23),1.14(s,3H,H-26),1.12(s,3H,H-25),1.01(m,1H),0.95(s,4H,H-20,H-30),0.82(s,3H,H-28),0.80(d,J＝6.4Hz,3H,H-29).13C NMR(150MHz,CDCl3):δ199.3(C-11),177.4(-CONH-),176.2(-CONH-),170.3(-COCH3),164.8(C-13),130.8(C-12),80.1(C-34),73.9,60.7,59.3,50.6,46.8,45.3,44.0,41.1,39.6(-NH-CH2-CH2-NH-),39.5(2C),37.6,35.2,34.2,33.4,31.1,29.1,28.6(3C),27.8,27.4,24.7,24.2,21.6,21.4,20.7,19.6,18.6,17.6,13.6.HR-ESI-MS m/z:677.4483(calcd forC39H62N2O6Na+[M+Na]+,677.4500)。
A-1:white solid.1H NMR(600MHz,CDCl3):δ7.00(s,1H,-NH-),6.59(s,1H,-NH-),5.54(s,1H,H-12),5.29(s,1H,H-3),3.51-3.31(m,4H,-NH-CH 2-CH 2-NH-),2.53-2.51(m,1H,H-1a),2.41(s,1H,H-9),2.37-2.32(m,1H,H-2a),2.12(m,1H,H-16a),2.08(s,3H,-COCH 3),1.91-1.20(m,16H,overlapped),1.34(s,3H,H-27),1.18(s,3H,H-23),1.12(s,3H,H-26),1.10(s,3H,H-25),1.02(m,1H),0.98(m,2H),0.95(s,4H,H-20,H-30),0.82(s,3H,H-28),0.79(d,J＝6.4Hz,5H,H-29).13C NMR(150MHz,CDCl3):δ199.4(C-11),177.0(-CONH-),175.9(-CONH-),170.5(-COCH3),165.1(C-13),130.7(C-12),73.7,60.6,59.2,50.5,46.8,45.2,44.0,41.1(C-22,-NHCH2-),40.2(-NHCH2-),39.5(2C),37.6,35.1,34.2,33.3,31.1,29.1,27.7,27.4,24.6,24.2,21.6,21.3,20.7,19.5,18.6,17.6,14.7 13.5,7.9,7.8.HR-ESI-MS m/z:645.4218(calcd for C38H58N2O5Na+[M+Na]+,645.4238)。
K-1:white solid.1H NMR(600MHz,CDCl3):δ6.46(t,J＝5.3Hz,1H,-NH-),6.37(t,J＝4.4Hz,1H,-NH-),5.53(s,1H,H-12),4.06(s,1H,H-3),3.52-3.27(m,4H,-NH-CH 2-CH 2-NH-),2.48(dt,J＝13.2,3.6Hz,1H,H-1a),2.42(s,1H,H-9),2.38(m,1H,H-2a),2.12-2.04(m,1H,H-16a),2.49-1.32(m,14H,overlapped),1.30(s,3H,H-27),1.26-1.24(m,1H),1.23(s,3H,H-23),1.21-1.19(m,1H),1.16(s,3H,H-26),1.09(s,3H,H-25),1.02(m,1H),0.96-0.93(m,6H,H-20,H-30),0.81(s,3H,H-28),0.78(d,J＝6.5Hz,2H,H-29),0.75-0.73(m,2H).13C NMR(150MHz,CDCl3):δ199.6(C-11),177.9(-CONH-),175.4(-CONH-),165.1(C-13),130.7(C-12),70.9,60.8,59.3,49.0,47.6,45.3,44.0,41.2(-NHCH2-),41.1,39.9(-NHCH2-),39.5(2C),37.7,34.5,34.2,33.4,31.1,29.1,27.7,27.4,26.8,25.1,21.3,20.7,19.6,18.5,17.6,14.8,13.7,7.5.HR-ESI-MS m/z:603.4110(calcd for C36H56N2O4Na+[M+Na]+,603.4132)。
实施例2化合物A/K-2制备
根据实施例1的方法，按如下合成路线选择原料制备得到A-2和K-2。
合成路线如下：
Figure BDA0003066446530000111
波谱数据：
A-2:white solid.1H NMR(600MHz,CDCl3):δ7.32(s,1H,-NH-),6.76(s,1H,-NH-),5.52(s,1H,H-12),5.28(s,1H,H-3),3.47-3.29(m,4H,-NH-CH 2-CH 2-NH-),2.51-2.49(m,1H,H-1a),2.39(s,1H,H-9),2.22(m,1H,-COCH-),2.33(m,1H,H-2a),2.07(m,1H,H-16a),2.06(s,3H,-COCH 3),1.89-1.18(m,25H,overlapped),1.33(s,3H,H-27),1.16(s,3H,H-23),1.11(s,3H,H-26),1.07(s,3H,H-25),1.02-0.99(m,1H),0.93(s,4H,H-20,H-30),0.80(s,3H,H-28),0.78(d,J＝6.4Hz,3H,H-29).13C NMR(150MHz,CDCl3):δ199.4(C-11),178.8(-CONH-),177.2(-CONH-),170.4(-COCH3),165.1(C-13),130.6(C-12),73.7,60.6,59.2,50.5,46.7,45.2,45.0(-COCH-),44.0,41.1,40.8(-NHCH2-),40.4(-NHCH2-),39.5,39.4,37.5,35.0,34.1,33.2,31.1,29.7,29.6,29.0,27.7,27.3,25.7(2C),24.5,24.2,21.6,21.3,21.2,20.6,19.4,18.5,17.6,13.4.HR-ESI-MS m/z:687.4701(calcd forC41H64N2O5Na+[M+Na]+,687.4707)。
K-2:white solid.1H NMR(600MHz,CDCl3):δ6.92(s,1H,-NH-),6.66(s,1H,-NH-),5.51(s,1H,H-12),4.06(s,1H,H-3),3.45-3.32(m,4H,-NH-CH 2-CH 2-NH-),2.46-2.43(m,1H,H-1a),2.41(s,1H,H-9),2.33(m,1H,-COCH-),2.14(m,1H,H-2a),2.06(m,1H,H-16a),1.87-1.17(m,25H,overlapped),1.29(s,3H,H-27),1.16(s,3H,H-23),1.23(s,3H,H-26),1.15(s,3H,H-25),1.01(m,1H),0.92(s,4H,H-20,H-30),0.79(s,3H,H-28),0.77(d,J＝6.4Hz,3H,H-29).13C NMR(150MHz,CDCl3):δ199.8(C-11),178.5(-CONH-),178.4(-CONH-),165.3(C-13),130.6(C-12),70.6,60.7,59.2,50.9,49.0,47.6,45.3(2C),44.0,41.1,40.9(-NHCH2-),40.1(-NHCH2-),39.4(2C),37.6,34.4,34.1,33.3,31.1,29.8,29.7,29.0,27.7,27.3,26.8,25.8(3C),25.2,20.7,19.5,18.5,17.6,13.7.HR-ESI-MS m/z:623.4767(calcdfor C39H63N2O4 +[M+H]+,623.4782)。
实施例3化合物A/K-3制备
根据实施例1的方法，按如下合成路线选择原料制备得到A-3和K-3。
合成路线如下：
Figure BDA0003066446530000121
波谱数据：
A-3:white solid.1H NMR(400MHz,CDCl3):δ7.80(d,J＝7.3Hz,2H),7.66(s,1H,-NH-),7.42(m,3H),6.64(s,1H,-NH-),5.49(s,1H,H-12),5.30(s,1H,H-3),3.64-3.34(m,4H,-NH-CH 2-CH 2-NH-),2.49-2.45(m,1H,H-1a),2.36(s,1H,H-9),2.32(m,1H,H-2a),2.06(m,1H,H-16a),2.04(s,3H,-COCH 3),1.84-1.14(m,15H,overlapped),1.30(s,3H,H-27),1.08(s,3H,H-23),1.04(s,3H,H-26),1.02(s,3H,H-25),0.97(m,1H),0.91(s,4H,H-20,H-30),0.78(s,3H,H-28),0.76(d,J＝6.4Hz,3H,H-29).13C NMR(100MHz,CDCl3):δ199.3(C-11),177.2(-CONH-),170.4(-COCH3),168.8(-CONH-),165.1(C-13),133.8,131.8,130.6(C-12),128.7(2C),127.2(2C),73.7,60.5,59.1,50.4,46.7,45.1,43.9,41.0,40.8(-NHCH2-),40.4(-NHCH2-),39.4(2C),37.5,35.0,34.1,33.1,31.0,29.0,27.6,27.3,24.5,24.1,21.5,21.3,20.6,19.4,18.3,17.5,13.4.HR-ESI-MS m/z:681.4223(calcd forC41H58N2O5Na+[M+Na]+,681.4238)。
K-3:white solid.1H NMR(600MHz,CDCl3):δ7.79(d,J＝8.5Hz,2H),7.48(t,J＝8.0Hz,1H,-NH-),7.42-7.37(m,3H),6.43(t,J＝4.9Hz,1H,-NH-),5.50(s,1H,H-12),4.08(s,1H,H-3),3.65-3.40(m,4H,-NH-CH 2-CH 2-NH-),2.45-2.43(m,1H,H-1a),2.39(s,1H,H-9),2.35(m,1H,H-2a),2.06(m,1H,H-16a),1.84-1.15(m,15H,overlapped),1.28(s,3H,H-27),1.21(s,3H,H-23),1.05(s,3H,H-26),1.04(s,3H,H-25),1.01-0.97(m,1H),0.92(s,4H,H-20,H-30),0.79(s,3H,H-28),0.76(d,J＝6.4Hz,3H,H-29).13C NMR(150MHz,CDCl3):δ199.6(C-11),178.5(-CONH-),168.7(-CONH-),165.2(C-13),133.9,131.8,130.6(C-12),128.8(2C),127.2(2C),70.8,60.6,59.2,48.9,47.5,45.2,44.0,41.1,40.8(-NHCH2-),40.6(-NHCH2-),39.4(2C),37.6,34.4,34.1,33.3,31.1,29.0,27.6,27.3,26.8,25.2,21.3,20.7,19.6,18.4,17.6,13.6.HR-ESI-MS m/z:617.4302(calcd for C39H57N2O4 +[M+H]+,617.4313)。
实施例4化合物A/K-4制备
根据实施例1的方法，按如下合成路线选择原料制备得到A-4和K-4。
合成路线如下：
Figure BDA0003066446530000131
波谱数据：
A-4:white solid.1H NMR(600MHz,CDCl3):δ6.64(s,1H,-NH-),6.50(s,1H,-NH-),5.52(s,1H,H-12),5.28(s,1H,H-3),3.52-3.23(m,4H,-NH-CH 2-CH 2-NH-),2.51-2.49(m,1H,H-1a),2.39(s,1H,H-9),2.36(m,1H,H-2a),2.07(m,2H,H-16a,-COCH-),2.06(s,3H,-COCH 3),1.84-1.18(m,23H,overlapped),1.33(s,3H,H-27),1.16(s,3H,H-23),1.09(s,3H,H-26),1.08(s,3H,H-25),1.02-0.97(m,1H),0.92(s,3H,H-30),0.88-0.83(m,7H,H-20,-CH2-CH 3),0.80(s,3H,H-28),0.76(d,J＝6.4Hz,3H,H-29).13C NMR(150MHz,CDCl3):δ199.4(C-11),178.1(-CONH-),176.6(-CONH-),170.3(-COCH3),165.0(C-13),130.6(C-12),73.8,60.6,59.2,50.4,47.6,46.6,45.2,43.9,41.8(-NHCH2-),41.0,39.6,39.5,39.4(-NHCH2-),37.5,35.3(2C),35.0,34.1,33.2,31.0,29.0,27.6,27.3,24.4,24.1,21.6,21.3,21.0(2C),20.6,19.3,18.5,17.6,14.3(2C),13.3.HR-ESI-MS m/z:703.5003(calcd forC42H68N2O5Na+[M+Na]+,703.5020)。
K-4:white solid.1H NMR(400MHz,CDCl3):δ6.54(s,1H,-NH-),6.38(s,1H,-NH-),5.52(s,1H,H-12),4.06(s,1H,H-3),3.51-328(m,4H,-NH-CH 2-CH 2-NH-),2.49-2.46(m,1H,H-1a),2.42(s,1H,H-9),2.38-2.34(m,1H,H-2a),2.11-2.03(m,2H),2.04(s,1H),1.90-1.24(m,23H,overlapped),1.30(s,3H,H-27),1.23(s,3H,H-23),1.16(s,3H,H-26),1.08(s,3H,H-25),1.01-0.97(m,1H),0.94(s,3H,H-30),0.87(t,J＝7.5Hz,7H,H-20,-CH2-CH 3),0.80(s,3H,H-28),0.78(d,J＝6.3Hz,3H,H-29).13C NMR(100MHz,CDCl3):δ199.6(C-11),178.1(-CONH-),171.9(-CONH-),165.0(C-13),130.7(C-12),70.9,60.7,59.3,49.0,47.7,47.5,45.3,44.0,41.5(-NHCH2-),41.1,39.8(-NHCH2-),39.5(2C),37.7,35.4,35.3,34.4,34.2,33.4,31.1,29.1,27.7,27.4,26.8,25.1,21.3,21.1,21.0,20.7,19.6,18.6,17.6,14.3,14.2,13.6.HR-ESI-MS m/z:661.4907(calcd for C40H67N2O4 +[M+H]+,661.4915)。
实施例5化合物A/K-5制备
根据实施例1的方法，按如下合成路线选择原料制备得到A-5和K-5。
合成路线如下：
Figure BDA0003066446530000141
波谱数据：
A-5:white solid.1H NMR(600MHz,CDCl3):δ:7.70(d,J＝7.9Hz,2H),7.21(d,J＝7.6Hz,2H),6.48(s,1H,-NH-),5.51(s,1H,H-12),5.32(s,1H,H-3),3.65-3.39(m,4H,-NH-CH 2-CH 2-NH-),2.50-2.48(m,1H,H-1a),2.37(s,4H,H-9,phenmethyl),2.33(m,1H,H-2a),2.07(m,1H,H-16a),2.06(s,3H,-COCH 3),1.87-1.17(m,15H,overlapped),1.32(s,3H,H-27),1.10(s,3H,H-23),1.05(s,3H,H-26),1.02(s,3H,H-25),1.00(m,1H),0.93(s,4H,H-20,H-30),0.80(s,3H,H-28),0.78(d,J＝6.4Hz,3H,H-29).13C NMR(150MHz,CDCl3):δ199.3(C-11),177.2(-CONH-),170.4(-COCH3),168.7(-CONH-),165.0(C-13),142.3,131.0,130.7(C-12),129.5(2C),127.2(2C),73.8,60.5,59.2,50.5,46.8,45.1,43.9,41.1(C-22,-NHCH2-),40.4(-NHCH2-),39.5(2C),37.6,35.0,34.2,33.2,31.1,29.0,27.7,27.3,24.6,24.1,21.6(2C),21.3(C-40),20.7,19.5,18.3,17.6,13.5.HR-ESI-MS m/z:695.4380(calcd for C42H60N2O5Na+[M+Na]+,695.4394)。
K-5:white solid.1H NMR(600MHz,CDCl3):δ7.76-7.65(m,2H),7.45(s,1H,-NH-),7.21(d,J＝7.5Hz,2H),6.59(s,1H,-NH-),5.50(s,1H,H-12),4.10(s,1H,H-3),3.62-3.38(m,4H,-NH-CH 2-CH 2-NH-),2.45-2.43(m,1H,H-1a),2.39(s,1H,H-9),2.37(s,3H,phenmethy),2.06-2.04(m,2H,H-2a,H-16a),1.82-1.15(m,15H,overlapped),1.27(s,3H,H-27),1.22(s,3H,H-23),1.03(s,3H,H-26),1.01(s,3H,H-25),1.00-0.98(m,1H),0.92(s,4H,H-20,H-30),0.78(s,3H,H-28),0.76(d,J＝6.4Hz,3H,H-29).13C NMR(150MHz,CDCl3):δ199.7(C-11),171.4(-CONH-),165.3(-CONH-),165.2(C-13),142.5,130.6,129.5(3C),127.3(2C),70.7,60.6,59.2,49.0,47.6,45.2,44.0,41.1,40.7(-NHCH2-CH2-NH-),39.4(2C),37.6,34.4,34.1,33.2,31.1,29.0,27.7,27.3,26.8,25.2,21.7,21.3,20.7,19.6,18.3,17.6,14.4.HR-ESI-MS m/z:653.4280(calcd for C40H59N2O4 +[M+H]+,653.4289)。
实施例6化合物A/K-6制备
根据实施例1的方法，按如下合成路线选择原料制备得到A-6和K-6。
合成路线如下：
Figure BDA0003066446530000151
波谱数据：
A-6:white solid.1H NMR(600MHz,CDCl3):δ6.61(s,1H,-NH-),5.53(s,1H,H-12),5.30(s,1H,H-3),3.47-3.35(m,4H,-NH-CH 2-CH 2-NH-),2.53-2.50(m,1H,H-1a),2.40(s,1H,H-9),2.33(m,1H,H-2a),2.25(m,2H,-COCH 2-),2.08(m,1H,H-16a),2.07(s,3H,-COCH 3),2.03-1.20(m,21H,overlapped),1.34(s,3H,H-27),1.18(s,3H,H-23),1.13(s,3H,H-26),1.09(s,3H,H-25),1.01(m,1H),0.94(s,4H,H-20,H-30),0.87(t,J＝6.7Hz,3H,-CH2-CH 3),0.81(s,3H,H-28),0.79(d,J＝6.4Hz,3H,H-29).13C NMR(151MHz,CDCl3):δ199.4(C-11),177.2(-CONH-),175.8(-CONH-),170.4(-COCH3),165.0(C-13),130.7(C-12),73.7,60.6,59.2,50.6,46.8,45.2,44.0,41.1,40.7(-NHCH2-),40.4(-NHCH2-),39.5(2C),37.6,36.3(-COCH2-),35.1,34.2,33.3,31.6,31.1,29.0,27.7,27.4,25.7,24.6,24.2,22.5,21.6,21.3,20.7,19.5,18.6,17.6,14.1(-CH2-CH3),13.5.HR-ESI-MS m/z:675.4703(calcd forC40H64N2O5Na+[M+Na]+,675.4707)。
K-6:white solid.1H NMR(600MHz,CDCl3):δ6.53(s,1H,-NH-),6.45(s,1H,-NH-),5.52(s,1H,H-12),4.06(s,1H,H-3),3.46-3.31(m,4H,-NH-CH 2-CH 2-NH-),2.47-2.45(m,1H,H-1a),2.42(s,1H,H-9),2.36(m,1H,H-2a),2.17(m,2H,-COCH 2-),2.06(m,1H,H-16a),1.88-1.17(m,21H,overlapped),1.29(s,3H,H-27),1.23(s,3H,H-23),1.16(s,3H,H-26),1.07(s,3H,H-25),0.99(m,1H),0.93(s,4H,H-20,H-30),0.87(t,J＝7.0Hz,3H,-CH2-CH 3),0.80(s,3H,H-28),0.77(d,J＝6.4Hz,3H,H-29).13C NMR(150MHz,CDCl3):δ199.7(C-11),178.1(-CONH-),175.2(-CONH-),165.3(C-13),130.6(C-12),70.8,60.6,59.2,48.9,47.5,45.2,44.0,41.1,40.9(-NHCH2-),39.8(-NHCH2-),39.4(2C),37.6,36.8(-COCH2-),34.4,34.1,33.3,31.6,31.1,29.0,27.7,27.3,26.8,25.6,25.2,22.6,21.3,20.7,19.5,18.5,17.6,14.1(-CH2-CH3),13.6.HR-ESI-MS m/z:611.4780(calcd for C38H63N2O4 +[M+H]+,611.4782)。
实施例7化合物A/K-7制备
根据实施例1的方法，按如下合成路线选择原料制备得到A-7和K-7。
合成路线如下：
Figure BDA0003066446530000161
波谱数据：
A-7:white solid.1H NMR(600MHz,CDCl3):δ6.97(s,1H,-NH-),6.62(s,1H,-NH-),5.51(s,1H,H-12),5.27(s,1H,H-3),3.42-3.28(m,4H,-NH-CH 2-CH 2-NH-),2.50-2.48(m,1H,H-1a),2.38(s,1H,H-9),2.32(m,1H,H-2a),2.18(t,J＝7.6Hz,2H,-COCH 2-),2.06(m,1H,H-16a),2.05(s,3H,-COCH 3),1.87-1.18(m,23H,overlapped),1.31(s,3H,H-27),1.15(s,3H,H-23),1.09(s,3H,H-26),1.06(s,3H,H-25),1.01-0.98(m,1H),0.91(s,4H,H-20,H-30),0.84(t,J＝6.7Hz,3H,-CH2-CH 3),0.79(s,3H,H-28),0.77(d,J＝6.4Hz,3H,H-29).13C NMR(151MHz,CDCl3):δ199.3(C-11),176.8(-CONH-),175.5(-CONH-),170.4(-COCH3),165.1(C-13),130.6(C-12),73.7,60.5,59.2,50.4,46.7,45.2,43.9,41.0(C-22,-NHCH2-),39.8(-NHCH2-),39.4(2C),37.5,36.6(-COCH2-),35.0,34.1,33.2,31.7,31.0,29.1,29.0,27.6,27.3,25.9,24.4,24.1,22.6,21.5,21.3,20.6,19.3,18.5,17.5,14.2(-CH2-CH3),13.4.HR-ESI-MS m/z:689.4854(calcd for C41H66N2O5Na+[M+Na]+,689.4864)。
K-7:white solid.1H NMR(600MHz,CDCl3):δ6.35(s,1H,-NH-),6.16(s,1H,-NH-),5.54(s,1H,H-12),4.08(s,1H,H-3),3.47-3.33(m,4H,-NH-CH 2-CH 2-NH-),2.51-2.48(m,1H,H-1a),2.43(s,1H,H-9),2.40(m,1H,H-2a),2.17(m,2H,-COCH 2-),2.08(m,1H,H-16a),1.90-1.17(m,23H,overlapped),1.31(s,3H,H-27),1.24(s,3H,H-23),1.17(s,3H,H-26),1.09(s,3H,H-25),0.99(m,1H),0.94(s,4H,H-20,H-30),0.87(t,J＝7.0Hz,3H,-CH2-CH 3),0.81(s,3H,H-28),0.79(d,J＝6.4Hz,3H,H-29).13C NMR(150MHz,CDCl3):δ199.6(C-11),177.9(-CONH-),175.0(-CONH-),165.1(C-13),130.7(C-12),70.9,60.7,59.2,49.0,47.5,45.3,44.0,41.1(C-22,-NHCH2-),39.9(-NHCH2-),39.5(2C),37.7,36.9(-COCH2-),34.4,34.2,33.4,31.8,31.1,29.2,29.1,27.7,27.3,26.8,25.9,25.2,22.7,21.3,20.7,19.6,18.6,17.6,14.3(-CH2-CH3),13.6.HR-ESI-MS m/z:647.4752(calcd for C39H64N2O4Na+[M+Na]+,647.4758)。
实施例8化合物A/K-8制备
根据实施例1的方法，按如下合成路线选择原料制备得到A-8和K-8。
合成路线如下：
Figure BDA0003066446530000171
波谱数据：
A-8:white solid.1H NMR(600MHz,CDCl3):δ8.16(s,1H,-NH-),6.81(s,1H,-NH-),5.54(s,1H,H-12),5.29(s,1H,H-3),3.52-3.38(m,4H,-NH-CH 2-CH 2-NH-),2.53-2.51(m,1H,H-1a),2.41(s,1H,H-9),2.38(m,2H,-COCH 2-),2.33(m,1H,H-2a),2.10(m,1H,H-16a),2.08(s,3H,-COCH 3),1.91-1.18(m,25H,overlapped),1.34(s,3H,H-27),1.18(s,3H,H-23),1.15(s,3H,H-26),1.08(s,3H,H-25),1.01(m,1H),0.94(s,4H,H-20,H-30),0.88(t,J＝6.4Hz,3H,-CH2-CH 3),0.82(s,3H,H-28),0.80(d,J＝6.4Hz,3H,H-29).13C NMR(150MHz,CDCl3):δ199.4(C-11),177.7(-CONH-),176.7(-CONH-),170.5(-COCH3),165.4(C-13),130.7(C-12),73.7,60.6,59.3,50.5,46.8,45.3,44.0,41.3(-NHCH2-),41.1,40.1(-NHCH2-),39.6,39.5,37.6,35.6(-COCH2-),35.1,34.2,33.2,31.5,31.1,29.1,27.7,27.4,25.8,25.7,24.6,24.2,22.5(2C),21.6,21.3,20.7,19.5,18.6,17.6,14.1(-CH2-CH3),13.5.HR-ESI-MS m/z:703.5007(calcd for C42H68N2O5Na+[M+Na]+,703.5020)。
K-8:white solid.1H NMR(400MHz,CDCl3):δ6.44(m,2H,-NH-),5.51(s,1H,H-12),4.05(s,1H,H-3),3.45-3.27(m,4H,-NH-CH 2-CH 2-NH-),2.48-2.44(m,1H,H-1a),2.41(s,1H,H-9),2.36(m,1H,H-2a),2.15(m,2H,-COCH 2-),2.06(m,1H,H-16a),1.89-1.15(m,25H,overlapped),1.29(s,3H,H-27),1.22(s,3H,H-23),1.15(s,3H,H-26),1.07(s,3H,H-25),0.98(m,1H),0.92(s,4H,H-20,H-30),0.85(t,J＝6.7Hz,3H,-CH2-CH 3),0.79(s,3H,H-28),0.77(d,J＝6.4Hz,3H,H-29).13C NMR(100MHz,CDCl3):δ199.6(C-11),178.0(-CONH-),175.0(-CONH-),165.1(C-13),130.7(C-12),70.8,60.7,59.2,48.9,47.5,45.2,44.0,41.1((C-22,-NHCH2-)),39.8(-NHCH2-),39.5(2C),37.7,36.9(-COCH2-),34.4,34.1,33.3,31.9,31.1,29.5,29.2,29.0,27.7,27.3,26.8,26.0,25.1,22.8,21.3,20.7,19.6,18.5,17.6,14.3(-CH2-CH3),13.6.HR-ESI-MS m/z:661.4905(calcd for C40H66N2O4Na+[M+Na]+,661.4915)。
实施例9化合物Br/P-1制备
取化合物A-N-B(0.16mmol，108mg)溶于2mL无水二氯甲烷中，缓慢滴加TFA(2mL)冰浴反应30分钟后，TLC检测反应完全，减压去除溶剂；取3溴丙酸(0.32mmol，49mg)溶于2mL无水二氯甲烷，滴加DIPEA(1.6mmol，0.3mL)冰水浴，加入HATU(0.62mmol，238mg)搅拌10分钟后加入水解掉保护基的A-N-B，氮气保护反应12小时TLC检测反应基本完成，加入二氯甲烷(20mL)，经饱和碳酸氢钠(20mL)、盐酸水溶液(1N,200mL)、饱和食盐水洗后，有机层经无水硫酸钠干燥过滤，旋蒸浓缩，硅胶柱色谱法(乙酸乙酯：石油醚1：4～1：1)分离得到白色粉末(Br-1)78mg，产率为68.6％。
取化合物Br-1(0.07mmol，50mg)和三苯基膦(0.21mmol，55mg)溶于3mL乙腈中，油浴80℃回流48小时，TLC检测反应基本完成，旋蒸浓缩，硅胶柱色谱法(二氯甲烷：甲醇1：60～1：20)分离得到白色粉末38mg，产率为55.1％。
合成路线如下：
Figure BDA0003066446530000181
波谱数据：
Br-1:white solid.1H NMR(600MHz,CDCl3):δ6.91(s,1H,-NH-),6.44(s,1H,-NH-),5.55(s,1H,H-12),5.30(s,1H,H-3),3.64(t,J＝6.4Hz,2H,-CH2Br),3.49-3.37(m,4H,-NH-CH 2-CH 2-NH-),2.80-1.21(m,21H,overlapped),2.08(s,3H,-COCH 3),1.34(s,3H,H-27),1.19(s,3H,H-23),1.14(s,3H,H-26),1.10(s,3H,H-25),1.03(m,1H),0.94(s,4H,H-20,H-30),0.82(s,3H,H-28),0.80(d,J＝6.3Hz,3H,H-29).13C NMR(150MHz,CDCl3):δ199.1(C-11),178.2(-CONH-),170.4(-CONH-,-COCH3),165.0(C-13),130.7(C-12),73.2,60.5,59.3,50.6,47.0,45.2,44.0,41.8,41.1,39.6,39.5,39.3,37.6,35.0,34.2(2C),33.3(2C),31.1,29.1,27.7,27.5,24.8,24.1,21.5,21.3,20.7,19.7,18.5,17.6,13.6.HR-ESI-MS m/z:711.3333(calcd for C37H57BrN2O5Na+[M+Na]+,711.3343)。
P-1:white solid.1H NMR(600MHz,CDCl3):δ8.85(s,1H,-NH-),7.82-7.70(m,15H),7.08(s,1H,-NH-),5.50(s,1H,H-12),5.31(s,1H,H-3),3.68-3.23(m,6H,-NH-CH 2-CH 2-NH-,-CH2Br),2.88-1.15(m,21H,overlapped),2.03(s,3H,-COCH 3),1.31(s,3H,H-27),1.20(s,3H,H-23),1.12(s,3H,H-26),1.06(s,3H,H-25),0.98(m,1H),0.93(s,4H,H-20,H-30),0.78(d,J＝6.5Hz,6H,H-28,H-29).13C NMR(150MHz,CDCl3):δ199.7(C-11),175.8(-CONH-),170.4(-COCH3),169.8(-CONH-),164.9(C-13),135.6,133.9,133.8,130.9,130.7(C-12),118.0,117.5,74.2,65.8,60.8,59.2,50.7,46.9,45.3,43.9,41.1,40.0,39.5,39.1,37.6,35.2,34.2,33.2,31.1,29.1,28.9,27.7,27.3,24.5,24.4,21.6,21.3,20.7,20.3,19.8,18.6,17.6,13.3.HR-ESI-MS m/z:871.5165(calcd for C55H72N2O5P+[M-Br]+,871.5173)。
实施例10化合物Br/P-2制备
根据实施例9的方法，按如下合成路线选择原料制备得到Br-2和P-2。
合成路线如下：
Figure BDA0003066446530000191
波谱数据：
Br-2:white solid.1H NMR(600MHz,CDCl3):δ6.45(s,1H,-NH-),6.37(s,1H,-NH-),5.54(s,1H,H-12),5.30(s,1H,H-3),3.48-3.28(m,6H,-NH-CH 2-CH 2-NH-,-CH2Br),2.54-1.21(m,25H,overlapped),2.08(s,3H,-COCH 3),1.34(s,3H,H-27),1.18(s,3H,H-23),1.12(s,3H,H-26),1.09(s,3H,H-25),1.03(m,1H),0.94(s,4H,H-20,H-30),0.82(s,3H,H-28),0.79(d,J＝6.4Hz,3H,H-29).13C NMR(150MHz,CDCl3):δ199.3(C-11),177.0(-CONH-),174.0(-CONH-),170.4(-COCH3),165.0(C-13),130.7(C-12),73.6,60.6,59.2,50.5,46.8,45.2,44.0,41.1,40.9,40.0,39.5(2C),37.6,35.6,35.1,34.2,33.3(2C),32.3,31.1,29.1,27.7,27.4,24.6,24.4,24.1,21.6,21.3,20.7,19.5,18.6,17.6,13.5.HR-ESI-MS m/z:637.4570(calcd for C39H61N2O5 +[M-Br]+,637.4570)。
P-2:white solid.1H NMR(600MHz,CDCl3):δ9.27(s,1H,-NH-),7.79-7.66(m,15H),7.31(s,1H,-NH-),5.49(s,1H,H-12),5.25(s,1H,H-3),3.68-3.20(m,6H,-NH-CH 2-CH 2-NH-,-CH2Br),2.60-1.14(m,25H,overlapped),2.02(s,3H,-COCH 3),1.30(s,3H,H-27),1.10(s,3H,H-23),1.06(s,3H,H-26),1.02(s,3H,H-25),0.96(m,1H),0.92(s,4H,H-20,H-30),0.77(d,J＝8.5Hz,6H,H-28,H-29).13C NMR(150MHz,CDCl3):δ199.7(C-11),175.6(-CONH-),174.3(-CONH-),170.5(-COCH3),165.0(C-13),135.4,133.8,133.7,130.7,130.6(C-12),118.4,117.9,74.2,60.7,59.1,50.6,46.6,45.2,43.9,41.1,40.9,39.4(2C),39.2,37.5,35.1,34.1,33.7,33.2,31.1,29.1,27.7,27.3,24.4,24.1,22.3,22.0,21.6,21.3,20.8,20.6,19.3,18.4,17.6,13.2.HR-ESI-MS m/z:899.5480(calcd for C57H76N2O5P+[M-Br]+,899.5486)。
实施例11化合物Br/P-3制备
根据实施例9的方法，按如下合成路线选择原料制备得到Br-3和P-3。
合成路线如下：
Figure BDA0003066446530000201
波谱数据：
Br-3:white solid.1H NMR(600MHz,CDCl3):δ7.68(s,1H,-NH-),6.68(s,1H,-NH-),5.53(s,1H,H-12),5.28(s,1H,H-3),3.48-3.34(m,6H,-NH-CH 2-CH2-NH-,-CH2Br),2.52-1.21(m,27H,overlapped),2.07(s,3H,-COCH 3),1.33(s,3H,H-27),1.17(s,3H,H-23),1.13(s,3H,H-26),1.08(s,3H,H-25),1.01(m,1H),0.93(s,4H,H-20,H-30),0.81(s,3H,H-28),0.79(d,J＝6.4Hz,3H,H-29).13C NMR(150MHz,CDCl3):δ199.4(C-11),177.3(-CONH-),175.4(-CONH-),170.5(-COCH3),165.3(C-13),130.6(C-12),73.6,60.5,59.2,50.5,46.8,45.2,44.0,41.1,40.5(2C),39.5(2C),37.5,35.9,35.0,34.2,33.7,33.2,32.5,31.1,29.1,27.9,27.7,27.4,25.1,24.6,24.1,21.6,21.3,20.7,19.5,18.6,17.6,13.4.HR-ESI-MS m/z:651.4723(calcd for C40H63N2O5 +[M-Br]+,651.4732)。
P-3:white solid.1H NMR(600MHz,CDCl3):δ8.46(s,1H,-NH-),7.81-7.68(m,15H),7.13(s,1H,-NH-),5.47(s,1H,H-12),5.26(s,1H,H-3),3.51-3.24(m,6H,-NH-CH 2-CH 2-NH-,-CH2Br),2.45-1.15(m,27H,overlapped),2.00(s,3H,-COCH 3),1.30(s,3H,H-27),1.13(s,6H,H-23,H-26),1.04(s,3H,H-25),0.97(m,1H),0.91(s,4H,H-20,H-30),0.78(s,3H,H-28),0.76(d,J＝6.4Hz,3H,H-29).13C NMR(150MHz,CDCl3):δ199.7(C-11),175.8(-CONH-),174.9(-CONH-),170.5(-COCH3),165.1(C-13),135.4,133.7,133.7,130.8,130.7,130.6(C-12),118.5,117.9,74.2,60.7,59.2,50.6,46.7,45.2,43.9,41.1,40.9,39.4,39.1,37.5,36.0,35.1,34.1,33.2,31.0,29.8,29.7,29.0,27.7,27.3,24.8,24.3,22.8,22.4,21.8,21.6,21.3,20.6,19.4,18.5,17.6,13.3.HR-ESI-MS m/z:913.5635(calcd forC58H78N2O5P+[M-Br]+,913.5643)。
实施例12化合物Br/P-4制备
根据实施例9的方法，按如下合成路线选择原料制备得到Br-4和P-4。
合成路线如下：
Figure BDA0003066446530000211
波谱数据：
Br-4:white solid.1H NMR(600MHz,CDCl3):δ6.84(s,1H,-NH-),6.52(s,1H,-NH-),5.53(s,1H,H-12),5.29(s,1H,H-3),3.45-3.31(m,6H,-NH-CH2-CH2-NH-,-CH2Br),2.52-1.20(m,31H,overlapped),2.07(s,3H,-COCH 3),1.33(s,3H,H-27),1.17(s,3H,H-23),1.13(s,3H,H-26),1.08(s,3H,H-25),1.00(m,1H),0.93(s,4H,H-20,H-30),0.81(s,3H,H-28),0.79(d,J＝6.4Hz,3H,H-29).13C NMR(150MHz,CDCl3):δ199.3(C-11),177.0(-CONH-),175.2(-CONH-),170.4(-COCH3),165.1(C-13),130.7(C-12),73.7,60.6,59.2,50.4,46.7,45.2,44.0,41.1,40.9,40.1,39.5,39.4,37.5,36.5,35.0,34.2,34.1,33.2,32.9,31.1,29.2,29.0,28.6,28.1,27.7,27.4,25.8,24.6,24.1,21.6,21.3,20.7,19.4,18.6,17.6,13.4.HR-ESI-MS m/z:781.4121(calcd for C42H67BrN2O5Na+[M+Na]+,781.4126)。
P-4:white solid.1H NMR(600MHz,CDCl3):δ7.82-7.69(m,15H),7.28(s,1H,-NH-),5.49(s,1H,H-12),5.27(s,1H,H-3),3.53-3.29(m,6H,-NH-CH 2-CH2-NH-,-CH2Br),2.47-1.18(m,31H,overlapped),2.03(s,3H,-COCH 3),1.31(s,3H,H-27),1.15(s,6H,H-23),1.14(s,3H,H-26),1.04(s,3H,H-25),0.98(m,1H),0.92(s,4H,H-20,H-30),0.79(s,3H,H-28),0.77(d,J＝5.9Hz,3H,H-29).13C NMR(150MHz,CDCl3):δ199.7(C-11),176.0(-CONH-),170.5(-CONH-,-COCH3),165.1(C-13),135.4,133.8,133.7,130.8,130.7(C-12),118.7,118.1,74.3,60.8,59.2,50.6,46.7,45.2,43.9,41.1,40.4,39.9,39.5(2C),37.5,35.1,34.2,33.1,31.1,29.9,29.8,29.6,29.1,27.9,27.7,27.3,27.1,25.4,24.3,22.8,22.4,21.6,21.3,20.7,19.4,18.5,17.6,13.3.HR-ESI-MS m/z:941.5945(calcd forC60H82N2O5P+[M-Br]+,941.5956)。
实施例13化合物Br/P-5制备
根据实施例9的方法，按如下合成路线选择原料制备得到Br-5和P-5。
合成路线如下：
Figure BDA0003066446530000221
波谱数据：
Br-5:white solid.1H NMR(600MHz,CDCl3):δ6.41(s,1H,-NH-),6.33(s,1H,-NH-),5.53(s,1H,H-12),5.30(s,1H,H-3),3.48-3.27(m,6H,-NH-CH 2-CH 2-NH-,-CH2Br),2.53-1.20(m,37H,overlapped),2.07(s,3H,-COCH 3),1.34(s,3H,H-27),1.17(s,3H,H-23),1.11(s,3H,H-26),1.09(s,3H,H-25),1.00(m,1H),0.94(s,4H,H-20,H-30),0.81(s,3H,H-28),0.79(d,J＝6.4Hz,3H,H-29).13C NMR(150MHz,CDCl3):δ199.3(C-11),176.8(-CONH-),175.0(-CONH-),170.4(-COCH3),165.0(C-13),130.7(C-12),73.8,60.6,59.2,50.5,46.7,45.2,44.0,41.2,41.1,39.8,39.5(2C),37.6,36.9,35.1,34.3,34.2,33.3,33.0,31.1,29.6,29.5(3C),29.1,28.9,28.3,27.7,27.4,25.9,24.6,24.1,21.6,21.3,20.7,19.5,18.6,17.6,13.4.HR-ESI-MS m/z:823.4586(calcd for C45H73BrN2O5Na+[M+Na]+,823.4595)。
P-5:white solid.1H NMR(400MHz,CDCl3):δ8.51(s,1H,-NH-),7.83-7.70(m,15H),7.24(s,1H,-NH-),5.50(s,1H,H-12),5.25(s,1H,H-3),3.61-3.24(m,6H,-NH-CH 2-CH 2-NH-,-CH2Br),2.46-1.21(m,37H,overlapped),2.04(s,3H,-COCH 3),1.31(s,3H,H-27),1.14(s,6H,H-23,H-26),1.04(s,3H,H-25),0.98(m,1H),0.93(s,4H,H-20,H-30),0.79(s,3H,H-28),0.77(s,3H,H-29).13C NMR(100MHz,CDCl3)δ199.6(C-11),176.1(-CONH-),175.8(-CONH-),175.3,175.2,170.3(-COCH3),165.2(C-13),135.3,135.2,133.4(d,J＝9.9Hz),130.6(d,J＝12.5Hz),130.5(C-12),118.4,117.8,74.1,60.5,59.1,50.3,46.5,45.0,43.8,40.9,40.4,39.2(3C),37.3,36.1,34.9,33.9,32.9,30.8,30.3,30.2,28.8(2C),28.7(2C),28.4,27.5,27.1,25.7,24.1,24.0,22.7,22.4(d,J＝3.9Hz),21.3,21.0(d,J＝7.7Hz),20.4,19.3,18.3,17.3,13.1.HR-ESI-MS m/z:983.6403(calcd for C63H88N2O5P+[M-Br]+,983.6425)。
实施例14化合物DKB制备
将AKBA(3.5mmol，1800mg)、溴化苄(3.8mmol，0.45mL)、K2CO3(7.2mmol，990mg)加入到30mL DMF中，油浴100℃反应4小时，TLC检测反应基本完成,取冰水100mL加入反应瓶中，水洗抽滤至中性，干燥得到的白色固体，随后溶于100mL CH3OH中搅拌加入KOH(31.5mmol，1765mg)加热回流2小时TLC检测反应基本完成。减压除去溶剂，加入100mL的水并取100mL乙酸乙酯萃取两次，合并乙酸乙酯无水硫酸钠干燥，过滤，减压去除，硅胶柱色谱法(乙酸乙酯：石油醚1：20～1：5)分离得到白色固体(KBn)1756mg，产率为89.5％。
取化合物KBn(0.5mmol，280mg)和IBX(2mmol，558mg)溶于5mL DMSO中，油浴85℃反应6小时，再次加入IBX(1mmol，280mg)反应12小时后重复加入IBX(1mmol，280mg)反应12小时，TLC检测反应基本完成，加入50mL水，乙酸乙酯50mL萃取三次后合并有机层，饱和碳酸氢钠100mL洗涤，无水硫酸钠干燥过滤，旋蒸浓缩，硅胶柱色谱法(乙酸乙酯：石油醚1：20～1：10)分离得到白色固体(DKBn)238mg，产率为85.6％。
将DKBn(0.15mmol，84mg)加入到5mL无水二氯甲烷中，缓慢滴加0.25mL TiCl4室温反应1小时后，TLC检测反应基本完成，加入10mL水，10mL二氯甲烷萃取三次后合并有机层，30mL饱和食盐水洗后，有机层经无水硫酸钠干燥过滤，旋蒸浓缩，硅胶柱色谱法(乙酸乙酯：石油醚1：30)分离得到白色固体(DKB)43mg，产率为67.8％。
合成路线如下：
Figure BDA0003066446530000231
波谱数据：
KBn:white solid.1H NMR(600MHz,CDCl3):δ7.35-7.29(m,5H,-CH2 Ph),5.53(s,1H,H-12),5.13(d,J＝12.3Hz,1H,-CH 2Ph),5.07(d,J＝12.3Hz,1H,-CH 2Ph),4.11(t,J＝2.5Hz,1H,H-3),2.47(dt,J＝13.2,3.2Hz,1H,H-1a),2.40(s,1H,H-9),2.28(m,1H,H-2a),2.07(td,J＝13.6,4.8Hz,1H,H-16a),1.88-1.32(m,14H,overlapped),1.30(s,3H,H-27),1.29(s,3H,H-23),1.19(m,1H),1.10(s,3H,H-26),0.96(s,3H,H-25),0.99(m,1H),0.93(s,4H,H-20,H-30),0.80(s,3H,H-28),0.78(d,J＝6.4Hz,3H,H-29).13C NMR(150MHz,CDCl3):δ199.7(C-11),176.6(C-24),165.1(C-13),136.0,130.7(C-12),128.7(2C),128.6(2C),128.4,70.9,66.4(-CH2Ph),60.6,59.2,49.2,47.8,45.3,44.0,41.1,39.5(2C),37.6,34.2,34.1,33.1,31.1,29.0,27.7,27.4,26.5,24.4,21.3,20.7,19.2,18.4,17.6,13.5.HR-ESI-MS m/z:583.3746(calcd for C37H52O4Na+[M+Na]+,583.3758)。
DKBn:white solid.1H NMR(600MHz,CDCl3):δ7.72(d,J＝10.4Hz,1H,H-1),7.34-7.27(m,5H,-CH2 Ph),5.89(d,J＝10.4Hz,1H,H-2),5.61(s,1H,H-12),5.10(d,J＝12.5Hz,1H,-CH 2Ph),5.05(d,J＝12.5Hz,1H,-CH 2Ph),2.58(s,1H,H-9),2.09(td,J＝13.6,4.9Hz,1H,H-16a),1.94-1.56(m,8H,overlapped),1.51(s,3H,H-27),1.44-1.49(m,2H),1.31-1.38(m,2H),1.29(s,3H,H-23),1.25(s,3H,H-26),1.22(m,1H),1.18(s,3H,H-25),1.03(m,1H),0.94(s,4H,H-20,H-30),0.82(s,3H,H-28),0.79(d,J＝6.5Hz,3H,H-29).13C NMR(150MHz,CDCl3):δ198.4(C-3),196.6(C-11),173.3(C-24),166.6(C-13),160.2(C-1),135.2,130.1(C-12),128.7(2C),128.4,128.3(2C),124.7(C-2),67.1,59.3,55.3,55.0,54.8,45.5,44.2,41.0,39.5(2C),39.2,34.2,32.7,31.0,29.0,27.6,27.4,21.4,21.3,20.6,19.1,18.9,17.6,16.4.HR-ESI-MS m/z:579.3430(calcd for C37H48O4Na+[M+Na]+,579.3445)。
DKB:white solid.1H NMR(600MHz,CDCl3):δ7.66(d,J＝10.1Hz,1H,H-1),5.76(d,J＝10.1Hz,1H,H-2),5.64(s,1H,H-12),2.67(s,1H,H-9),2.39(m,1H,H-24),2.11(td,J＝13.6,4.9Hz,1H,H-16a),1.91(td,J＝13.7,4.9Hz,1H,H-15a),1.73-1.44(m,9H,overlapped),1.43(s,3H,H-23),1.44-1.49(m,2H),1.31-1.38(m,2H),1.31(s,3H,H-27),1.22(s,3H,H-26),1.22(m,1H),1.15(s,3H,H-25),1.03(m,1H),0.95(s,4H,H-20,H-30),0.84(s,3H,H-28),0.81(d,J＝6.5Hz,3H,H-29).13C NMR(151MHz,CDCl3):δ201.9(C-3),198.8(C-11),166.6(C-13),161.9(C-1),130.2(C-12),125.2(C-2),59.4,54.4,51.4,45.2,44.2,42.1,41.1,39.5(2C),38.6,34.2,31.7,31.0,29.1,27.6,27.4,21.3,20.7,20.6,19.0,17.6,17.0,12.4.HR-ESI-MS m/z:445.3062(calcd for C29H42O2Na+[M+Na]+,445.3077)。
实施例15 AKBA与AKBA衍生物抗肿瘤活性对照研究
1.实验材料
对照药物：AKBA，盐酸阿霉素(简称：DO)；
实验药物：本发明实施例1-15制备的中间体A-N-B，中间体Br-1～5，中间体DKBn以及化合物A-1～8，K-1～8，P-1～5，DKB。
细胞培养：人非小细胞肺癌细胞A549购自上海中乔新舟生物科技有限公司；人前列腺癌细胞PC-3，人非小细胞肺癌细胞NCI-H460，人支气管上皮细胞HBE来自山东大学药学院。RPMI-1640培养液，F12K培养液，胎牛血清，含0.25％EDTA胰蛋白酶，MTT(四甲基偶氮唑)，DMSO(二甲基亚砜)，青霉素-链霉素溶液(100×)，0.5％乳酸环丙沙星氯化钠注射液，PBS(磷酸盐缓冲液)。
仪器：酶标仪：美国Bio Ted；移液器：德国Eppendorf；超净生物安全柜：美国Thermo Fisher Scientific；二氧化碳培养箱：美国Thermo Fisher Scientific；灭菌锅：日本Sanyo；倒置显微镜：日本Olympus；Minispin离心机：德国Eppendorf。
2.实验方法
A549使用含10％FBS的F12K培养基培养；NCI-H460，PC-3，HBE使用含10％FBS的RPMI-1640培养基培养；加药培养基为含2％FBS的RPMI-1640/F12K培养基。以PC-3细胞为例，具体操作如下：胰酶消化PC-3细胞，3分钟后10％FBS的RPMI-1640培养基终止消化，离心，弃上清，加入适量10％FBS的RPMI-1640培养基重悬铺96孔板(每孔100μL)，待细胞贴壁生长至对数生长期后，加入药物，设立溶剂对照组(含千分之一DMSO)，作用时间48h。药物作用时间结束，每孔加入10μL 5mg/mL MTT溶液，培养箱中培养4h。MTT孵育结束后，吸除含MTT培养基，每孔加入100μL DMSO，振摇1min，酶标仪570nm处测吸光值，计算化合物对应IC50值。
3.实验结果
AKBA衍生物与AKBA的IC50(μM)比较结果，见表1。
表1 AKBA衍生物与AKBA的IC50(μM)比较
Figure BDA0003066446530000251
Figure BDA0003066446530000261
a以上细胞均药物作用48h，所有实验结果重复三遍以上，结果通过IC50±SD呈现；bP<0.001
vs TP；cDOX，盐酸阿霉素组为阳性对照。
数据表明，相对AKBA(IC50值27μM)，大部分合成化合物的细胞毒性有不同程度的提高，特别是化合物A-1(对A549细胞IC50为7.16μM，正常细胞HBE为18.47μM)与线粒体靶向衍生物P-5(对A549细胞IC50为1.32μM，正常HBE细胞2.44μM)抗肿瘤活性最强。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，尽管参照前述实施例对本发明进行了详细的说明，对于本领域的技术人员来说，其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (9)

1.一种AKBA衍生物，其具有如下所示的结构：
Figure FDA0003703128320000011
2.一种制备权利要求1所述的AKBA衍生物的方法，其特征在于，所述方法通过如下反应路线实现：
Figure FDA0003703128320000012
Figure FDA0003703128320000021
3.如权利要求2所述的反应路线，其特征在于，所述中间体A-N-B及Br-1～5酰胺化反应的缩合剂选自O-(7-氮杂苯并三唑-1-基)-N，N，N，N-四甲基脲六氟磷酸酯或N,N-二异丙基乙胺。
4.一种药物组合物，其包含权利要求1中所述的AKBA衍生物。
5.一种药物制剂，其包含权利要求1中所述的AKBA衍生物和至少一种药学上可接受的载体或辅料。
6.一种靶向线粒体的药物载体，其包含权利要求1中所述的AKBA衍生物。
7.一种递药系统，其包含权利要求1中所述的AKBA衍生物或权利要求6中所述的靶向线粒体的药物载体。
8.权利要求1所述的AKBA衍生物或权利要求4所述的药物组合物或权利要求5所述的药物制剂或权利要求6所述的靶向线粒体的药物载体或权利要求7所述的递药系统在制备抗肿瘤药物中的应用。
9.根据权利要求8所述的应用，其特征在于，所述肿瘤为肺癌或前列腺癌。
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