CN113527399B - 人参皂苷ck衍生物及其在制备治疗抗肿瘤药物中的用途 - Google Patents

人参皂苷ck衍生物及其在制备治疗抗肿瘤药物中的用途 Download PDF

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CN113527399B
CN113527399B CN202110638125.7A CN202110638125A CN113527399B CN 113527399 B CN113527399 B CN 113527399B CN 202110638125 A CN202110638125 A CN 202110638125A CN 113527399 B CN113527399 B CN 113527399B
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ester hydrochloride
methyl ester
hydrochloride group
nmr
ginsenoside
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CN113527399A (zh
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范代娣
刘庆超
段志广
殷诗玉
同杨柳
严建亚
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NORTHWEST UNIVERSITY
Shaanxi Giant Biogene Technology Co ltd
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Abstract

本发明涉及人参皂苷CK衍生物，包含所述人参皂苷CK衍生物的药物组合物和它们的用途。

Description

人参皂苷CK衍生物及其在制备治疗抗肿瘤药物中的用途
技术领域
本发明属于化学药物技术领域，具体涉及人参皂苷CK衍生物及其在制备治疗抗肿瘤药物中的应用。
背景技术
人参具有抗衰老、抗炎、抗过敏、降血糖、修复神经损伤和保肝等作用。近年来的研究表明，人参皂苷具有抗肿瘤的作用，大部分都是以Rg3、Rh1、Rh2等为主要研究对象。他们在促进肿瘤细胞凋亡和肿瘤细胞分化等方面表现出显著作用，不同结构的人参皂苷在抗肿瘤活性方面存在差异，其中二醇型人参皂苷抗肿瘤活性明显强于三醇型人参皂苷。随着皂苷药代动力学研究的深入，发现真正发挥抗肿瘤作用的是皂苷动物体内的次级代谢产物Compound K也称人参皂苷Ml，人参皂苷Compound K(人参皂苷CK)属于原人参二醇型皂苷。研究表明人参皂苷Compound K的酯化衍生物具有更好的抗肿瘤活性。EMl(Ml的硬脂酸酯、棕榈酸酯和油酸酯的混合物)与人参皂苷CK相比具有更强的抗肿瘤活性。但是CK来源有限，难以分离纯化。而利用化学合成技术获得的系列人参皂苷CK衍生物水溶性差。采用酯键、醚键等方式给CK引入水溶性较好的基团，使其兼具脂溶性和水溶性，这对获得药效性和药代性良好的新化合物具有很重要的研究价值。
发明内容
针对现有技术存在的问题，本发明提供人参皂苷CK衍生物及其在制备治疗抗肿瘤药物中的用途。
具体来说，本发明涉及如下方面：
1.人参皂苷CK衍生物，其具有式(I)所示的结构：
Figure BDA0003106010210000021
其中，
R为-OH、-OC1-6烷基或-NH-X，其中X为氨基酸甲酯盐酸盐基团；
R1为H或O；
R2为H或-C(O)C1-6烷基；
并且R3为H或-OC1-6烷基。
2.人参皂苷CK衍生物，其具有式(II)所示的结构：
Figure BDA0003106010210000022
其中，
Y为芳基或-C5-20烷基。
3.人参皂苷CK衍生物，其具有式(III)所示的结构：
Figure BDA0003106010210000023
其中，
R2为H或-C(O)C1-6烷基；
并且Z为O、-N-OH或-N-OC1-6烷基。
4.根据项1所述的人参皂苷CK衍生物，其选自以下结构的化合物：
Figure BDA0003106010210000031
Figure BDA0003106010210000041
Figure BDA0003106010210000051
Figure BDA0003106010210000061
Figure BDA0003106010210000071
Figure BDA0003106010210000081
Figure BDA0003106010210000091
Figure BDA0003106010210000101
5.根据项1所述的人参皂苷CK衍生物，其中，
所述氨基酸甲酯盐酸盐基团选自：组氨酸甲酯盐酸盐基团、异亮氨酸甲酯盐酸盐基团、丙氨酸甲酯盐酸盐基团、D-丙氨酸甲酯盐酸盐基团、亮氨酸甲酯盐酸盐基团、苯丙氨酸甲酯盐酸盐基团、D-苯丙氨酸甲酯盐酸盐基团、4-硝基-苯丙氨酸甲酯盐酸盐基团、4-氯-DL-苯丙氨酸甲酯盐酸盐基团、脯氨酸甲酯盐酸盐基团、蛋氨酸甲酯盐酸盐基团、D-蛋氨酸甲酯盐酸盐基团、色氨酸甲酯盐酸盐基团、D-色氨酸甲酯盐酸盐基团、丝氨酸甲酯盐酸盐基团、甘氨酸甲酯盐酸盐基团、酪氨酸甲酯盐酸盐基团、天冬氨酸二甲酯盐酸盐基团、半胱氨酸甲酯盐酸盐基团、苏氨酸甲酯盐酸盐基团、谷氨酸二甲酯盐酸盐基团、缬氨酸甲酯盐酸盐基团、以及D-缬氨酸甲酯盐酸盐基团。
6.根据项1所述的人参皂苷CK衍生物，其选自以下结构的化合物：
Figure BDA0003106010210000111
7.根据项3所述的人参皂苷CK衍生物，其选自以下结构的化合物：
Figure BDA0003106010210000112
Figure BDA0003106010210000121
8.一种药物组合物，其包含项1-7中任一项所述的人参皂苷CK衍生物和至少一种赋形剂。
9.项1-7中任一项所述的人参皂苷CK衍生物或项8所述的药物组合物在制备抗肿瘤药物中的用途。
10.根据项9所述的用途，其中所述肿瘤为实体瘤，优选为肝癌、肺癌、胃癌、结肠癌或乳腺癌。
本发明的人参皂苷CK衍生物在抗肿瘤方面具有应用价值，药理活性测试显示对肝癌SMMC-7221细胞和肺癌A549细胞具有很好的抑制活性，说明此类人参皂苷CK衍生物可以作为一种新型的抗肿瘤药物而加以研究利用。
附图说明
图1显示肝癌皮下移植肿瘤模型给药后肿瘤体积的变化曲线；
图2为肝癌皮下移植肿瘤模型给药结束后肿瘤组织图片。
具体实施方式
下面结合实施例进一步说明本发明，应当理解，实施例仅用于进一步说明和阐释本发明，并非用于限制本发明。
除非另外定义，本说明书中有关技术的和科学的术语与本领域内的技术人员所通常理解的意思相同。虽然在实验或实际应用中可以应用与此间所述相似或相同的方法和材料，本文还是在下文中对材料和方法做了描述。在相冲突的情况下，以本说明书包括其中定义为准，另外，材料、方法和例子仅供说明，而不具限制性。以下结合具体实施例对本发明作进一步的说明，但不用来限制本发明的范围。
文中所用的术语“烷基”包括1至20个碳原子，或在一些实施例中包括1至6个碳原子的直链、支链或环状饱和烃基团。烷基的实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、正己基和异己基。
术语“芳基”包括6至18个碳，优选6至10个碳的芳族烃基，包括例如苯基、萘基和蒽基的基团。
本发明提供一种人参皂苷CK衍生物，其具有式(I)所示的结构：
Figure BDA0003106010210000131
其中，
其中，
R为-OH、-OC1-6烷基或-NH-X，其中X为氨基酸甲酯盐酸盐基团；
R1为H或O；
R2为H或-C(O)C1-6烷基；
并且R3为H或-OC1-6烷基。
在一个具体的实施方式中，R为-OH、-OCH3或-NH-X，其中X为氨基酸甲酯盐酸盐基团；
R1为H或O；
R2为H或Ac；
并且R3为H或Ac。如本文所用，说明书中的“Ac”代表乙酰基。
在一个具体的实施方式中，所述氨基酸甲酯盐酸盐基团选自：组氨酸甲酯盐酸盐基团、异亮氨酸甲酯盐酸盐基团、丙氨酸甲酯盐酸盐基团、D-丙氨酸甲酯盐酸盐基团、亮氨酸甲酯盐酸盐基团、苯丙氨酸甲酯盐酸盐基团、D-苯丙氨酸甲酯盐酸盐基团、4-硝基-苯丙氨酸甲酯盐酸盐基团、4-氯-DL-苯丙氨酸甲酯盐酸盐基团、脯氨酸甲酯盐酸盐基团、蛋氨酸甲酯盐酸盐基团、D-蛋氨酸甲酯盐酸盐基团、色氨酸甲酯盐酸盐基团、D-色氨酸甲酯盐酸盐基团、丝氨酸甲酯盐酸盐基团、甘氨酸甲酯盐酸盐基团、酪氨酸甲酯盐酸盐基团、天冬氨酸二甲酯盐酸盐基团、半胱氨酸甲酯盐酸盐基团、苏氨酸甲酯盐酸盐基团、谷氨酸二甲酯盐酸盐基团、缬氨酸甲酯盐酸盐基团、以及D-缬氨酸甲酯盐酸盐基团。
在一个具体的实施方式中，所述人参皂苷CK衍生物为化合物CK-3A、CK-4、CK-ALA-1、CK-D-ALA-1、CK-TRP-1、CK-ILE-1、CK-VAL-1、CK-D-VAL-1、CK-HIS-1。上述化合物分别对应的结构如下：
Figure BDA0003106010210000141
Figure BDA0003106010210000151
Figure BDA0003106010210000161
Figure BDA0003106010210000171
Figure BDA0003106010210000181
Figure BDA0003106010210000191
Figure BDA0003106010210000201
Figure BDA0003106010210000211
本发明还提供人参皂苷CK衍生物，其具有式(II)所示的结构：
Figure BDA0003106010210000221
其中，Y为芳基或-C5-20烷基。
在一个具体的实施方式中，Y为苯基或-(CH2)6CH3、-(CH2)14CH3或-(CH2)16CH3
在一个具体的实施方式中，所述人参皂苷CK衍生物选自以下结构的化合物：
Figure BDA0003106010210000222
其中，当n＝6时，所述人参皂苷衍生物为Y为CK-18，当n＝14时，所述人参皂苷衍生物为Y为CK-16，当n＝16时，所述人参皂苷衍生物为Y为CK-8。
本发明还提供人参皂苷CK衍生物，其具有式(III)所示的结构：
Figure BDA0003106010210000223
其中，
R2为H或-C(O)C1-6烷基；
并且Z为O、-N-OH或-N-OC1-6烷基、
在一个具体的实施方式中，Z为O或N-OCH3。
当R2为Ac，Z为O时，所述人参皂苷CK衍生物为化合物CK-Q。
当R2为Ac，Z为N-OCH3时，所述人参皂苷CK衍生物为化合物CK-M。
当R2为Ac，Z为N-OH时，所述人参皂苷CK衍生物为化合物CK-H。
当R2为H，Z为O时，所述人参皂苷CK衍生物为化合物CK-Q-1。
当R2为H，Z为N-OCH3时，所述人参皂苷CK衍生物为化合物CK-M-1。
具体的，上述化合物的结构如下：
Figure BDA0003106010210000231
本发明还提供一种药物组合物，其包含上述人参皂苷CK衍生物，以及药学上可接受的盐和至少一种赋形剂。
如本文所用，术语“赋形剂”是指与治疗剂例如人参皂苷CK衍生物一起施用的稀释剂、辅助剂或溶媒。这样的药物赋形剂可以是无菌液体，例如水和油，包括石油、动物、植物或合成来源的那些，包括但不限于花生油、大豆油、矿物油、芝麻油等。当口服施用药物组合物时，水是优选的赋形剂。当静脉内施用药物组合物时，盐水和葡萄糖水溶液是优选的赋形剂。盐水溶液和葡萄糖水溶液和甘油溶液优选用作可注射溶液的液体赋形剂。合适的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、甘露醇、海藻糖、明胶、麦芽、米、面粉、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、干脱脂乳、甘油、丙二醇、水、乙醇等。
如果需要，药物组合物还可以含有少量的润湿剂或乳化剂、pH缓冲剂等，例如乙酸盐、琥珀酸盐、tris、碳酸盐、磷酸盐、HEPES(4-(2-羟基乙基)-1-哌嗪乙磺酸)、MES(2-(N-吗啉代)乙磺酸)、或可以含有洗涤剂例如吐温、泊洛沙姆、泊洛沙胺、CHAPS、Igepal或氨基酸例如甘氨酸、赖氨酸或组氨酸。这些药物组合物可以采取溶液、混悬液、乳剂、片剂、丸剂、胶囊、散剂、持续释放制剂等的形式。药物组合物可以与传统的粘合剂和赋形剂如甘油三酯配制成栓剂。口服制剂可以包括标准赋形剂，例如药物级的甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等。这样的组合物将含有治疗有效量的药物或生物活性部分，以及合适量的赋形剂，以便为患者提供适当的施用形式。制剂应符合施用方式。
本发明还提供上述人参皂苷CK衍生物或药物组合物在制备抗肿瘤药物中的用途。
其中，所述肿瘤为实体瘤，优选为肝癌、肺癌、胃癌、结肠癌或乳腺癌。
下面通过具体的制备实施例和测试例进一步说明本发明。
实施例1合成化合物CK-1
用电子天平称取500mg的人参皂苷CK，溶解于25mL的无水二氯甲烷中，0℃下依次加入5mL三乙胺和1mL叔丁基二苯基氯硅烷，保持此温度10min，自然升至室温反应8h。薄层色谱TLC(D/M＝10:1)监测完全后，加入饱和氯化铵停止反应，用25mL二氯甲烷萃取3次，所得有机相饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得浓缩物通过硅胶柱色谱进行纯化(D/M＝10:1)，所得产物CK-1(600mg,收率88.4％)为白色固体。MS(ESI):calcdfor C52H81O8Si[M+H]+861.5695,found 861.5678.
实施例2合成化合物CK-2和CK-2-2
用电子天平称取136mg的人参皂苷CK-1，再称取10mg的4-二甲氨基吡啶(DMAP)，将其溶解于3mL的三乙胺和5mL的二氯甲烷中，并进行充分的搅拌，通入氮气保护。然后将三口圆底烧瓶放置于冰浴条件下，向反应液中加入0.30mL的乙酸酐AC2O，10min后升至室温继续反应，薄层色谱TLC监测反应进程(P/E＝1:1)。待反应6小时后，加入饱和氯化铵停止反应，用5mL二氯甲烷萃取3次，所得有机相饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得浓缩物通过硅胶柱色谱进行纯化(P/E＝3:1)，所得产物CK-2(131mg,收率77.5％)和CK-2-2(32mg,18.9％)均为白色固体。结构表征数据如下:
CK-2:1H NMR(CDCl3,400MHz):δ7.36-7.69(m,10H,Ph-H),5.20(t,J＝9.2Hz,1H,H-3'),5.14(t,J＝9.6Hz,1H,H-4'),5.00(t,J＝6.4Hz,1H,H-24),4.94(dd,J＝9.2,8.0Hz,1H,H-2'),4.86(td,J＝10.4,4.8Hz,1H,H-12),4.73(d,J＝7.6Hz,1H,H-1'),4.51(dd,J＝10.8,5.2Hz,1H,H-3),3.67-3.73(m,2H,H-6'),3.53-3.57(m,1H,H-5'),2.08,2.06,2.01,1.99,1.88(s each,3H each,COCH3×5),1.06(s,9H,t-Bu),1.62,1.59,1.24,1.01,0.93,0.91,0.87,0.85(s each,3H each,CH3×8)；13C NMR(CDCl3,100MHz):δ170.84,170.57,170.20,169.22,169.08(CH3CO),135.65,135.53,133.19,133.01(C-25),131.25,129.66,127.68,127.64,124.57(C-24),94.71(C-1'),82.86,80.68,75.24,74.34,73.78,72.24,68.78,62.72,55.94,53.11,50.04,47.47,45.37,39.58,39.39,38.53,37.90,37.01,34.50,31.81,29.18,27.97,26.67,26.42,25.62,23.59,23.23,22.44,21.82,21.27,20.87,20.69,20.53,19.16,18.19,18.15,17.74,16.45,16.24,15.44；MS(ESI):calcd forC62H94NO13Si[M+NH4]+1088.6489,found 1088.6438.
CK-2-2:1H NMR(CDCl3,400MH1z):δ7.34-7.66(m,10H,Ph-H),5.22(t,J＝9.2Hz,1H,H-3'),5.06(t,J＝6.8Hz,1H,H-24),5.00(t,J＝9.6Hz,1H,H-4'),4.86-4.93(m,2H,H-1',H-2'),4.48(dd,J＝10.0,6.8Hz,1H,H-12),4.29(br s,1H,H-3),3.69(dd,J＝11.2,6.0Hz,1H,H-6'-1),3.59(dd,J＝12.4,2.0Hz,1H,H-6'-2),3.44-3.50(m,1H,H-5'),2.04,2.03,1.98,1.82(s each,3H each,COCH3×4),1.02(s,9H,t-Bu),1.62,1.54,1.36,1.26,0.98,0.89,0.87,0.85(s each,3H each,CH3×8):13C NMR(CDCl3,100MHz):δ171.14,170.75,169.32,169.25(CH3CO),135.78,135.63,133.05,132.95(C-25),131.48,129.85,127.88,127.83,124.69(C-24),94.68(C-1'),85.23(C-3),80.98,75.06,73.82,72.47,70.03,68.94,63.10,56.08,52.14,51.28,49.88,48.57,39.92,38.73,37.98,37.24,37.12,35.50,34.80,32.08,30.34,30.02,29.84,28.12,27.24,26.79,26.63,25.83,23.82,22.84,22.65,22.16,21.47,20.94,20.82,20.62,19.20,18.31,17.84,17.22,16.61,16.20,15.99,14.28；MS(ESI):calcd for C62H92NO12Si[M+NH4]+1046.6383,found1046.6378.
实施例3合成化合物CK-2A
用电子天平称取100mg的人参皂苷CK，再称取12mg的4-二甲氨基吡啶(DMAP)，将其溶解于2.5mL的三乙胺和5mL的二氯甲烷中，并进行充分的搅拌，通入氮气保护。然后将三口圆底烧瓶放置于冰浴条件下，向反应液中加入0.30mL的乙酸酐AC2O，10min后升至室温继续反应。薄层色谱TLC(P/E＝1:1)监测反应完全后，加入饱和氯化铵停止反应，用5mL二氯甲烷萃取3次，所得有机相饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，所得浓缩物通过硅胶柱色谱进行纯化(P/E＝2:1)，所得产物CK-2A(130mg,收率92.8％)为白色固体。结构表征数据如下:
1H NMR(CDCl3,400MHz):δ5.19(t,J＝9.6Hz,1H,H-3'),5.00(t,J＝6.0Hz,1H,H-24),4.98(t,J＝9.6Hz,1H,H-4'),4.91(dd,J＝9.2,8.0Hz,1H,H-2'),4.82(td,J＝10.4,5.2Hz,1H,H-12),4.66(d,J＝7.6Hz,1H,H-1'),4.47(dd,J＝10.8,4.8Hz,1H,H-3),4.10-4.13(m,2H,H-6'),3.62-3.67(m,1H,H-5'),2.05,2.04,2.03,2.02,1.98,1.97(s each,3Heach,COCH3×6),1.64,1.59,1.17,0.96,0.92,0.87,0.84,0.84(s each,3H each,CH3×8)；13C NMR(CDCl3,100MHz):δ170.82,170.63,170.34,170.21,169.48,169.02(CH3CO),131.51(C-25),124.48(C-24),94.73(C-1'),83.22,80.64,75.15,68.91,62.63,55.91,53.08,49.94,47.78,45.59,39.55,39.06,38.49,37.88,36.99,34.45,31.72,29.13,27.96,26.40,25.64,23.57,22.80,21.89,21.81,21.25,20.79,20.61,18.17,18.05,17.70,16.45,16.19,15.42；MS(ESI):calcd for C48H78NO14[M+NH4]+892.5417,found892.5366.
实施例4合成化合物CK-3和CK-3A
用电子天平称取890mg的人参皂苷CK-2，溶解于10mL的四氢呋喃(THF)中，冰浴条件下依次加入0.3mL冰醋酸和434mg四丁基氟化铵(TBAF)，自然升至室温反应。薄层色谱TLC(P/E＝1:1)监测反应结束后，减压浓缩除掉THF，加入乙酸乙酯萃取，饱和食盐水洗涤有机相，无水Na2SO4干燥，过滤，减压浓缩，硅胶柱层析色谱纯化(P/E＝3:1～P/E＝1:1)，所得产物CK-3(544mg,78.7％)和CK-3A(139mg,20.1％)为白色固体。结构表征数据如下：
CK-3:1H NMR(CDCl3,400MHz):δ5.22(t,J＝9.2Hz,1H,H-3'),4.98(t,J＝6.8Hz,1H,H-24),4.96(t,J＝9.6Hz,1H,H-4'),4.92(dd,J＝9.6,7.6Hz,1H,H-2'),4.82(td,J＝10.8,5.6Hz,1H,H-12),4.70(d,J＝7.6Hz,1H,H-1'),4.48(dd,J＝10.8,4.8Hz,1H,H-3),3.47-3.60(m,3H,H-5',H-6'),2.04,2.03,2.03,1.99,1.97(s each,3H each,COCH3×5),1.66,1.60,1.17,0.96,0.92,0.86,0.84,0.84(s each,3H each,CH3×8)；13C NMR(CDCl3,100MHz):δ170.83,170.36,170.24,169.95,169.02(CH3CO),132.47(C-25),124.32(C-24),94.72(C-1'),83.42,80.61,75.30,74.20,73.23,71.97,68.70,61.89,55.87,53.06,49.80,47.10,45.70,39.55,39.33,38.47,37.88,36.98,34.42,31.51,28.97,27.96,26.30,25.59,23.56,22.55,21.83,21.32,21.25,20.77,20.62,18.15,17.89,16.45,16.15,15.42.MS(ESI):calcd for C46H76NO13[M+NH4]+850.5311,found 850.5269.
CK-3A:1H NMR(CDCl3,400MHz):δ5.01(t,J＝6.8Hz,1H,H-24),4.99(t,J＝9.2Hz,1H,H-3'),4.87(dd,J＝9.6,8.0Hz,1H,H-2'),4.82(td,J＝10.8,4.8Hz,1H,H-12),4.64(d,J＝7.6Hz,1H,H-1'),4.48(dd,J＝10.8,4.8Hz,1H,H-3),4.31-4.34(m,2H,H-6'),3.53(t,J＝9.2Hz,1H,H-4'),3.45-3.49(m,1H,H-5'),2.08,2.07,2.05,2.03,1.97(s each,3Heach,COCH3×5),1.65,1.58,1.16,0.95,0.92,0.87,0.84,0.84(s each,3H each,CH3×8)；13C NMR(CDCl3,100MHz):δ171.69,171.59,170.99,170.39,169.34(CH3CO),131.57(C-25),124.71(C-24),94.87(C-1'),83.19,80.79,76.44,75.31,73.88,71.93,69.56,63.57,56.04,53.20,50.05,47.94,45.71,39.69,39.22,38.62,38.03,37.14,34.59,31.82,29.24,28.10,26.51,25.79,23.71,22.95,21.95,21.40,20.98,20.89,18.31,18.15,17.86,16.59,16.32,15.58；MS(ESI):calcd for C46H76NO13[M+NH4]+850.5311,found850.5266.
实施例5合成化合物CK-4
用电子天平称取200mg CK-3(0.24mmol)溶解于2mL乙腈和水(MeCN:H2O,V:V 1:1)混合溶剂中，然后依次加入10mg 2,2,6,6-四甲基哌啶氧化物(TEMPO)和230mg二乙酰氧基碘苯(PhI(OAC)2)，室温下搅拌反应。薄层色谱TLC(P/E＝1:3)监测反应结束后，加入饱和Na2S2O3终止反应，加入乙酸乙酯萃取3次，饱和食盐水洗涤有机相，无水Na2SO4干燥，过滤，减压浓缩，硅胶柱色谱(P/E＝1:3)纯化，所得产物CK-4(145mg,0.17mmol,71.4％)为白色固体粉末。化合物结构表征数据为：
1H NMR(CD3OD,400MHz):δ5.31(t,J＝9.6Hz,1H,H-3'),5.16(t,J＝9.6Hz,1H,H-4'),5.09(t,J＝6.8Hz,1H,H-24),4.99(d,J＝7.6Hz,1H,H-1'),4.87(dd,J＝9.6,7.6Hz,1H,H-2'),4.85(td,J＝10.8,5.6Hz,1H,H-12),4.49(dd,J＝10.4,5.6Hz,1H,H-3),4.20(d,J＝10.0Hz,1H,H-5'),2.06,2.04,2.02,2.00,1.99(s each,3H each,COCH3×5),1.68,1.62,1.25,1.03,0.99,0.94,0.91,0.89(s each,3H each,CH3×8).13C NMR(CD3OD,100MHz):δ171.40(C-6'),171.10,170.24,169.69,169.41,169.03(CH3CO),130.69(C-25),124.56(C-24),94.49(C-1'),83.37,80.87,75.15,72.93,71.87,71.56,69.69,55.80,52.64,49.80,48.12,45.47,39.45,38.14,37.54,36.77,34.19,31.14,28.65,27.05,26.01,24.46,23.22,22.46,20.97,20.66,19.72,19.59,19.17,19.13,17.87,17.09,16.50,15.51,15.28,14.78；MS(ESI):calcd for C46H74NO14[M+NH4]+864.5104,found864.5067.
实施例6合成化合物CK-2A
用电子天平称取100mg的人参皂苷CK，再称取12mg的4-二甲氨基吡啶(DMAP)，将其溶解于2.5mL的三乙胺和5mL的二氯甲烷中，并进行充分的搅拌，通入氮气保护。然后将三口圆底烧瓶放置于冰浴条件下，向反应液中加入0.30mL的乙酸酐AC2O，10min后升至室温继续反应。薄层色谱TLC(P/E＝1:1)监测反应完全后，加入饱和氯化铵停止反应，用5mL二氯甲烷萃取3次，所得有机相饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，所得浓缩物通过硅胶柱色谱进行纯化(P/E＝2:1)，所得产物CK-2A(130mg,收率92.8％)为白色固体。化合物结构表征数据为：
1H NMR(CDCl3,400MHz):δ5.19(t,J＝9.6Hz,1H,H-3'),5.00(t,J＝6.0Hz,1H,H-24),4.98(t,J＝9.6Hz,1H,H-4'),4.91(dd,J＝9.2,8.0Hz,1H,H-2'),4.82(td,J＝10.4,5.2Hz,1H,H-12),4.66(d,J＝7.6Hz,1H,H-1'),4.47(dd,J＝10.8,4.8Hz,1H,H-3),4.10-4.13(m,2H,H-6'),3.62-3.67(m,1H,H-5'),2.05,2.04,2.03,2.02,1.98,1.97(s each,3Heach,COCH3×6),1.64,1.59,1.17,0.96,0.92,0.87,0.84,0.84(s each,3H each,CH3×8)；13C NMR(CDCl3,100MHz):δ170.82,170.63,170.34,170.21,169.48,169.02(CH3CO),131.51(C-25),124.48(C-24),94.73(C-1'),83.22,80.64,75.15,68.91,62.63,55.91,53.08,49.94,47.78,45.59,39.55,39.06,38.49,37.88,36.99,34.45,31.72,29.13,27.96,26.40,25.64,23.57,22.80,21.89,21.81,21.25,20.79,20.61,18.17,18.05,17.70,16.45,16.19,15.42；MS(ESI):calcd for C48H78NO14[M+NH4]+892.5417,found892.5366.
实施例7合成化合物CK-3和CK-3A
用电子天平称取890mg的人参皂苷CK-2，溶解于10mL的四氢呋喃(THF)中，冰浴条件下依次加入0.3mL冰醋酸和434mg四丁基氟化铵(TBAF)，自然升至室温反应。薄层色谱TLC(P/E＝1:1)监测反应结束后，减压浓缩除掉THF，加入乙酸乙酯萃取，饱和食盐水洗涤有机相，无水Na2SO4干燥，过滤，减压浓缩，硅胶柱层析色谱纯化(P/E＝3:1～P/E＝1:1)，所得产物CK-3(544mg,78.7％)和CK-3A(139mg,20.1％)为白色固体。结构表征数据如下：
CK-3:1H NMR(CDCl3,400MHz):δ5.22(t,J＝9.2Hz,1H,H-3'),4.98(t,J＝6.8Hz,1H,H-24),4.96(t,J＝9.6Hz,1H,H-4'),4.92(dd,J＝9.6,7.6Hz,1H,H-2'),4.82(td,J＝10.8,5.6Hz,1H,H-12),4.70(d,J＝7.6Hz,1H,H-1'),4.48(dd,J＝10.8,4.8Hz,1H,H-3),3.47-3.60(m,3H,H-5',H-6'),2.04,2.03,2.03,1.99,1.97(s each,3H each,COCH3×5),1.66,1.60,1.17,0.96,0.92,0.86,0.84,0.84(s each,3H each,CH3×8)；13C NMR(CDCl3,100MHz):δ170.83,170.36,170.24,169.95,169.02(CH3CO),132.47(C-25),124.32(C-24),94.72(C-1'),83.42,80.61,75.30,74.20,73.23,71.97,68.70,61.89,55.87,53.06,49.80,47.10,45.70,39.55,39.33,38.47,37.88,36.98,34.42,31.51,28.97,27.96,26.30,25.59,23.56,22.55,21.83,21.32,21.25,20.77,20.62,18.15,17.89,16.45,16.15,15.42.MS(ESI):calcd for C46H76NO13[M+NH4]+850.5311,found 850.5269.
CK-3A:1H NMR(CDCl3,400MHz):δ5.01(t,J＝6.8Hz,1H,H-24),4.99(t,J＝9.2Hz,1H,H-3'),4.87(dd,J＝9.6,8.0Hz,1H,H-2'),4.82(td,J＝10.8,4.8Hz,1H,H-12),4.64(d,J＝7.6Hz,1H,H-1'),4.48(dd,J＝10.8,4.8Hz,1H,H-3),4.31-4.34(m,2H,H-6'),3.53(t,J＝9.2Hz,1H,H-4'),3.45-3.49(m,1H,H-5'),2.08,2.07,2.05,2.03,1.97(s each,3Heach,COCH3×5),1.65,1.58,1.16,0.95,0.92,0.87,0.84,0.84(s each,3H each,CH3×8)；13C NMR(CDCl3,100MHz):δ171.69,171.59,170.99,170.39,169.34(CH3CO),131.57(C-25),124.71(C-24),94.87(C-1'),83.19,80.79,76.44,75.31,73.88,71.93,69.56,63.57,56.04,53.20,50.05,47.94,45.71,39.69,39.22,38.62,38.03,37.14,34.59,31.82,29.24,28.10,26.51,25.79,23.71,22.95,21.95,21.40,20.98,20.89,18.31,18.15,17.86,16.59,16.32,15.58；MS(ESI):calcd for C46H76NO13[M+NH4]+850.5311,found850.5266.
实施例8合成化合物CK-4
用电子天平称取200mg CK-3(0.24mmol)溶解于2mL乙腈和水(MeCN:H2O,V:V 1:1)混合溶剂中，然后依次加入10mg 2,2,6,6-四甲基哌啶氧化物(TEMPO)和230mg二乙酰氧基碘苯(PhI(OAC)2)，室温下搅拌反应。薄层色谱TLC(P/E＝1:3)监测反应结束后，加入饱和Na2S2O3终止反应，加入乙酸乙酯萃取3次，饱和食盐水洗涤有机相，无水Na2SO4干燥，过滤，减压浓缩，硅胶柱色谱(P/E＝1:3)纯化，所得产物CK-4(145mg,0.17mmol,71.4％)为白色固体粉末。化合物结构表征数据为：
1H NMR(CD3OD,400MHz):δ5.31(t,J＝9.6Hz,1H,H-3'),5.16(t,J＝9.6Hz,1H,H-4'),5.09(t,J＝6.8Hz,1H,H-24),4.99(d,J＝7.6Hz,1H,H-1'),4.87(dd,J＝9.6,7.6Hz,1H,H-2'),4.85(td,J＝10.8,5.6Hz,1H,H-12),4.49(dd,J＝10.4,5.6Hz,1H,H-3),4.20(d,J＝10.0Hz,1H,H-5'),2.06,2.04,2.02,2.00,1.99(s each,3H each,COCH3×5),1.68,1.62,1.25,1.03,0.99,0.94,0.91,0.89(s each,3H each,CH3×8).13C NMR(CD3OD,100MHz):δ171.40(C-6'),171.10,170.24,169.69,169.41,169.03(CH3CO),130.69(C-25),124.56(C-24),94.49(C-1'),83.37,80.87,75.15,72.93,71.87,71.56,69.69,55.80,52.64,49.80,48.12,45.47,39.45,38.14,37.54,36.77,34.19,31.14,28.65,27.05,26.01,24.46,23.22,22.46,20.97,20.66,19.72,19.59,19.17,19.13,17.87,17.09,16.50,15.51,15.28,14.78；MS(ESI):calcd for C46H74NO14[M+NH4]+864.5104,found864.5067.
上述实施例合成化合物的主要反应式如下：
Figure BDA0003106010210000311
实施例9合成化合物CK-5
用电子天平称取100mg CK-4(0.118mmol)溶解于10mL二氯甲烷-甲醇(V:V，1：1)混合溶剂中，室温条件下加入催化量的甲醇钠。薄层色谱TLC(D/M＝5:1)监测反应结束后，加入阳离子交换树脂中和至pH＝6，过滤去除阳离子交换树脂，滤液浓缩，浓缩物经硅胶柱色谱(D/M＝5:1)纯化，所得产物CK-5(50mg,58.8％)为白色固体。MS(ESI):calcd forC40H68NO11[M+NH4]+738.4787,found 738.4755；calcd for C40H63O11[M-H]-719.4376,found719.4397。
化合物的主要反应式如下：
Figure BDA0003106010210000321
实施例10合成化合物CK-6
用电子天平称取100mg CK-4(0.118mmol)溶解于10mL无水二氯甲烷中，DCC作为缩合剂，DMAP作为催化剂，加入1.2当量的甲醇进行酯化反应，薄层色谱TLC(P/E＝1:1)检测反应，待反应过夜，用5mL饱和碳酸氢钠溶液萃取有机相3次，所得有机相用水洗涤1次，无水硫酸钠干燥，过滤，减压浓缩，所得浓缩物通过硅胶柱色谱进行纯化(P/E＝3:1)，所得白色泡沫状固体化合物CK-6(87.8mg,85.3％)。化合物结构表征数据为：
1H NMR(CDCl3,400MHz):δ5.31(t,J＝9.6Hz,1H,H-3'),5.16(t,J＝9.6Hz,1H,H-4'),5.09(t,J＝6.8Hz,1H,H-24),4.99(d,J＝7.6Hz,1H,H-1'),4.87(dd,J＝9.6,7.6Hz,1H,H-2'),4.85(td,J＝10.8,5.6Hz,1H,H-12),4.49(dd,J＝10.4,5.6Hz,1H,H-3),4.20(d,J＝10.0Hz,1H,H-5'),2.06,2.04,2.02,2.00,1.99(s each,3H each,COCH3×5),1.68,1.62,1.25,1.03,0.99,0.94,0.91,0.89(s each,3H each,CH3×8)；13C NMR(CDCl3,100MHz):δ170.88(C-6'),170.32,170.32,169.40,168.99,167.24(CH3CO),131.48(C-25),124.46(C-24),95.01(C-1'),83.79,80.64,75.23,72.68,72.18,71.75,69.44,55.88,53.01,52.68,49.83,49.19,48.09,45.73,39.53,38.58,38.46,37.88,36.98,34.40,33.94,31.61,28.99,27.96,26.37,25.67,25.61,24.94,23.57,22.51,21.80,21.42,21.30,20.79,20.66,20.56,18.16,17.91,17.71,16.46,16.16,15.41；MS(ESI):calcd forC47H72NaO14[M+Na]+883.4814,found 883.4774。
实施例11合成化合物CK-7
称取100mg CK-6(0.116mmol)溶解于10mL二氯甲烷-甲醇(V:V，1：1)混合溶剂中，室温条件下加入催化量的甲醇钠。薄层色谱TLC(D/M＝5:1)监测反应结束后，加入阳离子交换树脂中和至pH＝7，过滤去除阳离子交换树脂，滤液浓缩，浓缩物经硅胶柱色谱(D/M＝8:1)纯化，所得白色泡沫状固体产物CK-7(75mg,88.2％)为白色固体。化合物结构表征数据为：
1H NMR(CDCl3,400MHz):δ5.09(t,J＝6.8Hz,1H,H-24),4.98(td,J＝10.4,6.0Hz,1H,H-12),4.48(dd,J＝10.8,4.8Hz,1H,H-3),4.37(d,J＝8.0Hz,1H,H-1'),3.78(s,3H,OCH3),3.75(dd,J＝9.6,8.0Hz,1H,H-2'),3.72(d,J＝9.6Hz,1H,H-5'),3.56(t,J＝8.8Hz,1H,H-3'),3.13(t,J＝8.0Hz,1H,H-4'),2.03,2.03(s each,3H each,COCH3×2),1.68,1.60,1.26,0.97,0.92,0.86,0.85,0.84(s each,3H each,CH3×8)；13C NMR(CDCl3,100MHz):δ172.94(C-6'),170.89,170.16(CH3CO),130.93(C-25),125.22(C-24),97.68(C-1'),83.13,80.56,75.79,74.27,73.60,72.55,71.35,55.68,52.57,51.78,51.17,49.18,44.91,39.54,38.40,37.85,36.94,35.23,34.09,29.79,29.67,28.22,27.99,26.17,25.75,23.54,22.02,21.90,21.30,21.10,18.06,17.77,17.69,16.53,15.89,15.80；MS(ESI):calcd for C41H66NaO11[M+Na]+757.4497,found 757.4479。
化合物的主要反应式如下：
Figure BDA0003106010210000331
实施例12合成化合物CK-X(X为氨基酸甲酯盐酸盐简写)
称取100mg CK-4(0.118mmol)溶解于10mL无水二氯甲烷中，冰浴，氮气保护下依次加入1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDC HCl)，1-羟基苯并三唑(HOBt),N,N-二异丙基乙胺(DIPEA),冰浴下搅拌30min后，以1.5倍当量加入氨基酸甲酯盐酸盐反应。薄层色谱TLC(P/E＝1:1)检测反应结束后，减压浓缩，所得浓缩物通过硅胶柱色谱进行纯化(P/E＝2:1)，所得白色泡沫状固体化合物CK-X(X为氨基酸甲酯盐酸盐简写)。
其中，上述氨基酸甲酯盐酸盐选自：组氨酸甲酯盐酸盐，异亮氨酸甲酯盐酸盐，丙氨酸甲酯盐酸盐，D-丙氨酸甲酯盐酸盐，亮氨酸甲酯盐酸盐，苯丙氨酸甲酯盐酸盐，D-苯丙氨酸甲酯盐酸盐，4-硝基-苯丙氨酸甲酯盐酸盐，4-氯-DL-苯丙氨酸甲酯盐酸盐，脯氨酸甲酯盐酸盐，蛋氨酸甲酯盐酸盐，D-蛋氨酸甲酯盐酸盐，色氨酸甲酯盐酸盐，D-色氨酸甲酯盐酸盐，丝氨酸甲酯盐酸盐，甘氨酸甲酯盐酸盐，酪氨酸甲酯盐酸盐，天冬氨酸二甲酯盐酸盐，半胱氨酸甲酯盐酸盐，苏氨酸甲酯盐酸盐，谷氨酸二甲酯盐酸盐，缬氨酸甲酯盐酸盐，D-缬氨酸甲酯盐酸盐。分别使用不同的氨基酸甲酯盐酸盐，可以分别得到23个化合物，表示为CK-X(X为氨基酸甲酯盐酸盐简写)。
合成的23个CK-X化合物的对应反应物及产率如表1所示。
表1为23个CK-X化合物的反应物和产率
Figure BDA0003106010210000341
Figure BDA0003106010210000351
化合物CK-HIS的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ7.68(d,J＝10.5Hz,1H),6.79(s,1H),5.30(t,J＝9.6Hz,1H),5.00(t,J＝9.8Hz,1H,H-C24)),4.92(q,J＝7.9,7.1Hz,2H),4.77(t,J＝10.1Hz,2H),4.64(q,J＝4.5Hz,1H),4.47(dd,J＝10.9,4.9Hz,1H),3.83(d,J＝10.0Hz,1H),3.75(s,3H,CH3O),3.38(d,J＝12.7Hz,1H),3.19(t,J＝4.6Hz,2H),2.15-2.00(m,14H),1.95-1.84(m,6H),1.78(dd,J＝11.6,4.0Hz,3H),1.54(d,J＝48.0Hz,13H),1.28-1.23(m,4H),1.17(s,3H),0.94(s,3H),0.92-0.78(m,16H).13C NMR(101MHz,CDCl3)δ171.53,171.06,170.36,170.21,170.16,169.24,167.16,135.17,131.72,124.44,94.96,84.18,80.76,75.30,72.58,72.10,71.98,70.51,56.02,53.17,53.02,52.88,50.02,47.56,45.66,39.66,39.44,38.59,38.00,37.10,34.53,31.93,29.21,28.08,27.22,26.36,25.75,23.68,23.03,22.24,21.91,21.42,21.05,20.88,20.77,18.27,18.11,17.83,16.58,16.32,15.54.HRMS(ESI)calcd forC53H79N3O15Na[M+Na]+:1020.5403,found 1020.5347.
化合物CK-ILE的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ6.89(d,J＝8.7Hz,1H,NH),5.25(t,J＝9.5Hz,1H),5.11(t,J＝9.7Hz,1H,H-C24),5.01(d,J＝7.1Hz,1H),4.98-4.92(m,1H),4.80(t,J＝7.3Hz,2H),4.47(dt,J＝8.3,4.7Hz,2H),3.89(d,J＝10.0Hz,1H,H-1’),3.69(s,3H,CH3O),2.07-1.96(m,17H),1.90-1.79(m,5H),1.58(d,J＝40.9Hz,15H),1.46-1.40(m,2H),1.25-1.14(m,5H),1.13-1.00(m,3H),0.97(s,3H),0.95-0.80(m,20H).13C NMR(101MHz,CDCl3)δ171.58,171.05,170.36,170.29,169.79,169.26,166.87,131.79,124.37,94.81,83.97,80.76,77.36,75.28,72.73,72.18,71.95,69.75,56.77,56.04,53.24,52.18,50.10,47.38,45.60,39.79,39.69,38.61,38.00,37.11,34.58,31.95,31.27,29.26,28.08,26.48,25.74,23.69,23.21,22.37,21.94,21.41,20.92,20.82,20.73,18.29,18.26,17.89,17.84,16.57,16.35,15.55.HRMS(ESI)calcd for C53H83NO15Na[M+Na]+:996.5655,found 996.5604.
化合物CK-ALA的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ6.95(d,J＝7.5Hz,1H,NH),5.25(m,1H),5.09(t,J＝9.7Hz,1H,H-C24),5.00(t,J＝6.1Hz,1H),4.93(t,J＝8.6Hz,1H),4.79(dd,J＝9.7,6.3Hz,2H),4.48(td,J＝9.4,3.6Hz,2H),3.87(d,J＝9.9Hz,1H),3.72(s,3H,CH3O),2.07-1.95(m,16H),1.93-1.76(m,7H),1.65-1.51(m,13H),1.40(dd,J＝20.2,8.4Hz,5H),1.20(s,3H),1.15-1.01(m,4H),1.00-0.80(m,17H).13CNMR(101MHz,CDCl3)δ172.65,171.06,170.38,170.29,169.94,169.24,166.52,131.89,124.41,94.85,84.06,80.75,77.24,75.32,72.56,72.23,71.98,69.65,56.01,53.23,52.55,50.03,47.77,47.43,45.71,39.67,38.59,38.00,37.10,34.55,31.89,29.20,28.07,26.48,25.71,23.68,23.01,22.01,21.93,21.41,20.91,20.84,20.74,18.28,18.19,17.89,16.57,16.32,15.54.HRMS(ESI)calcd for C50H77NO15Na[M+Na]+:954.5185,found 954.5117.
化合物CK-D-ALA的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ6.96(d,J＝7.5Hz,1H,N-H),5.25(t,J＝9.5Hz,1H),5.10(t,J＝9.7Hz,H-C24),4.95(dd,J＝11.1,6.4Hz,2H,4.86-4.74(m,2H),4.53-4.43(m,2H),3.91(d,J＝9.9Hz,1H),3.75(s,3H,CH3O),2.07-2.01(m,9H),1.98(d,J＝11.2Hz,7H),1.91-1.78(m,6H),1.58(d,J＝31.5Hz,12H).1.48-1.39(m,3H),1.35(d,J＝7.2Hz,3H),1.20(s,3H),1.15-1.02(m,3H),0.98-0.80(m,18H).13C NMR(101MHz,CDCl3)δ172.56,171.11,170.43,170.35,169.78,169.22,166.56,132.07,124.26,94.87,84.03,80.78,77.36,75.36,72.74,72.05,71.83,69.62,56.02,53.24,52.71,50.01,47.91,47.64,45.82,39.67,38.58,38.00,37.11,34.55,31.87,29.18,28.08,26.55,25.75,23.67,22.92,22.86,21.93,21.42,20.90,20.82,20.74,18.28,18.24,17.89,16.57,16.31,15.53.HRMS(ESI)calcd for C50H77NO15Na[M+Na]+:954.5185,found 954.5086.
化合物CK-LEU的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ6.70(d,J＝8.4Hz,1H,N-H),5.25(t,J＝9.5Hz,1H),5.10(t,J＝9.7Hz,1H,H-C24),5.03(d,J＝6.1Hz,1H),4.95(t,J＝8.6Hz,1H),4.85-4.74(m,2H),4.50(ddt,J＝15.8,10.8,4.9Hz,2H),3.90(d,J＝10.0Hz,1H),3.69(s,3H,CH3O),2.07-1.96(m,16H),1.92-1.77(m,5H),1.66-1.52(m,17H),1.43(d,J＝9.5Hz,2H),1.21(s,3H),1.09(dt,J＝20.2,8.4Hz,3H),1.01-0.79(m,24H).13C NMR(101MHz,CDCl3)δ172.65,171.06,170.36,170.30,169.77,169.27,166.73,131.96,124.39,94.87,84.09,80.76,77.36,75.30,72.72,72.09,71.93,69.65,56.03,53.25,52.35,50.37,50.04,47.46,45.70,41.28,39.84,39.69,38.60,38.01,37.12,34.57,31.88,29.21,28.09,26.49,25.74,24.86,23.69,23.07,22.96,21.97,21.95,21.42,20.92,20.80,20.74,18.29,18.22,17.92,16.58,16.34,15.55.HRMS(ESI)calcd for C53H83NO15Na[M+Na]+:996.5655,found 996.5616.
化合物CK-PHE的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ7.31(dd,J＝8.1,6.5Hz,2H),7.23(d,J＝7.3Hz,1H,N-H),7.18-7.11(m,2H),6.86(d,J＝7.9Hz,1H),5.25(t,J＝9.5Hz,1H),5.07(t,J＝9.7Hz,1H,H-C24),4.95-4.86(m,2H),4.79(dt,J＝8.3,5.5Hz,2H),4.75(d,J＝7.9Hz,1H),4.48(dd,J＝10.9,5.0Hz,1H),3.88(d,J＝10.0Hz,1H),3.65(s,3H,CH3O),3.17-3.01(m,2H,H-CH2-Ph),2.08-1.99(m,13H),1.94(s,4H),1.62(d,J＝8.9Hz,7H),1.56-1.42(m,10H),1.25(d,J＝1.7Hz,3H),1.18-1.06(m,6H),0.96(s,3H),0.90-0.83(m,15H).13C NMR(101MHz,CDCl3)δ171.06,170.36,170.31,169.96,169.26,166.55,135.75,131.73,129.41,128.78,127.30,124.40,94.80,83.93,80.77,77.36,75.27,72.65,72.11,71.94,69.70,56.04,53.19,52.79,52.31,50.07,47.38,45.58,39.67,38.61,38.01,37.85,37.12,34.58,31.91,29.24,28.09,26.46,25.73,23.69,23.10,22.38,21.93,21.42,20.92,20.88,20.77,18.30,18.18,17.86,16.58,16.35,15.53.HRMS(ESI)calcd for C56H81NO15Na[M+Na]+:1030.5498,found 1030.544.
化合物CK-D-PHE的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ7.23(t,J＝7.6Hz,3H,NH,H-Ph),7.11-7.05(m,2H),6.85(d,J＝7.9Hz,1H),5.23(t,J＝9.5Hz,1H),5.07(t,J＝9.7Hz,1H,H-C24),4.93(dt,J＝22.0,7.9Hz,2H),4.86-4.72(m,3H),4.48(dd,J＝10.9,5.0Hz,1H),3.89(d,J＝9.9Hz,1H),3.70(s,3H,CH3O),3.14-3.01(m,2H,H-CH2-Ph),2.10-1.94(m,18H),1.80(ddt,J＝33.8,15.8,5.3Hz,5H),1.68-1.41(m,15H),1.34-1.23(m,2H),1.22-1.09(m,5H),0.99-0.82(m,16H).13C NMR(101MHz,CDCl3)δ171.18,171.08,170.36,170.32,169.68,169.16,166.68,135.89,132.01,129.23,128.74,127.29,124.28,94.79,83.77,80.79,77.36,75.32,72.69,72.30,71.76,69.66,56.05,53.31,53.20,52.52,50.14,47.18,45.43,40.02,39.69,38.62,38.04,38.01,37.11,34.60,31.98,29.32,28.09,26.54,25.80,23.69,23.37,22.80,21.98,21.43,20.92,20.81,20.72,18.30,18.23,17.93,16.58,16.37,15.50.HRMS(ESI)calcd for C56H81NO15Na[M+Na]+:1030.5498,found1030.5385.
化合物CK-PHE-NO2的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ8.19(d,J＝8.3Hz,2H),7.36(d,J＝8.3Hz,2H),6.97(d,J＝7.4Hz,1H,NH),5.27(t,J＝9.5Hz,1H),5.04(t,J＝9.8Hz,1H,H-C24),4.96-4.87(m,2H),4.86-4.80(m,1H),4.77(dd,J＝10.2,6.2Hz,2H),4.47(dd,J＝10.8,5.0Hz,1H),3.88(d,J＝10.0Hz,1H),3.69(s,3H,CH3O),3.20(d,J＝5.5Hz,2H),2.11-2.01(m,16H),1.97-1.81(m,8H),1.66-1.48(m,14H),1.17(s,5H),0.95(s,4H),0.91-0.81(m,14H).13C NMR(101MHz,CDCl3)δ171.10,170.48,170.35,170.27,170.09,169.25,166.83,147.38,143.68,131.82,130.43,124.34,123.93,94.87,84.07,80.78,77.36,75.30,72.42,72.19,71.87,69.73,56.02,53.19,52.64,52.51,50.04,47.35,45.63,39.65,38.59,38.00,37.68,37.10,34.52,31.82,29.22,28.08,26.39,25.74,23.68,23.03,22.22,21.91,21.42,20.89,20.85,20.76,18.27,18.16,17.83,16.57,16.33,15.51.HRMS(ESI)calcd for C56H84N3O17[M+NH4]+:1070.5795,found 1070.5685.
化合物CK-PHE-Cl的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ7.22(d,J＝8.0Hz,2H),7.01(d,J＝8.1Hz,2H),6.84(d,J＝7.9Hz,1H,NH),5.24(t,J＝9.4Hz,1H),5.06(t,J＝9.7Hz,1H,H-C24),5.00-4.94(m,1H),4.91(t,J＝8.7Hz,1H),4.86-4.70(m,3H),4.48(dd,J＝10.9,5.0Hz,1H),3.89(d,J＝9.9Hz,1H),3.71(s,3H,CH3O),3.12-2.97(m,2H),2.07-1.96(m,19H),1.80(ddd,J＝25.1,12.9,4.9Hz,5H),1.62(d,J＝17.3Hz,8H),1.56-1.42(m,7H),1.22(d,J＝22.8Hz,4H),0.99-0.82(m,18H).13C NMR(101MHz,CDCl3)δ171.05,170.97,170.35,170.29,169.71,169.15,166.72,134.41,133.25,132.20,130.59,128.91,124.21,94.82,83.84,80.77,77.36,75.29,72.61,72.32,71.73,69.66,56.04,53.31,53.02,52.64,50.13,47.23,45.46,39.69,38.61,38.01,37.39,37.12,34.60,32.00,29.33,28.09,26.51,25.82,23.70,23.33,22.74,21.99,21.42,20.92,20.81,20.72,18.30,18.23,17.96,16.58,16.37,15.51.HRMS(ESI)calcdfor C56H80NO15Na[M+Na]+:1064.5109,found 1064.5990.
化合物CK-PRO的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ5.40(t,J＝9.7Hz,1H),4.97(td,J＝9.2,6.7Hz,2H,1H-C24),4.83(dq,J＝10.7,6.3Hz,1H),4.76(t,J＝9.1Hz,1H),4.51-4.42(m,2H),4.16(d,J＝9.8Hz,1H),3.68(s,3H,CH3O),2.10-1.91(m,23H),1.91-1.75(m,6H),1.61(d,J＝10.1Hz,10H),1.55-1.39(m,6H),1.19(s,4H),1.04-0.93(m,5H),0.93-0.79(m,14H).13C NMR(101MHz,CDCl3)δ172.11,171.08,170.72,170.46,169.41,169.08,164.24,132.02,124.19,95.44,83.34,80.82,77.36,75.33,72.97,72.56,71.85,69.11,59.37,56.08,53.39,52.34,50.24,47.36,46.97,45.56,40.13,39.67,38.64,38.00,37.12,34.60,32.09,29.41,29.02,28.08,26.53,25.84,24.97,23.69,23.15,22.74,22.01,21.42,20.94,20.82,20.74,18.27,17.82,16.56,16.40,15.45.HRMS(ESI)calcd for C52H79NO15Na[M+Na]+:980.5342,found 980.5236.
化合物CK-MET的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ7.06(d,J＝8.0Hz,1H,N-H),5.32-5.21(m,1H),5.09(t,J＝9.8Hz,1H),5.01(d,J＝6.4Hz,1H,H-C24),4.95(t,J＝8.6Hz,1H),4.81(dt,J＝17.3,6.1Hz,2H),4.64(q,J＝7.2Hz,1H),4.47(dd,J＝10.9,5.0Hz,1H),3.87(d,J＝9.9Hz,1H),3.72(d,J＝1.2Hz,3H,CH3O),2.57-2.49(m,2H),2.12-1.95(m,24H),1.60(d,J＝24.5Hz,11H),1.23(d,J＝18.5Hz,10H),0.99-0.83(m,21H).13C NMR(101MHz,CDCl3)δ171.63,171.06,170.36,170.26,169.86,169.25,166.87,131.86,124.41,94.85,84.03,80.76,77.36,75.32,72.54,72.32,71.98,69.72,56.03,53.27,52.62,51.10,50.09,47.35,45.63,39.79,39.69,38.61,38.01,37.12,34.58,31.97,31.69,29.78,29.26,28.08,26.47,25.76,23.69,23.16,22.31,21.95,21.42,20.92,20.81,20.74,18.29,18.22,17.89,16.58,16.35,15.55,15.47.HRMS(ESI)calcd for C52H81NO15SNa[M+Na]+:1014.5219,found1014.5111.
化合物CK-D-MET的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ6.98(d,J＝7.9Hz,1H,N-H),5.25(t,J＝9.5Hz,1H),5.10(t,J＝9.7Hz,1H,H-C24),4.96(dt,J＝12.4,7.4Hz,2H),4.87-4.75(m,2H),4.60(h,J＝6.2,5.6Hz,1H),4.47(dd,J＝10.9,5.0Hz,1H),3.93(d,J＝10.0Hz,1H),3.77(s,3H,CH3O),2.44(t,J＝7.4Hz,2H),2.01(dd,J＝25.9,9.9Hz,21H),1.94-1.89(m,2H),1.82(tdd,J＝12.1,9.3,4.2Hz,5H),1.67-1.41(m,17H),1.20(s,3H),1.00-0.82(m,18H).13C NMR(101MHz,CDCl3)δ171.57,171.06,170.37,170.32,169.75,169.19,166.87,132.22,124.13,94.83,83.95,80.76,77.36,75.30,72.69,72.17,71.81,69.60,56.03,53.29,52.78,51.35,50.09,47.40,45.67,39.82,39.69,38.61,38.01,37.12,34.57,31.96,31.55,29.87,29.27,28.08,26.55,25.81,23.69,23.11,22.31,21.96,21.42,20.91,20.83,20.74,18.28,17.91,16.58,16.35,15.56,15.53.HRMS(ESI)calcd for C52H81NO15SNa[M+Na]+:1014.5219,found1014.5110.
化合物CK-TRP的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ8.18(d,J＝2.5Hz,1H,pyrrle-NH),7.55(d,J＝7.8Hz,1H),7.35(d,J＝8.0Hz,1H,),7.19(t,J＝7.5Hz,1H),7.15-7.10(m,2H,6.93(d,J＝8.1Hz,1H,NH),5.33-5.19(m,1H),5.07(t,J＝9.7Hz,1H,H-C24),4.90(dd,J＝10.2,7.5Hz,2H),4.86-4.76(m,2H),4.73(d,J＝7.9Hz,1H),4.47(dd,J＝10.8,5.0Hz,1H),3.88(d,J＝10.0Hz,1H),3.60(s,3H,CH3O),3.40-3.20(m,2H),2.09-2.00(m,12H),1.91(s,3H),1.83(qd,J＝13.2,11.1,6.6Hz,6H),1.61(d,J＝15.9Hz,9H),1.48-1.40(m,4H),1.12(d,J＝22.1Hz,5H),0.97-0.80(m,21H).13C NMR(101MHz,CDCl3)δ171.53,171.07,170.40,170.28,170.11,169.28,166.52,136.28,131.75,127.63,124.42,123.39,122.29,119.71,118.75,111.36,109.81,94.79,83.93,80.76,77.36,75.24,72.70,72.20,71.87,69.77,56.01,53.10,52.45,52.19,50.00,47.64,45.65,39.64,39.37,38.58,38.00,37.10,34.55,31.83,29.18,28.08,27.61,26.37,25.70,23.68,22.94,22.07,21.86,21.42,20.90,20.76,18.28,18.09,17.83,16.58,16.31,15.53.HRMS(ESI)calcd for C58H82N2O15Na[M+Na]+:1069.5607,found1069.5559.
化合物CK-D-TRP的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ8.43(d,J＝2.5Hz,1H,pyrrle-NH),7.49(d,J＝8.0Hz,1H),7.35(d,J＝8.1Hz,1H,,7.18(t,J＝7.5Hz,1H),7.09(t,J＝7.5Hz,1H),6.99(d,J＝7.1Hz,1H,NH),6.92(d,J＝2.3Hz,1H),5.24(t,J＝9.5Hz,1H),5.10(t,J＝9.7Hz,1H,H-C24),4.97(d,J＝7.3Hz,1H),4.92(dd,J＝9.6,7.8Hz,1H),4.78-4.68(m,3H),4.50(dd,J＝11.0,4.6Hz,1H),3.94(d,J＝9.9Hz,1H),3.67(s,3H,CH3O),3.48-3.26(m,2H),2.08-1.97(m,16H),1.90(dt,J＝8.6,4.3Hz,2H),1.85-1.77(m,3H),1.72-1.57(m,13H),1.52-1.35(m,6H),1.12(d,J＝14.1Hz,5H),0.95-0.81(m,15H).13C NMR(101MHz,CDCl3)δ171.52,171.07,170.86,170.32,169.82,169.18,166.57,136.31,132.26,127.64,124.40,122.93,122.27,119.68,118.69,111.37,109.78,95.12,83.77,80.84,77.36,75.67,72.65,72.19,71.84,69.66,56.00,53.11,52.87,52.65,49.90,48.35,45.90,39.57,38.70,38.60,37.99,37.10,34.43,32.07,29.24,28.14,27.09,26.52,25.83,23.70,22.75,21.98,21.95,21.44,20.89,20.75,18.25,17.97,17.59,16.56,16.35,15.40.HRMS(ESI)calcd for C58H82N2O15Na[M+Na]+:1069.5607,found1069.5563.
化合物CK-SER的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ7.29(d,J＝6.0Hz,1H,NH),5.28(m,1H),5.07(t,J＝9.8Hz,1H,H-C24)),5.00-4.93(m,2H),4.79(t,J＝6.9Hz,2H),4.50-4.41(m,2H),4.04(m,1H),3.92-3.81(m,2H),3.79(s,3H,CH3O),2.90(t,J＝7.2Hz,1H,H-OH),2.10-1.99(m,14H),1.96(s,3H),1.64(d,J＝9.4Hz,8H),1.55(d,J＝13.2Hz,6H),1.43(d,J＝9.9Hz,2H),1.29-1.22(m,4H),1.18(s,3H),0.97(s,3H),0.93-0.79(m,18H).13C NMR(101MHz,CDCl3)δ171.28,171.05,170.38,170.19,169.21,167.18,131.78,124.49,94.95,84.17,80.77,77.36,75.37,73.19,72.19,71.94,70.62,61.61,56.03,55.14,53.23,52.94,50.06,47.54,45.78,39.69,39.24,38.61,38.01,37.12,34.57,31.95,29.83,29.21,28.09,26.50,25.76,23.69,22.95,22.06,21.92,21.42,20.88,20.75,18.29,18.17,17.85,16.58,16.34,15.54.HRMS(ESI)calcd forC50H77NO16Na[M+Na]+:970.5135,found 970.5078.
化合物CK-GLY的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ6.86(t,J＝5.3Hz,1H,N-H),5.25(t,J＝9.5Hz,1H),5.11(t,J＝9.7Hz,1H，H-C24),5.00-4.90(m,2H),4.80(t,J＝6.8Hz,2H),4.47(dd,J＝10.8,5.0Hz,1H),4.03(dd,J＝18.3,5.6Hz,1H),3.96-3.86(m,2H),3.75(s,3H,CH3O),2.06-1.94(m,17H),1.60(d,J＝23.8Hz,14H),1.55-1.40(m,5H),1.20(s,3H),1.16-1.01(m,4H),0.98-0.81(m,18H).13C NMR(101MHz,CDCl3)δ171.06,170.39,170.32,169.92,169.49,169.20,167.20,132.15,124.32,94.88,84.11,80.75,77.36,75.36,72.65,72.05,71.85,69.61,56.01,53.25,52.52,50.00,47.25,45.71,40.93,39.68,38.59,38.00,37.10,34.55,31.80,29.17,28.08,26.49,25.72,23.68,22.91,21.94,21.85,21.42,20.90,20.85,20.74,18.28,18.09,17.94,16.58,16.32,15.52.HRMS(ESI)calcd for C49H75NO15Na[M+Na]+:940.5029,found940.4951.
化合物CK-TYR的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ7.00(d,J＝8.1Hz,2H),6.86(d,J＝7.8Hz,1H,NH),6.78(d,J＝8.1Hz,2H),5.24(t,J＝9.5Hz,1H),5.04(t,J＝9.7Hz,1H,H-C24),4.97-4.84(m,2H),4.84-4.66(m,3H),4.58-4.42(m,1H),3.88(d,J＝10.0Hz,2H),3.66(s,3H,CH3O),3.02(t,J＝5.8Hz,2H),2.07-1.98(m,13H),1.95-1.86(m,5H),1.92-1.80(m,4H),1.62-1.39(m,12H),1.16(s,4H),1.12-0.98(m,4H),0.95(s,3H),0.91-0.78(m,15H).13C NMR(101MHz,CDCl3)δ171.20,171.17,170.64,170.35,170.05,169.39,166.63,155.28,131.75,130.57,127.45,124.41,115.80,94.82,84.00,80.83(C-3),77.36,75.36,72.70,72.09,71.91,69.75,56.00,53.11,52.36,49.98,47.79,45.64,39.65,39.38,38.56,37.99,37.09,36.95,34.52,31.78,29.16,28.08,26.45,25.73,23.67,23.00,22.13,21.91,21.43,20.92,20.86,20.76,18.27,18.11,17.86,16.57,16.31,15.53.HRMS(ESI)calcd for C56H81NO16Na[M+Na]+:1046.5448,found1046.5375.
化合物CK-ASP的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ7.39(d,J＝8.1Hz,1H,N-H),5.25(t,J＝9.6Hz,1H),5.10-5.00(m,2H,1H-C24),4.94(dd,J＝9.5,7.8Hz,1H),4.84-4.70(m,3H),4.47(dd,J＝10.9,5.0Hz,1H),3.88(d,J＝10.0Hz,1H),3.72(d,J＝4.3Hz,6H,2CH3O),2.91(ddd,J＝71.7,17.4,4.4Hz,2H),2.08-1.95(m,18H),1.95-1.81(m,6H),1.66-1.50(m,15H),1.27-1.18(m,5H),1.00-0.81(m,17H).13C NMR(101MHz,CDCl3)δ171.38,171.04,170.55,170.37,170.26,169.97,169.24,166.84,131.74,124.48,94.81,83.95,80.77,75.31,72.48,72.39,71.97,69.73,56.05,53.25,52.88,52.15,50.13,48.10,47.38,45.57,39.70,39.59,38.62,38.01,37.12,35.68,34.59,32.04,29.31,28.09,26.44,25.76,23.70,23.25,22.61,21.97,21.42,20.92,20.83,20.74,18.30,18.25,17.88,16.58,16.37,15.54.HRMS(ESI)calcd forC52H83N2O17Na[M+NH4]+:1007.5686,found 1007.5557.
化合物CK-CYS的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ7.31(d,J＝7.1Hz,1H,NH),5.28(t,J＝9.5Hz,1H),5.09(t,J＝9.8Hz,1H,H-C24),4.94(m,2H),4.87-4.71(m,3H),4.48(dd,J＝10.8,5.0Hz,1H),3.87(d,J＝9.9Hz,1H),3.77(s,3H,CH3O),2.99(dq,J＝8.3,4.3,3.7Hz,2H),2.09-1.95(m,19H),1.58(dd,J＝24.0,15.2Hz,15H),1.23(d,J＝19.7Hz,7H),1.00-0.81(m,21H).13C NMR(101MHz,CDCl3)δ171.06,170.37,170.26,170.18,169.79,169.24,166.94,131.78,124.48,94.89,84.10,80.77,75.32,72.57,72.35,72.02,69.96,56.04,53.36,53.24,52.89,50.08,47.48,45.69,39.69,39.57,38.61,38.01,37.12,34.57,31.99,29.25,28.09,26.50,26.38,25.78,23.69,23.11,22.28,21.96,21.42,20.91,20.82,20.75,18.30,18.22,17.88,16.58,16.35,15.55.HRMS(ESI)calcd for C50H85N3O15S[M+NH4]+:981.5352,found 981.5226.
化合物CK-THR的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ7.11(d,J＝8.8Hz,1H,N-H),5.27(t,J＝9.6Hz,1H),5.14(t,J＝9.7Hz,1H,H-C24)),4.99(dt,J＝17.3,7.3Hz,2H),4.81(t,J＝5.8Hz,2H),4.52-4.43(m,2H),4.29(dd,J＝8.7,4.4Hz,1H),3.92(d,J＝9.9Hz,1H),3.73(s,3H,CH3O),2.16(d,J＝4.9Hz,1H,H-OH),2.08-1.96(m,17H),1.95-1.79(m,7H),1.66-1.52(m,14H),1.43(d,J＝9.9Hz,2H),1.23(dd,J＝13.1,6.7Hz,8H),0.97(s,3H),0.93-0.82(m,13H).13C NMR(101MHz,CDCl3)δ171.06,170.72,170.39,170.28,170.13,169.25,167.57,131.84,124.46,94.93,84.02,80.76,77.36,75.31,72.56,72.43,72.00,69.93,68.40,57.09,56.04,53.24,52.66,50.11,47.54,45.68,39.69,39.59,38.61,38.01,37.12,34.57,32.00,29.28,28.08,26.47,25.76,23.69,23.14,22.32,21.95,21.42,20.92,20.83,20.75,19.93,18.29,18.25,17.86,16.58,16.35,15.55.HRMS(ESI)calcd for C51H79NO16Na[M+Na]+:984.5291,found984.5185.
化合物CK-GLU的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ7.01(d,J＝8.0Hz,1H),5.25(t,J＝9.5Hz,1H),5.08(t,J＝9.7Hz,1H),4.99(d,J＝6.9Hz,1H),4.94(dd,J＝9.5,7.9Hz,1H),4.86–4.81(m,1H),4.79(d,J＝7.9Hz,1H),4.59–4.53(m,1H),4.51(s,1H),4.48(dd,J＝10.8,5.0Hz,1H),3.87(d,J＝9.9Hz,2H),3.72(s,3H),3.69(s,3H),2.41(tdd,J＝15.2,8.5,1.8Hz,2H),2.25–2.17(m,1H),2.10–2.03(m,14H),1.98(d,J＝11.2Hz,9H),1.63(s,6H),1.56(dd,J＝13.7,2.0Hz,7H),1.29–1.20(m,7H),0.97(s,3H),0.93(s,3H),0.86(d,J＝12.2Hz,12H).13C NMR(101MHz,CDCl3)δ173.28,171.56,171.03,170.35,170.25,169.88,169.22,167.04,131.84,124.43,94.90,84.05,80.79,75.34,72.58,72.37,72.03,69.78,64.64,60.53,56.07,53.28,52.60,51.90,51.22,50.12,47.42,45.67,39.73,38.64,38.03,37.15,34.62,31.99,29.75,29.29,28.10,27.34,25.73,23.71,23.17,22.32,21.94,21.40,20.91,20.77,20.72,18.32,18.23,17.87,16.59,16.35,15.58.HRMS(ESI)calcd for C53H85N2O17[M+NH4]+:1021.5843,found1021.57910.
化合物CK-VAL的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ6.90(d,J＝8.8Hz,1H,N-H),5.25(t,J＝9.5Hz,1H),5.12(t,J＝9.7Hz,1H,H-C24)),5.00(d,J＝7.0Hz,1H),4.96(t,J＝8.7Hz,1H),4.80(t,J＝7.2Hz,2H),4.45(ddd,J＝19.3,9.8,4.9Hz,2H),3.90(d,J＝10.0Hz,1H),3.70(s,3H,CH3O),2.08-2.01(m,12H),1.98(d,J＝10.6Hz,7H),1.67-1.50(m,16H),1.43(d,J＝9.8Hz,2H),1.33-1.26(m,2H),1.24(d,J＝7.1Hz,2H),1.21(s,3H),0.97(s,3H),0.95-0.83(m,21H).13C NMR(101MHz,CDCl3)δ171.58,171.05,170.36,170.29,169.79,169.26,166.87,131.79,124.37,94.81,83.97,80.76,77.36,75.28,72.73,72.18,71.95,69.75,56.77,56.04,53.24,52.18,50.10,47.38,45.60,39.79,39.69,38.61,38.00,37.11,34.58,31.95,31.27,29.26,28.08,26.48,25.74,23.69,23.21,22.37,21.94,21.41,20.92,20.82,20.73,18.78,18.29,17.89,17.84,16.57,16.35,15.55.HRMS(ESI)calcd for C52H81NO15Na[M+Na]+:982.5498,found982.5438.
化合物CK-D-VAL的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ6.88(d,J＝9.0Hz,1H,N-H),5.26(t,J＝9.5Hz,1H),5.10(t,J＝9.7Hz,1H,H-C24)),4.96(dd,J＝10.7,6.6Hz,2H),4.88-4.76(m,2H),4.46(td,J＝9.8,8.9,4.9Hz,2H),3.94(d,J＝10.0Hz,1H),3.76(s,3H,CH3O),2.09-1.96(m,18H),1.83(dq,J＝10.5,6.7Hz,5H),1.67-1.50(m,14H),1.23(d,J＝13.1Hz,5H),1.18-1.08(m,3H),0.95(d,J＝18.8Hz,7H),0.87(dd,J＝14.4,7.2Hz,16H).13C NMR(101MHz,CDCl3)δ171.55,171.05,170.35,169.71,169.16,166.83,132.03(C-25),124.08(C-24),94.74(C-1’),83.72(C-20),80.77(C-3),77.36,75.27,72.73,72.16,71.84,69.65,56.81,56.06,53.33,52.39,50.16,47.19,45.42,40.30,39.69,38.63,38.01,37.12,34.60,32.04,31.23,29.36,28.08,26.46,25.78,23.69,23.41,22.91,21.98,21.42,20.92,20.82,20.74,18.90,18.29,17.79,17.75,16.57,16.38,15.52.HRMS(ESI)calcd for C52H81NO15Na[M+Na]+:982.5498,found982.5399.
实施例13合成化合物CK-X-1(X为氨基酸甲酯盐酸盐简写)
称取50mg CK-X(实施例12获得的化合物)溶解于10mL二氯甲烷-甲醇(V:V，1：1)混合溶剂中，室温条件下加入催化量的甲醇钠。薄层色谱TLC(D/M＝30:1)监测反应结束后，加入阳离子交换树脂中和至pH＝7，过滤去除阳离子交换树脂，滤液浓缩，浓缩物经硅胶柱色谱(D/M＝30:1)纯化，所得产物CK-X-1为白色固体。
合成的22个CK-X-1化合物及产率如表2所示。
表2为22个CK-X-1化合物的反应物和产率
Figure BDA0003106010210000451
Figure BDA0003106010210000461
化合物CK-HIS-1的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ7.90(s,1H),7.66(d,J＝97.6Hz,1H),7.32(d,J＝8.6Hz,1H,H-NH),6.87(s,1H),5.12(t,J＝7.1Hz,1H,H-C24),4.98–4.89(m,3H),4.50–4.44(m,2H),3.73(s,3H,OCH3),3.60(t,J＝9.4Hz,2H),3.42(d,J＝9.3Hz,1H),3.32(d,J＝14.1Hz,1H),3.18(t,J＝8.6Hz,1H),2.95(dd,J＝14.8,8.4Hz,1H),2.22–2.14(m,2H),2.04(d,J＝6.7Hz,9H),1.91(d,J＝10.2Hz,2H),1.80(q,J＝7.8,6.7Hz,3H),1.68(s,4H),1.61(d,J＝15.6Hz,6H),1.25(s,11H),0.97(s,4H),0.91(s,4H),0.85(d,J＝7.4Hz,10H)..HRMS(ESI)calcd for C47H74N3O12[M+H]+:872.5267,found 872.5242.
化合物CK-ILE-1的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ7.07(d,J＝9.1Hz,1H,H-NH),5.14(t,J＝7.3Hz,1H,H-C24),5.00(td,J＝10.4,6.1Hz,1H),4.57(dd,J＝9.1,4.4Hz,1H),4.48(dd,J＝9.7,5.4Hz,2H),4.29(q,J＝5.8,5.1Hz,1H),3.72(s,3H,OCH3),3.68(d,J＝9.7Hz,1H),3.61(d,J＝8.1Hz,2H),3.12(t,J＝7.8Hz,1H),2.19(q,J＝9.9Hz,2H),2.04(d,J＝6.9Hz,8H),1.91(t,J＝10.7Hz,2H),1.69(s,4H),1.64-1.51(m,9H),1.35-1.23(m,10H),0.96(d,J＝8.2Hz,5H),0.93(s,4H),0.91-0.83(m,18H).13C NMR(101MHz,CDCl3)δ172.98,171.56,171.04,170.97,131.25,124.75,97.61,83.18,80.66,76.13,74.42,72.57,72.20,72.02,65.70,55.92,52.35,51.69,51.22,49.26,44.93,39.68,38.50,38.04,38.00,37.05,34.17,30.69,29.83,28.28,28.11,26.30,25.92,24.99,23.65,22.47,21.96,21.50,21.43,19.31,18.17,17.97,17.81,16.66,16.06,15.91,15.61.HRMS(ESI)calcd for C47H77NO12K[M+K]+:886.5077,found 886.50226.
化合物CK-ALA-1的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ7.11(d,J＝7.6Hz,1H,N-NH),5.16(t,J＝7.18Hz,1H,H-C24),4.99(td,J＝10.4,6.0Hz,1H),4.59–4.52(m,1H),4.48(dd,J＝11.1,5.7Hz,2H),4.29(q,J＝5.8,5.1Hz,1H),3.74(s,3H,OCH3),3.69–3.64(m,1H),3.64–3.58(m,2H),3.12(t,J＝8.0Hz,1H),2.17(t,J＝9.8Hz,2H),2.04(d,J＝3.5Hz,8H),1.91(d,J＝22.0Hz,2H),1.85–1.76(m,3H),1.65(d,J＝35.1Hz,10H),1.55(dd,J＝12.2,5.6Hz,3H),1.41(d,J＝7.4Hz,6H),1.32–1.22(m,8H),1.04(dt,J＝12.4,4.5Hz,2H),0.95(d,J＝20.6Hz,7H),0.88–0.82(m,11H).13C NMR(101MHz,CDCl3)δ172.94,172.59,171.05,170.70,131.38,124.84,97.52,83.22,80.65,76.02,74.40,72.52,72.01,71.90,55.76,52.72,51.65,51.25,49.26,47.65,44.94,39.66,38.48,37.95,37.03,34.16,29.86,28.29,28.10,26.28,25.91,23.63,22.35,21.97,21.49,21.43,18.43,18.15,17.94,17.87,16.65,16.02,15.90.HRMS(ESI)calcdfor C44H71NO12K[M+K]+:844.4608,found 844.45532.
化合物CK-D-ALA-1的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ7.11(d,J＝7.2Hz,1H,N-NH),5.13(t,J＝6.6Hz,1H,H-C24),4.98(td,J＝10.4,5.9Hz,1H),4.52(d,J＝7.1Hz,1H),4.49–4.46(m,2H),4.30(t,J＝6.5Hz,2H),3.74(s,3H,OCH3),3.69–3.65(m,1H),3.64–3.60(m,2H),3.15(t,J＝8.1Hz,1H),2.21–2.14(m,2H),2.04(d,J＝4.5Hz,8H),1.91(t,J＝11.0Hz,2H),1.84–1.77(m,2H),1.69(s,4H),1.61(s,6H),1.58–1.50(m,4H),1.43–1.37(m,6H),1.26(d,J＝11.7Hz,9H),0.96(d,J＝7.8Hz,4H),0.92(s,4H),0.88–0.82(m,12H).13C NMR(101MHz,CDCl3)δ172.89,172.48,171.12,170.88,131.48,124.74,97.47,83.14,80.69,75.99,74.43,72.49,72.17,71.95,55.77,52.74,51.34,49.31,47.80,45.00,39.66,38.48,37.95,37.03,34.17,30.67,29.97,28.33,28.09,26.31,25.93,23.63,22.42,21.99,21.60,21.44,19.30,18.15,17.96,17.87,16.64,15.99,15.92.HRMS(ESI)calcd for C44H71NO12K[M+K]+:844.4608,found844.45526.
化合物CK-LEU-1的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ6.92(d,J＝8.5Hz,1H,H-NH),5.14(d,J＝7.5Hz,1H,H-C24),5.01(dd,J＝10.5,6.2Hz,1H),4.59(td,J＝8.4,5.1Hz,1H),4.48(dd,J＝10.8,5.7Hz,2H),4.30(t,J＝6.5Hz,1H),3.72(s,3H,OCH3),3.68(d,J＝8.1Hz,1H),3.61(d,J＝7.9Hz,2H),3.13(t,J＝7.7Hz,1H),2.21–2.14(m,2H),2.04(d,J＝2.7Hz,6H),1.69(s,4H),1.60(s,5H),1.30(s,5H),1.26(m,14H),0.97(d,J＝8.5Hz,5H),0.92(q,J＝6.3,4.6Hz,10H),0.86(m,18H).13C NMR(101MHz,CDCl3)δ172.89,172.59,171.03,170.92,131.06,124.75,97.52,83.24,80.66,76.04,74.41,72.55,72.16,72.00,65.70,55.78,52.53,51.27,50.31,49.28,44.96,41.62,39.68,38.50,37.96,37.05,34.18,30.69,29.83,28.31,28.11,26.31,25.90,25.02,23.64,22.73,22.43,21.94,21.42,19.31,18.17,17.95,17.89,16.65,16.04,15.91.HRMS(ESI)calcd for C47H77NO12K[M+K]+:886.5077,found 886.50281.
化合物CK-PHE-1的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ7.23(d,J＝7.2Hz,3H,H-Ph),7.04(t,J＝9.4Hz,3H,2H-Ph,1H-NH),5.09(d,J＝6.5Hz,1H,H-C24),4.99(td,J＝10.3,6.0Hz,1H),4.84(q,J＝6.8Hz,1H),4.48(dd,J＝11.1,4.7Hz,1H),4.43(d,J＝7.9Hz,1H),4.30(t,J＝6.6Hz,2H),3.70(s,3H,CH3O),3.66–3.56(m,2H),3.44(t,J＝9.2Hz,1H),3.17(dd,J＝13.8,5.7Hz,1H),3.08(t,J＝8.6Hz,1H),2.98(dd,J＝13.8,6.8Hz,1H),2.16(q,J＝9.7Hz,1H),2.04(d,J＝4.3Hz,6H),1.69(s,4H),1.53(s,5H),1.25(t,J＝6.6Hz,13H),0.96(d,J＝6.2Hz,5H),0.91(s,4H),0.86(dd,J＝10.8,4.6Hz,15H).13C NMR(101MHz,CDCl3)δ172.87,171.13,170.57,167.88,135.48,131.25,129.27,128.62,127.39,124.92,97.36,83.12,80.65,75.92,74.43,72.47,72.08,71.95,65.70,55.76,52.67,52.56,51.23,49.28,44.96,39.66,38.49,37.95,37.03,34.16,30.68,29.83,28.30,28.10,26.24,25.95,23.64,22.28,21.88,21.43,19.30,18.16,17.95,17.84,16.65,16.03,15.92.HRMS(ESI)calcd for C50H75NO12Na[M+Na]+:904.5181,found904.51587.
化合物CK-D-PHE-1的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ7.23(d,J＝6.5Hz,3H,H-Ph),7.04(d,J＝7.1Hz,3H,2H-Ph,1H-NH),5.08(t,J＝7.0Hz,1H,H-C24),4.98(td,J＝10.4,6.1Hz,1H),4.84(q,J＝6.3Hz,1H),4.48(dd,J＝11.1,4.8Hz,2H),4.40(d,J＝8.0Hz,1H),4.29(q,J＝5.8,5.0Hz,1H),3.70(s,3H,CH3O),3.60(h,J＝5.4Hz,3H),3.20(dd,J＝13.9,5.6Hz,1H),3.06(td,J＝13.6,6.7Hz,2H),2.20–2.13(m,1H),2.03(d,J＝4.5Hz,7H),1.69(d,J＝5.5Hz,4H),1.56(d,J＝6.5Hz,6H),1.31–1.20(m,11H),1.12(s,3H),0.96(d,J＝5.0Hz,5H),0.91(s,3H),0.89–0.81(m,13H).13C NMR(101MHz,CDCl3)δ173.03,171.05,170.76,167.88,135.59,131.37,129.23,128.69,127.32,124.83,97.58,83.01,80.65,76.09,74.38,72.38,72.07,71.87,65.70,55.76,52.87,52.58,51.21,49.25,44.93,39.66,38.48,37.95,37.03,34.16,30.68,29.83,28.27,28.10,26.28,25.94,23.63,22.27,21.95,21.43,19.30,18.15,17.95,17.89,16.65,16.03,15.90.HRMS(ESI)calcd for C50H75NO12Na[M+Na]+:904.5181,found904.51611.
化合物CK-PHE-NO2-1的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ8.10(dd,J＝13.5,8.1Hz,2H,H-Ph),7.22(t,J＝8.5Hz,2H,H-Ph),7.11(t,J＝6.3Hz,1H,H-NH),5.04(t,J＝8.0Hz,1H,H-C24),4.97(dt,J＝12.4,6.6Hz,1H),4.89(q,J＝6.1Hz,1H),4.51–4.39(m,2H),4.28(dt,J＝11.3,6.4Hz,2H),3.73(s,3H,CH3O),3.70–3.57(m,3H),3.29–3.16(m,2H),3.10(t,J＝8.4Hz,1H),2.16(dd,J＝10.4,4.9Hz,1H),2.04(t,J＝10.2Hz,6H),1.64(dq,J＝9.9,5.2Hz,6H),1.45(t,J＝11.5Hz,7H),1.25(dd,J＝13.9,6.5Hz,11H),0.96(t,J＝3.4Hz,5H),0.91(s,4H),0.86(h,J＝5.0,4.1Hz,13H).13C NMR(101MHz,CDCl3)δ173.05,171.05,170.42,167.87,147.36,143.48,131.28,130.24,124.76,123.69,97.47,83.12,80.66,75.90,74.42,72.53,72.20,71.88,65.70,55.77,52.84,52.47,52.22,51.16,49.26,44.93,39.66,37.96,37.03,34.15,30.68,29.82,28.26,28.10,26.23,25.86,23.64,22.27,21.92,21.43,19.30,18.15,17.96,17.73,16.65,16.04,15.90.HRMS(ESI)calcd for C50H74N2O14Na[M+Na]+:949.5032,found949.50098.
化合物CK-PHE-Cl-1的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ7.21(d,J＝8.1Hz,2H,H-Ph),7.04(d,J＝7.5Hz,1H,H-NH),6.96(d,J＝8.0Hz,2H,H-Ph),5.08(d,J＝7.2Hz,1H),4.98(td,J＝10.4,6.1Hz,1H),4.82(q,J＝5.8Hz,1H),4.48(dd,J＝11.1,4.8Hz,1H),4.44–4.37(m,2H),4.30(t,J＝6.5Hz,1H),3.71(s,3H,CH3O),3.60(t,J＝7.7Hz,3H),3.18(dd,J＝14.0,5.7Hz,1H),3.06(tt,J＝11.5,6.4Hz,2H),2.15(dd,J＝13.2,6.8Hz,1H),2.03(d,J＝5.2Hz,7H),1.71(s,5H),1.52(d,J＝9.4Hz,6H),1.27(dt,J＝13.4,4.9Hz,10H),1.11(s,3H),0.96(d,J＝5.2Hz,5H),0.91(s,4H),0.88–0.81(m,12H).13CNMR(101MHz,CDCl3)δ173.05,171.05,170.76,167.88,134.12,133.32,131.39,130.59,128.85,124.79,97.61,83.07,80.65,76.08,74.40,72.37,72.11,71.87,65.71,55.76,52.69,52.66,51.21,49.26,44.94,39.66,38.49,37.96,37.03,34.16,30.68,29.83,28.28,28.10,26.26,25.95,23.64,22.27,21.95,21.43,19.31,18.16,17.95,17.82,16.65,16.03,15.91.HRMS(ESI)calcd for C50H74NClO12K[M+K]+:938.4792,found954.45117.
化合物CK-PRO-1的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ5.07(d,J＝6.6Hz,1H,H-C24),4.97(td,J＝10.5,5.8Hz,1H),4.53–4.45(m,3H),4.30(t,J＝6.6Hz,2H),3.89(d,J＝9.7Hz,2H),3.75(d,J＝6.0Hz,1H),3.73(s,3H),3.63(t,J＝8.8Hz,1H),3.19(t,J＝8.5Hz,1H),2.20–2.13(m,2H),2.02(d,J＝6.8Hz,8H),1.95(d,J＝4.7Hz,2H),1.84–1.76(m,3H),1.70–1.63(m,6H),1.45–1.40(m,4H),1.26(q,J＝8.9,7.8Hz,10H),0.96(s,3H),0.92(s,3H),0.87–0.83(m,12H).13C NMR(101MHz,CDCl3)δ172.71,171.04,167.87,167.56,131.41,124.82,97.79,82.65,80.69,74.86,74.42,74.02,72.95,71.67,65.70,59.53,55.83,52.61,51.67,49.48,47.40,45.06,39.69,38.52,37.97,37.06,34.26,30.69,28.84,28.53,28.11,26.33,25.88,24.92,23.66,22.64,21.99,21.43,19.31,18.19,17.97,17.85,16.64,15.99,15.95.HRMS(ESI)calcd for C46H73NO12K[M+K]+:870.4764,found 870.47095.
化合物CK-MET-1的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ7.18(d,J＝8.3Hz,1H,H-NH),5.15(t,J＝7.2Hz,1H,H-C24),5.00(td,J＝10.3,6.0Hz,1H),4.71(q,J＝7.0Hz,1H),4.48(dd,J＝9.6,5.2Hz,2H),4.29(dq,J＝11.4,6.1Hz,2H),3.75(s,3H,CH3O),3.70–3.66(m,1H),3.64–3.59(m,2H),3.13(t,J＝7.9Hz,1H),2.51–2.42(m,2H),2.20–2.13(m,3H),2.08–2.02(m,10H),1.69(s,5H),1.61(s,5H),1.32–1.21(m,12H),0.99–0.90(m,9H),0.86(dq,J＝8.2,5.3,4.2Hz,14H).13C NMR(101MHz,CDCl3)δ173.53,171.56,170.98,167.89,131.43,124.81,97.58,83.25,80.67,76.06,74.42,72.51,72.11,65.71,55.76,52.80,51.24,50.96,49.26,44.94,39.66,38.48,37.95,37.03,34.15,31.99,30.67,29.96,29.84,28.28,28.10,26.29,25.93,23.63,22.38,21.99,21.44,19.30,18.15,17.95,17.90,16.65,16.03,15.91,15.59.HRMS(ESI)calcd for C46H75NO12Na[M+Na]+:888.4902,found 888.48816.
化合物CK-D-MET-1的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ7.17(d,J＝7.7Hz,1H,H-NH),5.15(d,J＝6.0Hz,1H,H-C24),4.99(td,J＝10.4,5.9Hz,1H),4.68(p,J＝6.7,6.3Hz,1H),4.48(dd,J＝9.7,4.3Hz,2H),4.29(q,J＝5.8,5.1Hz,2H),3.74(s,3H,CH3O),3.70(d,J＝9.2Hz,1H),3.65–3.60(m,2H),3.14(t,J＝8.1Hz,1H),2.46(t,J＝7.3Hz,2H),2.17(dd,J＝15.1,7.9Hz,3H),2.07–2.02(m,10H),1.70(s,5H),1.62(s,5H),1.26(d,J＝11.5Hz,12H),0.96(d,J＝8.3Hz,5H),0.93(d,J＝3.5Hz,4H),0.86(dd,J＝10.3,4.3Hz,14H).13C NMR(101MHz,CDCl3)δ172.93,171.44,171.04,167.87,131.53,124.71,97.54,83.13,80.65,76.00,74.43,72.46,72.24,65.70,55.77,52.80,51.31,51.10,49.30,44.99,39.66,38.48,37.95,37.03,34.17,34.12,31.70,31.50,30.67,29.89,28.32,28.09,26.30,25.95,23.63,22.47,21.98,21.42,19.30,18.16,17.98,17.90,16.64,16.01,15.92,15.58.HRMS(ESI)calcd for C46H75NO12Na[M+Na]+:888.4902,found 888.48846.
化合物CK-TRP-1的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ8.26(s,1H,H-indole-NH),7.49(d,J＝7.9Hz,1H,H-NH),7.30(d,J＝8.1Hz,1H),7.17(d,J＝7.3Hz,1H),7.14–7.06(m,2H),6.96(d,J＝2.4Hz,1H),5.11(d,J＝6.5Hz,1H,H-C24),5.00–4.91(m,2H),4.47(dd,J＝10.9,4.9Hz,2H),4.40(d,J＝7.8Hz,1H),3.66(s,3H,OCH3),3.61(d,J＝9.7Hz,1H),3.56(t,J＝8.9Hz,1H),3.40(t,J＝9.0Hz,1H),3.37–3.31(m,1H),3.23(dd,J＝14.9,6.4Hz,1H),3.03(t,J＝8.5Hz,1H),2.15(q,J＝9.9Hz,2H),2.02(d,J＝12.5Hz,7H),1.97–1.91(m,3H),1.87(t,J＝10.7Hz,2H),1.72(s,4H),1.57–1.47(m,8H),1.24(d,J＝9.2Hz,10H),0.96(s,3H),0.91–0.81(m,15H).13C NMR(101MHz,CDCl3)δ172.99,171.61,171.09,170.54,136.18,131.51,127.53,125.11,122.72,122.36,119.64,118.62,111.39,109.77,97.45,83.00,80.67,76.12,74.47,72.49,72.00,71.90,55.75,52.60,52.33,51.42,51.21,49.25,44.93,39.64,38.46,37.94,37.02,34.14,29.84,28.26,28.15,28.10,26.26,26.00,23.63,22.26,22.02,21.48,21.45,18.14,17.96,17.72,16.65,16.03,15.91.HRMS(ESI)calcd for C52H76N2O12K[M+K]+:959.5030,found959.49713.
化合物CK-D-TRP-1的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ8.21(s,1H,H-indole-NH),7.46(d,J＝7.9Hz,1H,H-NH),7.32(d,J＝8.1Hz,1H),7.17(t,J＝7.6Hz,1H),7.12–7.05(m,2H),6.92(d,J＝2.3Hz,1H),5.07(t,J＝7.1Hz,1H,H-C24),4.92(ddt,J＝13.4,9.8,5.7Hz,2H),4.56(s,1H),4.48(dd,J＝11.1,4.6Hz,1H),4.32(d,J＝7.8Hz,1H),3.67(s,3H,OCH3),3.62–3.56(m,3H),3.34(qd,J＝14.9,5.3Hz,2H),3.08(td,J＝8.0,4.1Hz,1H),2.92(s,1H),2.08(d,J＝9.9Hz,1H),2.03(d,J＝10.3Hz,8H),1.83(t,J＝11.2Hz,3H),1.72(d,J＝5.4Hz,6H),1.65–1.59(m,3H),1.51(s,6H),1.24(q,J＝10.3,8.0Hz,8H),0.95(s,3H),0.90–0.79(m,15H).13C NMR(101MHz,CDCl3)δ172.94,171.36,171.08,170.80,136.20,131.60,127.72,124.94,122.68,122.39,119.83,118.58,111.35,109.81,97.51,82.91,80.67,76.09,74.49,72.43,72.28,71.90,55.75,52.68,52.63,51.31,51.24,49.26,45.04,39.61,38.47,37.94,37.02,34.14,30.03,28.33,28.10,27.38,26.28,25.96,23.63,22.21,21.96,21.45,21.13,18.14,17.83,17.78,16.64,15.96,15.93.HRMS(ESI)calcd for C52H76N2O12K[M+K]+:959.5030,found 959.49579.
化合物CK-SER-1的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ7.45(d,J＝7.6Hz,1H,H-NH),5.13(q,J＝6.2Hz,1H,H-C24),4.98(tt,J＝11.1,6.2Hz,1H),4.62(tt,J＝6.8,3.7Hz,1H),4.50–4.40(m,3H),4.00(dd,J＝11.0,4.8Hz,1H),3.95–3.89(m,1H),3.77(s,3H,OCH3),3.73–3.69(m,1H),3.62(dt,J＝19.7,8.5Hz,2H),3.15(dtd,J＝13.4,8.1,4.7Hz,1H),3.07(d,J＝3.7Hz,1H),2.24–2.13(m,2H),2.09–1.97(m,8H),1.90(td,J＝10.9,6.4Hz,2H),1.84–1.75(m,3H),1.66–1.58(m,6H),1.54(dd,J＝11.7,5.2Hz,3H),1.45–1.36(m,3H),1.33–1.20(m,8H),0.97(s,3H),0.92(s,3H),0.88–0.80(m,10H).13CNMR(101MHz,CDCl3)δ172.98,171.42,171.06,170.10,131.46,124.98,97.61,83.23,80.69,76.11,74.44,72.52,72.26,72.03,63.15,55.78,54.23,52.97,51.53,51.26,49.28,44.98,39.68,38.50,37.96,37.05,34.19,29.90,28.30,28.10,26.30,25.92,23.64,22.34,22.00,21.42,18.17,18.10,17.97,17.84,16.64,16.03,15.98,15.91.HRMS(ESI)calcd for C44H71NO13K[M+K]+:860.4557,found 860.45068.
化合物CK-GLY-1的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ7.07(t,J＝5.2Hz,1H,NH),5.14(t,J＝6.8Hz,1H,H-C24,4.99(td,J＝10.4,6.0Hz,1H),4.51-4.40(m,3H),4.16-3.93(m,2H),3.84(s,1H),3.75(s,3H,CH3O),3.70(q,J＝5.6,5.0Hz,1H),3.66-3.57(m,2H),3.13(t,J＝8.1Hz,1H),2.24-2.16(m,1H),2.03(dd,J＝30.4,4.0Hz,8H),1.92(t,J＝10.9Hz,1H),1.61(t,J＝34.3Hz,13H),1.46-1.38(m,3H),1.27(d,J＝16.8Hz,8H),1.04(m,2H),1.00-0.80(m,17H).13C NMR(101MHz,CDCl3)δ172.84,171.34,171.03,169.43,131.53(C-25),124.89(C-24),97.55,83.23,80.68,76.06,74.46,72.53,72.25,72.03,55.81,52.61,51.38,51.35,49.33,45.06,40.78,39.70,38.52,37.98,37.07,34.22,29.97,28.35,28.12,26.32,25.90,23.66,22.40,21.95,21.59,21.41,18.18,17.97,17.84,16.65,16.03,15.93.HRMS(ESI)calcd for C43H69NO12Na[M+Na]+:814.4712,found 814.4674.
化合物CK-TYR-1的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ6.99(d,J＝8.7Hz,1H,H-NH),6.91(d,J＝8.0Hz,2H,H-Ph),6.77(d,J＝7.9Hz,2H,H-Ph),5.13(d,J＝7.4Hz,1H,H-C24),4.99(td,J＝10.2,5.8Hz,1H),4.80(q,J＝7.4Hz,1H),4.46(dd,J＝13.8,6.4Hz,3H),4.29(dt,J＝11.5,6.3Hz,1H),3.74(s,3H,OCH3),3.59(d,J＝9.4Hz,2H),3.29(t,J＝9.3Hz,1H),3.21(dd,J＝13.9,5.3Hz,1H),3.09(t,J＝8.6Hz,1H),2.79(dd,J＝14.0,7.8Hz,1H),2.24–2.14(m,2H),2.04(d,J＝6.2Hz,8H),1.90(t,J＝11.0Hz,2H),1.83–1.76(m,3H),1.64–1.53(m,9H),1.25(d,J＝6.8Hz,8H),0.97(s,3H),0.92(s,3H),0.85(d,J＝7.5Hz,12H).13C NMR(101MHz,CDCl3)δ173.21,171.30,171.13,170.40,155.76,131.29,130.48,126.82,125.02,115.83,97.20,83.08,80.77,76.05,74.57,72.63,72.29,71.93,55.87,52.71,52.60,51.25,49.35,45.03,39.69,38.51,37.97,37.70,37.06,34.20,30.69,29.92,28.29,28.14,26.27,25.96,23.65,22.37,21.86,21.43,19.31,18.18,18.03,17.89,16.64,16.05,15.94.HRMS(ESI)calcd for C50H75NO13Na[M+Na]+:920.5131,found 920.50836.
化合物CK-ASP-1的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ7.54(dd,J＝19.5,8.3Hz,1H,H-NH),5.16(d,J＝8.5Hz,1H,H-C24),4.99(td,J＝10.5,6.2Hz,1H),4.81(ddd,J＝12.7,8.6,4.4Hz,1H),4.47(q,J＝8.8,6.9Hz,2H),3.73(s,3H,OCH3),3.72-3.69(m,1H),3.66(d,J＝4.7Hz,1H),3.64(s,3H,OCH3),3.62-3.59(m,1H),3.13(q,J＝8.4Hz,1H),3.02(ddd,J＝17.2,8.9,4.6Hz,1H),2.82(ddd,J＝17.1,12.1,4.6Hz,1H),2.20(dd,J＝10.1,4.6Hz,2H),2.08-2.01(m,7H),1.98(d,J＝7.3Hz,1H),1.92(t,J＝10.9Hz,1H),1.85-1.76(m,2H),1.69(d,J＝4.1Hz,3H),1.61(s,6H),1.53(dd,J＝18.5,10.8Hz,4H),1.46-1.37(m,3H),1.34-1.21(m,8H),1.04(dt,J＝13.7,3.6Hz,2H),0.97(s,3H),0.92(s,3H),0.89-0.80(m,10H).13C NMR(101MHz,CDCl3)δ172.98,171.04,170.95,170.44,170.33,131.12,125.14,97.67,83.18,80.68,76.20,74.50,72.55,72.17,71.95,55.79,53.04,52.10,51.27,49.31,48.05,45.00,39.70,38.51,37.98,37.06,36.07,35.87,34.20,29.93,28.32,28.12,26.32,25.93,23.66,21.93,21.43,18.18,18.02,17.86,16.66,16.07,15.93.HRMS(ESI)calcd for C46H73NO14Na[M+Na]+:886.4923,found886,48859.
化合物CK-THR-1的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ7.29(d,J＝8.8Hz,1H,H-NH),5.12(d,J＝7.6Hz,1H,H-CH3),4.99(q,J＝9.1,7.1Hz,1H),4.52(d,J＝8.7Hz,1H),4.50–4.44(m,3H),4.35(d,J＝5.7Hz,1H),4.29(q,J＝6.1,5.5Hz,1H),3.76(s,3H,OCH3),3.72(s,1H),3.63(t,J＝6.9Hz,2H),3.14(q,J＝6.6Hz,1H),2.21–2.14(m,2H),2.04(d,J＝5.9Hz,8H),1.94–1.89(m,2H),1.83–1.77(m,3H),1.68(s,5H),1.61(s,7H),1.31–1.24(m,9H),1.20(d,J＝6.4Hz,3H),0.97(s,3H),0.92(s,3H),0.85(d,J＝7.8Hz,12H).13C NMR(101MHz,CDCl3)δ172.96,171.69,171.04,170.65,131.05,124.99,97.61,83.22,80.67,76.12,74.42,72.59,72.27,67.90,56.75,55.78,52.85,52.81,51.26,49.28,44.96,39.68,38.50,37.96,37.04,34.18,30.68,29.89,28.30,28.10,26.31,25.93,23.64,22.41,21.98,21.51,21.41,20.15,19.30,18.17,17.97,17.84,16.64,16.03,15.91.HRMS(ESI)calcd for C45H73NO13Na[M+Na]+:858.4974,found858.49274.
化合物CK-GLU-1的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ7.15(d,J＝8.1Hz,1H,H-NH),5.15(t,J＝7.0Hz,1H,H-C24),5.00(td,J＝10.3,6.1Hz,1H),4.63(tt,J＝9.0,4.6Hz,1H),4.48(dd,J＝10.6,5.7Hz,2H),4.28(dt,J＝11.2,6.4Hz,2H),3.74(s,3H,CH3O),3.66(d,J＝4.5Hz,3H,CH3O),3.63–3.59(m,2H),3.13(t,J＝7.0Hz,1H),2.92(d,J＝30.7Hz,1H),2.34(dd,J＝15.3,7.4Hz,2H),2.17(dt,J＝18.3,8.4Hz,3H),2.05(d,J＝9.0Hz,7H),1.70(d,J＝7.6Hz,4H),1.64(s,6H),1.33–1.22(m,12H),0.98–0.91(m,9H),0.86(h,J＝5.8,4.9Hz,14H).13C NMR(101MHz,CDCl3)δ173.00,172.84,171.48,171.07,167.89,131.39,124.84,97.59,83.26,80.66,76.08,74.43,72.53,72.10,65.71,55.77,52.81,51.99,51.25,50.98,49.27,44.94,39.66,38.49,37.96,37.03,34.16,30.68,29.95,29.83,28.29,28.10,27.84,26.29,25.92,23.63,22.33,22.00,21.53,21.43,19.30,18.16,17.96,17.84,16.65,16.03,15.91.HRMS(ESI)calcd for C47H75NO14Na[M+Na]+:900.5080,found 900.50555.
化合物CK-VAL-1的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ7.07(d,J＝9.1Hz,1H,H-NH),5.13(t,J＝7.1Hz,1H,H-C24),5.00(td,J＝10.3,5.9Hz,1H),4.57–4.45(m,4H),3.73(s,3H,OCH3),3.70–3.66(m,1H),3.61(d,J＝6.9Hz,2H),3.13(q,J＝7.1Hz,1H),2.18(dd,J＝11.9,7.8Hz,2H),2.04(d,J＝6.3Hz,7H),1.92(t,J＝11.0Hz,2H),1.81(dt,J＝14.8,4.9Hz,3H),1.68(s,4H),1.61–1.52(m,7H),1.32(s,4H),1.26(d,J＝10.9Hz,6H),0.98(s,4H),0.93(t,J＝3.4Hz,7H),0.89–0.82(m,15H).13C NMR(101MHz,CDCl3)δ172.94,171.58,171.10,171.03,131.26,124.75,97.61,83.17,80.66,76.15,74.43,72.60,72.28,72.09,56.47,55.79,52.38,51.60,51.24,49.29,44.96,39.69,38.51,37.97,37.06,34.18,31.39,29.88,29.83,28.30,28.11,26.30,25.91,23.65,22.45,21.94,21.55,21.42,19.06,18.18,17.99,17.84,17.46,16.65,16.06,15.91.HRMS(ESI)calcd for C46H75NO12K[M+K]+:872.4921,found 872.48657.
化合物CK-D-VAL-1的化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ7.07(d,J＝8.8Hz,1H,H-NH),5.11(d,J＝7.0Hz,1H,H-C24),4.99(td,J＝10.4,5.9Hz,1H),4.53–4.44(m,3H),4.40(s,1H),3.73(s,3H,OCH3),3.70(d,J＝4.6Hz,1H),3.64–3.59(m,2H),3.15(dq,J＝8.5,4.7Hz,1H),2.18(td,J＝10.5,8.7,4.3Hz,2H),2.05(d,J＝10.0Hz,7H),1.93(t,J＝10.9Hz,2H),1.86–1.75(m,3H),1.61(d,J＝15.7Hz,6H),1.54(dd,J＝12.1,6.1Hz,3H),1.26(d,J＝15.0Hz,8H),0.97(s,4H),0.92(d,J＝6.6Hz,7H),0.89–0.81(m,15H).13C NMR(101MHz,CDCl3)δ172.87,171.37,171.17,171.03,131.45,124.62,97.58,83.03,80.66,76.16,74.42,72.46,72.22,71.90,56.66,55.79,52.40,51.34,51.25,49.33,44.97,39.69,38.50,37.97,37.05,34.19,31.09,29.99,28.35,28.11,26.27,25.93,23.65,22.58,21.99,21.69,21.42,19.08,18.17,18.01,17.82,17.59,16.65,16.03,15.93.HRMS(ESI)calcd for C46H74NO12[M-H]-:832.5217,found 832.52393.
实施例14合成化合物CK-8
用电子天平称取100mg CK-3(0.12mmol)溶解于10mL无水二氯甲烷中，加入50mgDCC作为缩合剂，30mg DMAP作为催化剂，加入1.2当量的正辛酸进行酯化反应，薄层色谱TLC(P/E＝2:1)检测反应，待反应过夜，用5mL饱和碳酸氢钠溶液萃取有机相3次，所得有机相用水洗涤1次，无水硫酸钠干燥，过滤，减压浓缩，所得浓缩物通过硅胶柱色谱进行纯化(P/E＝3:1)，所得白色泡沫状固体化合物CK-8(93.4mg,81.2％)。
化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ5.29(s,1H),5.18(t,J＝9.4Hz,1H,H-C24),5.04-4.96(m,2H),4.91(t,J＝8.7Hz,1H),4.81(td,J＝10.8,4.9Hz,1H),4.66(d,J＝7.8Hz,1H),4.47(dd,J＝10.9,4.9Hz,1H),4.12(d,J＝4.0Hz,1H),3.64(dt,J＝9.0,4.0Hz,1H),2.30(t,J＝7.7Hz,2H).2.05-1.96(m,16H),1.66-1.57(m,12H),1.28(dd,J＝16.4,9.2Hz,18H),1.16(s,4H),0.95(s,3H),0.92-0.82(m,21H).13C NMR(101MHz,CDCl3)δ173.68,171.06,170.58,170.42,169.62,169.24,131.65,124.61,94.85,83.36,80.77,75.30,73.47,72.08,71.70,68.95,62.48,56.01,53.16,50.02,47.88,45.67,39.65,38.59,37.99,37.10,34.54,34.09,31.82,31.77,29.83,29.23,29.20,29.16,29.10,28.08,26.50,25.81,24.93,23.69,22.91,22.75,21.96,21.43,20.95,20.78,18.28,18.15,17.88,16.59,16.31,15.53,14.21.HRMS(ESI)calcd for C53H86O14Na[M+Na]+:981.5960,found 981.5863.
实施例15合成化合物CK-16
用电子天平称取100mg CK-3(0.12mmol)溶解于10mL无水二氯甲烷中，加入50mgDCC作为缩合剂，30mg DMAP作为催化剂，加入1.2当量的软脂酸进行酯化反应，薄层色谱TLC(P/E＝2:1)检测反应，待反应过夜，用5mL饱和碳酸氢钠溶液萃取有机相3次，所得有机相用水洗涤1次，无水硫酸钠干燥，过滤，减压浓缩，所得浓缩物通过硅胶柱色谱进行纯化(P/E＝3:1)，所得白色泡沫状固体化合物CK-16(104.7mg,81.5％)。
化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ5.30(s,1H),5.18(t,J＝9.4Hz,1H,H-C24),5.00(t,J＝9.6Hz,2H),4.91(t,J＝8.7Hz,1H),4.82(td,J＝10.7,4.9Hz,1H),4.66(d,J＝7.9Hz,1H),4.47(dd,J＝10.9,4.9Hz,1H),4.11(s,1H),3.64(dt,J＝9.2,4.0Hz,1H),2.31(q,J＝8.3,7.5Hz,2H),2.07-1.95(m,14H),1.84-1.72(m,3H),1.65(s,11H),1.53-1.48(m,3H),1.32-1.14(m,38H),0.98-0.79(m,21H).13C NMR(101MHz,CDCl3)δ173.68,171.05,170.59,170.41,169.62,169.23,131.65,124.61,94.84,83.35,80.77,75.30,73.48,72.09,71.70,68.95,62.47,56.01,53.16,50.03,47.86,45.65,39.66,39.19,38.60,38.00,37.10,34.55,34.10,32.06,31.80,29.84,29.80,29.65,29.50,29.30,29.21,28.09,26.50,25.82,24.95,23.69,22.94,22.83,22.02,21.96,21.43,20.95,20.78,18.29,18.15,17.88,16.59,16.32,15.53,14.26.HRMS(ESI)calcdfor C61H102O14Na[M+Na]+:1093.7162,found 1093.7125.
实施例16合成化合物CK-18
用电子天平称取100mg CK-3(0.12mmol)溶解于10mL无水二氯甲烷中，加入50mgDCC作为缩合剂，30mg DMAP作为催化剂，加入1.2当量的硬脂酸进行酯化反应，薄层色谱TLC(P/E＝2:1)检测反应，待反应过夜，用5mL饱和碳酸氢钠溶液萃取有机相3次，所得有机相用水洗涤1次，无水硫酸钠干燥，过滤，减压浓缩，所得浓缩物通过硅胶柱色谱进行纯化(P/E＝3:1)，所得白色泡沫状固体化合物CK-18(108.1mg,82％)。
化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ7.62(dt,J＝74.8,4.2Hz,1H),5.17(d,J＝9.4Hz,1H),5.06–4.96(m,2H),4.91(t,J＝8.7Hz,1H),4.82(q,J＝6.0Hz,1H),4.67(d,J＝7.9Hz,1H),4.48(dd,J＝10.9,4.9Hz,1H),4.30(q,J＝6.1,5.5Hz,1H),4.11(d,J＝6.4Hz,2H),3.64(dd,J＝9.4,4.7Hz,1H),2.30(t,J＝7.6Hz,2H),2.05–1.96(m,13H),1.58(s,12H),1.26(d,J＝10.6Hz,42H),0.96(s,4H),0.92–0.83(m,21H).13CNMR(101MHz,CDCl3)δ173.70,171.07,170.60,170.43,169.63,169.25,131.66,124.62,94.85,83.36,80.78,75.31,73.49,72.10,71.71,68.95,62.48,56.02,53.17,50.03,47.87,45.66,39.66,39.20,38.60,38.01,37.24,37.11,34.55,34.11,33.92,32.89,32.07,30.18,29.85,29.81,29.74,29.66,29.58,29.51,29.39,29.31,29.21,28.09,27.23,26.51,25.83,24.95,24.85,23.69,22.95,22.84,21.97,21.43,20.96,20.79,19.87,18.15,17.89,16.59,16.33,15.54,14.27.HRMS(ESI)calcd for C63H106O14Na[M+Na]+:1121.7475,found 1121.7434.
实施例14-16化合物的合成反应式如下：
Figure BDA0003106010210000571
实施例16合成化合物CK-PC-a
用电子天平称取100mg CK-3(0.12mmol)溶解于10mL无水二氯甲烷中，加入50mgDCC作为缩合剂，30mg DMAP作为催化剂，加入1.2当量的苯甲酸进行酯化反应，薄层色谱TLC(P/E＝2:1)检测反应，待反应过夜，用5mL饱和碳酸氢钠溶液萃取有机相3次，所得有机相用水洗涤1次，无水硫酸钠干燥，过滤，减压浓缩，所得浓缩物通过硅胶柱色谱进行纯化(P/E＝3:1)，所得白色泡沫状固体化合物CK-PC-a(52.1mg,46.4％)。
化合物结构表征数据为：
CK-PC-a：1H NMR(400MHz,Chloroform-d)δ8.04(d,J＝7.7Hz,2H),7.63-7.54(m,1H),7.46(t,J＝7.6Hz,2H),5.23(t,J＝9.4Hz,1H),5.12(t,J＝9.6Hz,1H,H-C24),5.00-4.86(m,2H),4.79(dt,J＝10.8,5.2Hz,1H),4.74(t,J＝7.2Hz,1H),4.50-4.40(m,2H),4.30(dd,J＝12.1,5.6Hz,1H),3.89-3.73(m,1H),2.02(dd,J＝14.9,5.8Hz,13H),1.89-1.78(m,4H),1.76-1.67(m,2H),1.58(dd,J＝24.2,14.1Hz,11H),1.49-1.37(m,4H),1.26(dq,J＝7.9,4.2,3.7Hz,2H),1.16(s,4H),0.94(s,4H),0.90-0.78(m,14H).13C NMR(101MHz,CDCl3)δ171.08,170.59,170.41,169.65,169.29,166.34,133.39,131.65,129.88,129.70,128.59,124.50,94.95,83.49,80.75,75.31,73.45,72.10,71.59,69.12,63.34,55.94,53.04,49.91,48.02,45.71,39.60,38.95,38.56,37.97,37.05,34.45,31.64,29.09,28.06,26.51,25.73,23.66,22.75,21.94,21.71,21.44,20.97,20.80,18.24,18.00,17.86,16.58,16.27,15.51.HRMS(ESI)calcd for C53H80NO14[M+NH4]+:954.9573,found954.55518.
实施例17合成化合物CK-Q
利用swern氧化，在氮气保护下，将11μL草酰氯(0.13mmol)滴加于无水二氯甲烷(0.2M)中，然后将该反应浴置于-78℃下，在该混合液中滴加20μL,DMSO(0.26mmol)后，加入100mg CK-3(0.12mmol)，搅拌30min后滴加84μL三乙胺(0.6mmol)，然后将反应置于室温下继续反应4个小时，薄层色谱TLC(P/E＝3:1)监测反应完全后，加入饱和氯化铵停止反应，用5mL二氯甲烷萃取3次，所得有机相饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，所得浓缩物通过硅胶柱色谱进行纯化(P/E＝3:1)，所得产物CK-Q(74.7mg,72.5％)。
化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ9.25(s,1H,-O-CH＝),5.97(d,J＝4.5Hz,1H),5.49(d,J＝2.7Hz,1H),5.23(d,J＝4.5Hz,1H,H-C24),5.02(s,1H),5.01–4.95(m,1H),4.48(dd,J＝11.0,4.9Hz,1H),2.16–2.11(m,1H),2.08(s,7H),2.03(s,4H),1.97(s,3H),1.86(t,J＝9.8Hz,3H),1.73(dd,J＝10.8,5.9Hz,3H),1.62(d,J＝10.7Hz,8H),1.54(d,J＝9.1Hz,6H),1.43(d,J＝9.4Hz,2H),1.27(d,J＝13.3Hz,5H),0.98(s,4H),0.94(s,4H),0.85(d,J＝12.8Hz,11H).13C NMR(101MHz,CDCl3)δ186.78,171.03,170.46,170.21,169.62,150.02,131.68,124.42,114.92,91.54,84.56,80.73,75.12,69.53,64.76,56.01,53.26,50.18,47.12,46.19,40.26,39.71,38.59,38.00,37.14,34.54,32.16,29.19,28.08,26.51,25.75,23.69,23.00,21.88,21.42,20.98,20.95,20.66,18.51,18.29,17.80,16.57,16.35,15.60.HRMS(ESI)calcd for C46H68NaO12[M+Na]+:835.4603,found.
实施例18合成化合物CK-H
称取100mg CK-Q(0.12mmol)溶解于580μL无水乙醇中，在冰浴，氮气保护条件下加入12mg盐酸羟胺(0.16mmol)和16mg碳酸氢钠固体(0.2mmol)，薄层色谱TLC(P/E＝3:1)检测反应结束后，进行过滤，将滤液浓缩柱层析后得到产物得白色泡沫状固体化合物CK-H(101mg,99％)。
化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ7.51(s,1H,-O-CH＝),5.42(d,J＝2.7Hz,1H),5.31(d,J＝4.7Hz,1H),5.13(t,J＝5.1,2.1Hz,H-C24),5.00(t,J＝3.0Hz,2H),4.82(td,J＝10.8,4.7Hz,1H),4.48(dd,J＝10.9,5.0Hz,1H),2.15–2.10(m,1H),2.08(s,3H),2.05(d,J＝7.8Hz,7H),1.98(s,3H),1.86(dd,J＝11.4,8.7Hz,3H),1.77(dd,J＝13.3,4.3Hz,3H),1.64(s,7H),1.53(d,J＝2.5Hz,6H),1.45–1.40(m,2H),1.30–1.23(m,7H),0.98(s,4H),0.94(d,J＝10.1Hz,4H),0.86(d,J＝13.0Hz,11H).13C NMR(101MHz,CDCl3)171.09,170.61,170.48,169.77,146.57,145.69,131.47,124.65,104.27,91.45,84.01,80.77,75.20,69.39,65.19,56.04,53.31,50.28,47.24,46.22,39.87,39.71,38.60,38.01,37.15,34.56,32.34,29.83,29.25,28.08,26.52,25.80,23.69,23.03,21.90,21.44,21.19,21.14,21.04,20.74,18.56,18.30,17.79,16.57,16.38,15.60.HRMS(ESI)calcd for C46H69KO12[M+K]+:866.4452,found 868.46539.
实施例19合成化合物CK-M
称取100mg CK-Q(0.12mmol)溶解于无水吡啶中，在冰浴，氮气保护条件下加入15mg甲氧氨基盐酸盐(0.18mmol)，薄层色谱TLC(P/E＝3:1)检测反应结束后，减压除去溶剂，用5mL二氯甲烷萃取3次，所得有机相水洗涤，无水硫酸钠干燥，过滤，浓缩，所得浓缩物通过硅胶柱色谱进行纯化(P/E＝4:1)，得到产物得白色泡沫状固体化合物CK-M(103mg,99％)。
化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ7.44(s,1H,-O-CH＝),5.46(d,J＝2.6Hz,1H),5.28(d,J＝4.7Hz,1H),5.12(d,J＝4.1Hz,1H,H-C24),5.03(t,J＝7.0Hz,1H),4.98(s,1H),4.81(td,J＝10.8,4.7Hz,1H),4.47(dd,J＝10.8,5.0Hz,1H),4.30(t,J＝6.7Hz,1H),3.92(s,3H,OCH3),2.16(td,J＝8.7,5.3Hz,1H),2.08–2.02(m,9H),1.97(s,3H),1.89–1.83(m,3H),1.83–1.77(m,3H),1.62(d,J＝14.4Hz,7H),1.57(s,6H),1.46–1.40(m,2H),1.27(d,J＝15.2Hz,6H),0.99(s,4H),0.95(d,J＝2.8Hz,4H),0.85(d,J＝12.7Hz,11H).13C NMR(101MHz,CDCl3)δ171.05,170.48,170.45,169.80,146.55,144.33,131.35,124.76,104.22,91.24,84.12,80.75,75.22,69.49,65.18,62.58,56.05,53.34,50.25,47.41,46.30,39.73,39.70,38.59,38.01,37.15,34.58,32.35,30.70,29.21,28.09,26.51,25.78,23.69,22.96,21.85,21.43,21.16,21.01,20.65,18.58,18.30,17.78,16.57,16.37,15.60.HRMS(ESI)calcd for C47H70NNaO12[M-H]-:840.4892,found840.49237.
实施例20合成化合物CK-Q-1
称取50mg CK-Q(0.06mmol)溶解于5mL二氯甲烷-甲醇(V:V，1：1)混合溶剂中，室温条件下加入催化量的甲醇钠。薄层色谱TLC(D/M＝40:1)监测反应结束后，加入阳离子交换树脂中和至pH＝7，过滤去除阳离子交换树脂，滤液浓缩，浓缩物经硅胶柱色谱(D/M＝40:1)纯化，所得白色泡沫状固体产物CK-Q-1(43.3mg,99％)。
化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ9.22(s,1H,-O-CH＝),5.89(d,J＝3.6Hz,1H),5.20(d,J＝5.9Hz,1H),5.06(t,J＝7.2Hz,1H,H-C24),4.93(td,J＝10.5,5.6Hz,1H),4.47(dd,J＝11.1,4.8Hz,1H),4.30(q,J＝7.3,6.0Hz,1H),3.67(t,J＝5.7Hz,1H),2.23–2.14(m,1H),2.02(d,J＝9.3Hz,7H),1.83(dd,J＝16.0,8.7Hz,4H),1.67(s,5H),1.60(s,4H),1.57–1.52(m,3H),1.46(dt,J＝13.7,3.9Hz,4H),1.31–1.23(m,9H),0.97(s,3H),0.93(s,3H),0.85(d,J＝8.5Hz,12H).13C NMR(101MHz,CDCl3)δ186.44,172.22,171.10,148.88,131.66,124.62,120.02,96.09,84.77,80.73,80.69,74.64,70.60,67.69,55.84,51.98,50.35,49.54,45.55,39.65,38.50,37.96,37.05,34.24,31.71,30.60,28.62,28.08,26.44,25.85,23.64,22.78,22.48,21.95,21.44,21.24,18.18,18.04,17.86,16.62,16.06,15.82.HRMS(ESI)calcd for C42H64NaO10[M+Na]+:751.4392,found.
实施例21合成化合物CK-M-1
称取50mg CK-M(0.06mmol)溶解于5mL二氯甲烷-甲醇(V:V，1：1)混合溶剂中，室温条件下加入催化量的甲醇钠。薄层色谱TLC(D/M＝40:1)监测反应结束后，加入阳离子交换树脂中和至pH＝7，过滤去除阳离子交换树脂，滤液浓缩，浓缩物经硅胶柱色谱(D/M＝40:1)纯化，所得白色泡沫状固体产物CK-Q-1(45mg,99％)。
化合物结构表征数据为：1H NMR(400MHz,Chloroform-d)δ7.44(s,1H,-O-CH＝),5.32–5.28(m,2H),5.07(t,J＝7.1Hz,1H,H-C24),4.88(td,J＝10.7,5.2Hz,1H),4.48(dd,J＝10.9,4.9Hz,1H),4.07(d,J＝5.9Hz,1H),3.90(s,3H,OCH3),3.82–3.74(m,1H),2.21(td,J＝9.7,4.8Hz,1H),2.03(s,3H),2.00(s,4H),1.84(q,J＝10.9,8.8Hz,4H),1.65(d,J＝8.5Hz,5H),1.61(s,4H),1.49(ddd,J＝17.5,12.0,6.4Hz,6H),1.26(d,J＝10.0Hz,8H),1.10–1.04(m,3H),0.97(s,3H),0.94(s,3H),0.85(d,J＝9.3Hz,12H).13C NMR(101MHz,CDCl3)δ171.30,171.04,144.43,144.19,131.59,124.61,109.00,95.21,84.76,80.71,74.87,70.24,66.82,62.48,55.96,52.63,49.83,49.41,46.04,39.69,38.56,37.99,37.96,37.11,34.38,31.35,29.83,28.89,28.10,26.53,25.81,23.67,22.68,21.90,21.43,20.93,18.25,17.85,16.61,16.20,15.69.HRMS(ESI)calcd for C43H67NNaO10[M+Na]+:780.4657.
实施例17-21所合成化合物的主要反应式如下所示：
Figure BDA0003106010210000621
试验例1
人参皂苷CK衍生物在制备治疗抗肿瘤药物中的应用
本实验采用MTT法检测人参皂苷CK衍生物对肝癌细胞SMMC-7221、肺癌细胞A549增殖的抑制作用。取生长状态良好、细胞密度达到80％以上的SMMC-7221和A549细胞，加入胰酶消化，调整细胞密度为1×105个/mL，加入到96孔板中，每孔体积100μL，培养于37℃，5％细胞培养箱。24h后，弃掉上清，加入不同浓度的人参皂苷CK衍生物化合物(所述化合物来自本发明的实施例)(化合物用DMSO配置成母液，用培养基稀释)，对照组加入等体积的含0.25％DMSO的细胞培养基中，每个浓度设置6个复孔。48h后，每孔加入150μL MTT和细胞培养液的混合液，其对应的体积比为1:2，继续培养4h。小心移除培养基，加入150μL DMSO，缓慢振荡10min，使其溶解生成的蓝紫色结晶Formazan。最后在490nm处检测每个孔对应的吸光度OD值，并利用以下公式来计算细胞抑制率：细胞抑制率(％)＝(1-加药组平均OD值/对照组平均OD值)×100％。
MTT结果如表3和表4所示，在以人参皂苷CK为对照药，研究人参皂苷CK衍生物对肝癌细胞SMMC-7221、肺癌细胞A549的增殖抑制作用，通过对比半数抑制浓度(IC50)发现：人参皂苷CK系列衍生物CK-3、CK-4、CK-ILE-1、CK-TRP-1、CK-CK-PHE-1等的体外抗肿瘤活性均优于对照药人参皂苷CK。
表3人参皂苷CK衍生物对肝癌SMMC-7221细胞的抑制活性
Figure BDA0003106010210000631
表4人参皂苷CK衍生物对肺癌A549细胞的抑制活性
Figure BDA0003106010210000632
Figure BDA0003106010210000641
试验例2人参皂苷CK衍生物CK-ILE-1在肝癌皮下移植肿瘤模型中的药效评价
在人肝癌裸鼠异种移植瘤模型中，评价人参皂苷CK衍生物CK-ILE-1的疗效：4～5周龄的雌性BALB/c裸鼠，左侧腋窝皮下接种HCC-LM3细胞，每只裸鼠注射5×106个细胞。肿瘤体积达到100mm3以上时，将裸鼠随机分组，每组6只动物。组别分别为①模型组；②人参皂苷CK组，灌胃给药，人参皂苷CK给药剂量为50mg/kg；③CK-3低剂量组，灌胃给药，给药剂量为20mg/kg；④CK-ILE-1高剂量组，灌胃给药，给药剂量为50mg/kg。各组给药体积10mL/kg，每天给药一次，连续给药28天。每天观察1次，记录动物的临床状态，观察内容包括是否死亡、濒死、外观、精神状况及活动状况等。每周两次测试瘤长和瘤宽，并按如下公式计算肿瘤体积和抑瘤(％)。V＝0.5×a×b×b，a是肿瘤的长，b是肿瘤的宽。抑瘤率(％)＝(模型组V-实验组V)/模型组V×100％。
连续给药28天，动物临床症状无异常表现，各组体重均有一定程度的上升。肿瘤体积测试结果如图1和图2所示(均值±SEM)。其中，图1为给药后肿瘤体积随时间的变化曲线，图2为给药结束后肿瘤组织图片。结果显示，在人肝癌裸鼠异种移植瘤模型中，连续给药28天，模型组、人参皂苷CK、CK-ILE-1低剂量组和CK-ILE-1高剂量组的肿瘤体积分别为2669mm3、2076mm3、1727mm3和1142mm3，人参皂苷CK 50mg/kg组、CK-ILE-1 20mg/kg组和CK-ILE-1 50mg/kg组对肿瘤的抑制率分别为22.22％、35.29％和57.20％，可见，人参皂苷CK50mg/kg在该模型中没有明显的抑制效果，而CK-ILE-1 20mg/kg和50mg/kg抑瘤效果均优于人参皂苷CK 50mg/kg，具有明显的剂量依赖关系，且CK-ILE-1 50mg/kg与模型组相比，具有统计学差异。

Claims (7)

1.人参皂苷CK衍生物，其具有式(I)所示的结构：
Figure FDA0003931551080000011
其中，
R为氨基酸甲酯盐酸盐基团；
R1为O；
R2为H或乙酰基；
并且R3为乙酰基。
2.根据权利要求1所述的人参皂苷CK衍生物，其选自以下结构的化合物：
Figure FDA0003931551080000012
Figure FDA0003931551080000021
Figure FDA0003931551080000031
Figure FDA0003931551080000041
Figure FDA0003931551080000051
Figure FDA0003931551080000061
Figure FDA0003931551080000071
Figure FDA0003931551080000081
Figure FDA0003931551080000091
3.根据权利要求1所述的人参皂苷CK衍生物，其中，
所述氨基酸甲酯盐酸盐基团选自：组氨酸甲酯盐酸盐基团、异亮氨酸甲酯盐酸盐基团、丙氨酸甲酯盐酸盐基团、D-丙氨酸甲酯盐酸盐基团、亮氨酸甲酯盐酸盐基团、苯丙氨酸甲酯盐酸盐基团、D-苯丙氨酸甲酯盐酸盐基团、4-硝基-苯丙氨酸甲酯盐酸盐基团、4-氯-DL-苯丙氨酸甲酯盐酸盐基团、脯氨酸甲酯盐酸盐基团、蛋氨酸甲酯盐酸盐基团、D-蛋氨酸甲酯盐酸盐基团、色氨酸甲酯盐酸盐基团、D-色氨酸甲酯盐酸盐基团、丝氨酸甲酯盐酸盐基团、甘氨酸甲酯盐酸盐基团、酪氨酸甲酯盐酸盐基团、天冬氨酸二甲酯盐酸盐基团、半胱氨酸甲酯盐酸盐基团、苏氨酸甲酯盐酸盐基团、谷氨酸二甲酯盐酸盐基团、缬氨酸甲酯盐酸盐基团、以及D-缬氨酸甲酯盐酸盐基团。
4.一种药物组合物，其包含权利要求1-3中任一项所述的人参皂苷CK衍生物和至少一种赋形剂。
5.权利要求1-3中任一项所述的人参皂苷CK衍生物或权利要求4所述的药物组合物在制备抗肿瘤药物中的用途。
6.根据权利要求5所述的用途，其中所述肿瘤为实体瘤。
7.根据权利要求6所述的用途，其中所述肿瘤为肝癌、肺癌、胃癌、结肠癌或乳腺癌。
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