CN111153910B - 地胆草种内酯衍生物及其制备方法和用途 - Google Patents
地胆草种内酯衍生物及其制备方法和用途 Download PDFInfo
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- CN111153910B CN111153910B CN202010020906.5A CN202010020906A CN111153910B CN 111153910 B CN111153910 B CN 111153910B CN 202010020906 A CN202010020906 A CN 202010020906A CN 111153910 B CN111153910 B CN 111153910B
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- pharmaceutically acceptable
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- elephantopin
- alkyl
- lactone derivative
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Abstract
本发明属于药物技术领域，具体涉及地胆草种内酯衍生物或其盐及其组合物，以及它们作为有效成分在制备治疗肿瘤或炎症药物中的应用。本发明提供了通式I、II、III、IV、V所示地胆草种内酯衍生物或其药学上可接受的盐与前药，其中，R1‑R5如权利要求书和说明书所述。
Description
技术领域
本发明属于药物技术领域，具体涉及地胆草种内酯衍生物或其盐及其组合物，以及它们作为有效成分在制备治疗肿瘤或炎症药物中的应用。
背景技术
天然活性产物具有结构新颖，药理活性多样的特点，是新药创制的重要来源，1981-2014年间上市的1211个药物小分子新化学实体药物中，约65％直接或间接来源于天然产物。我国药用植物资源丰富，从中发现新的活性分子，并对其结构改造将为进一步开发候选药物提供丰富多样的结构类型。
地胆草(Elephantopus scaber Linn.)为菊科地胆草属植物，广泛分布于美洲、亚洲、非洲等地区，在我国产于广东、广西、福建、江西、贵州及云南等地，全草入药，具有清热解毒、凉血、利湿之功效，用于治疗肺炎、肝炎、胃肠炎、扁桃体炎、咽喉炎、肾炎、细菌性痢疾。药理研究表明地胆草中主要活性成分为倍半萜内酯，因其具有显著的抗肿瘤、抗炎、肝保护等活性而备受关注。地胆草种内酯(scabertopin，cas：185213-52-9)为地胆草中含量较高的倍半萜内酯类成分，通过对其进行结构修饰和改造，将有助于进一步开发高效低毒的抗肿瘤、抗炎药物。
发明内容
本发明的目的是在不破坏活性中心α-亚甲基-γ-内酯的前提下，通过对地胆草种内酯的羟基进行结构修饰，以获得抗肿瘤、抗炎活性更好的地胆草种内酯新型衍生物，并提供这些衍生物的制备方法。本发明还提供地胆草种内酯衍生物的抗肿瘤、抗炎筛选结果及在制备抗肿瘤、抗炎药物中的用途。
发明的目的是通过以下具体技术方案实现的：
通式I、II、III、IV、V所示地胆草种内酯衍生物或其药学上可接受的盐与前药。
式I中，R1为H、C1-8直链或支链烷基、C1-8烷氧基、C3-6环烷基、未取代或取代的苄基、C1-8烷酰基、未取代或取代的苯甲酰基、未取代或取代肉桂酰基、联苯酰基、1-萘酰基、2-萘酰基、含1-3个选自N、O、S的杂原子的五元或六元杂芳酰基、-CO(CH2)nCOOH、-CO(CH2)mP+(Ph)3Br-，其中n和m分别为2-10之间的整数；所述的取代基为：卤素、C1-C6烷氧基、硝基、卤代C1-C6烷基、卤代C1-C6烷氧基、C1-C4酰基、氨基、3，4-亚甲二氧基。
优选地，所述R1为：H、C1-C4烷基、苯甲酰基、4-三氟甲基苯甲酰基、4-氟苯甲酰基、4-甲氧基苯甲酰基、4-硝基苯甲酰基、4-乙酰基苯甲酰基、肉桂酰基、4-氟肉桂酰基、4-氯肉桂酰基、4-甲氧基肉桂酰基、3-三氟甲基肉桂酰基、3，4亚甲二氧基肉桂酰基、3-甲氧基肉桂酰基、4-二甲氨基肉桂酰基、4-三氟甲基肉桂酰基、3，4-二氟肉桂酰基、2-萘甲酰基、2，2二甲基丁酰基、2-溴丁酰基、环丙甲酰基、环己甲酰基、4，4-二氟环己甲酰基、异戊酰基、己酰基、5-溴戊酰基、
苄基，4-氟苄基、4-溴苄基、4-氯苄基、4-甲氧基苄基、正戊基、异戊基、甲基、4-三氟甲基苄基、3-甲氧基苄基、3-三氟甲基苄基、4-硝基苄基、4-甲基苄基、3,4-二氟苄基、-CO(CH2)2COOH、-CO(CH2)4COOH、-CO(CH2)6COOH、-CO(CH2)3P+(Ph)3Br-、-CO(CH2)5P+(Ph)3Br-、-CO(CH2)7P+(Ph)3Br-；
优选地，n＝2-6，m＝3-7；
式II中，R2为C1-8直链或支链烷基、C1-8烷氧基、C1-8烷硫基、含1-3个选自N、O、S的杂原子的五元或六元杂芳酰基、未取代或取代的苯基或苄基；所述取代基为：卤素、C1-C6烷基，卤代C1-C6烷基、卤代C1-C6烷氧基、硝基、氨基；
R3为H、C3-6环烷基、C1-C6；
X为H、Boc保护基；
优选地，R2为甲基、
R3为H、环戊烷、环己烷、甲基，
X为H、Boc保护基；
式III中，R4为叠氮基、卤素、
其中R’为C1-8直链或支链烷基、C1-8烷氧基、C3-6环烷基、未取代或取代的苯基或苄基，含1-3个选自N、O、S的杂原子的五元或六元杂芳基；所述取代基为：卤素、C1-C6烷基，卤代C1-C6烷基；
优选地，R4为-N3、Cl、Br、
式IV中，R5为C1-8直链或支链烷基、C1-8烷氧基、C3-6环烷基、未取代或取代的苯基或苄基，含1-3个选自N、O、S的杂原子的五元或六元杂芳基；所述取代基为：卤素、C1-C6烷基，卤代C1-C6烷基；
优选地，R5为
式V中，R6为
-(CH2)p-，其中p为2-10之间的整数，或-(CH2)qR”r(CH2)q-，其中R”为硫或硒原子，q为2-5之间的整数，r为1-2的整数；
优选地，p＝4-6。
本发明包含但不仅限于以上取代基或侧链，一切符合本发明要求的衍生物都应包含在本发明保护的范围以内。
本发明进一步优选地胆草种内酯衍生物或其药学上可接受的盐与前药为下列化合物之一：
本发明中所述的结构通式I-V的化合物，其不仅包括单一的某种化合物形式，还包括多种结构满足通式I-V要求的化合物的混合物形式。“药学上可接受的盐”是指在可靠的医药评价范围内，包括但不限于硫酸盐、盐酸盐、氢溴酸盐、磷酸盐、醋酸盐、甲磺酸盐、苯磺酸盐、甲基苯磺酸盐、酒石酸盐、马来酸盐、苯甲酸盐、琥珀酸盐、延胡索酸盐、富马酸盐、酒石酸盐、没食子酸盐、柠檬酸盐以及铵盐、钠盐、钾盐等。
本发明中所述的“前药”是指药学上可接受的衍生物，以便这些衍生物所得的生物转换产物是如式I-V化合物所定义的活性药物,可有效地用于其预期的用途。
本发明所述药物组合物包含本发明通式I-V化合物与常规药用载体或赋形剂，可通过例如口服或非肠道等途径给药。本发明的药物组合物可按本领域常规方法制备成各种剂型，包括但不限于、胶囊片剂、溶液、悬浮液、颗粒剂或注射剂等。
本发明所述的地胆草种内酯衍生物或其盐及其组合物具有明显的抗肿瘤或抗炎作用，可以作为有效成分制备抗肿瘤或抗炎症药物。
具体实施方式
下面通过具体实施例对本发明作进一步的描述，这些描述并不是本发明作进一步的限定。本领域的技术人员应理解，对本发明的技术特征所作的等同替换或相应的改进，仍属于本发明的保护范围之内。本发明的典型化合物包括如下化合物或其药学上可接受的盐，但不限于这些：
实施例1：S1的制备
(a)向50mL圆底烧瓶中加入地胆草种内酯(200mg,0.56mmol)，无水K2CO3(38.68mg,0.28mmol)，无水甲醇10mL，室温搅拌4h。反应结束后加适量稀盐酸调节至中性，减压蒸干，加水搅拌，再经乙酸乙酯萃取三次，合并有机相，减压蒸馏除去溶剂，得到粗产物中间体1。再经反相半制备液相制备，流动相MeCN-H2O(85:15,v/v)，得到中间体1，结构鉴定数据如下：m/z:[M+Na]+＝331.1155,1H NMR(CDCl3,400MHz):δ6.97(s,1H),5.34(d,J＝3.7Hz,1H),4.99(d,J＝9.6Hz,1H),4.22(td,J＝10.2,2.3Hz,1H),3.84(m,1H),3.74(dd,J＝8.8,3.4Hz,1H),3.62(m,1H),3.43(s,3H),2.97(td,J＝6.9,3.5Hz,1H),2.90(d,J＝4.0Hz,1H),2.88(d,J＝4.8Hz,1H),2.75(t,J＝11.9Hz,1H),2.57(dt,J＝10.2,6.5Hz,1H),2.21(dd,J＝14.7,4.8Hz,1H),1.59(s,3H)；13C NMR(CDCl3,100MHz):δ175.4,174.1,147.4,131.3,130.8,130.1,81.7,79.6,72.4,71.8,59.5,51.4,46.3,40.1,30.8,21.7.
(b)向50mL圆底烧瓶中加入中间体1(120mg,0.39mmol)，甲苯25mL，搅拌的条件下加入DBU(118.5mg,0.78mmol)，60℃搅拌反应8h。反应结束后加适量稀盐酸调节至中性，减压蒸干，加水搅拌，再经乙酸乙酯萃取三次，合并有机相，减压蒸馏除去溶剂，得到粗产物S1。再经反相半制备液相制备，流动相MeCN-H2O(85:15,v/v)，得到S1单体化合物，结构鉴定数据如下：m/z:[M+Na]+＝299.0892,1H NMR(CDCl3,400MHz):δ7.03(s,1H),6.42(d,J＝2.4Hz,1H),6.15(d,J＝1.5Hz,1H),5.37(d,J＝3.9Hz,1H),5.03(d,J＝9.6Hz,1H),4.24(t,J＝9.7Hz,1H),3.78(dt,J＝11.4,4.2Hz,1H),3.07(m,1H),2.94(dd,J＝8.8,2.9Hz,1H),2.90(d,J＝7.9Hz,1H),2.72(t,J＝12.0Hz,1H),2.25(dd,J＝14.7,4.7Hz,1H),1.61(s,3H)；13C NMR(CDCl3,100MHz):δ174.3,169.7,148.0,134.4,131.8,131.0,129.9,128.4,81.0,79.7,70.6,49.8,40.0,30.6,21.9.
实施例2：S2的制备
(1)向10mL圆底烧瓶中加入中间体1(10mg,32.4μmol)，干燥的THF 3mL，NaH(7.8mg,0.32mmol)，0℃搅拌30分钟后，加入溴化苄(27.7mg,0.16mmol)，TBAB(5mg,0.032mmol)，室温搅拌反应8h。反应完全后加3mL水终止反应，将反应液置于分液漏斗中，取有机层，水相再经乙酸乙酯萃取，合并有机相，减压蒸馏除去溶剂，得到粗产物S2a。再经反相半制备液相制备，流动相MeCN-H2O(45:55,v/v)，得到S2a单体化合物(8.3mg,收率66.4％)，结构鉴定数据如下：m/z:[M+H]+＝385.4314,1H NMR(CDCl3,400MHz):δ8.02(d,J＝7.3Hz,2H),7.59(t,J＝7.5Hz,1H),7.47(t,J＝7.7Hz,2H),7.07(s,1H),6.34(d,J＝2.7Hz,1H),5.92(d,J＝2.3Hz,1H),5.58(t,J＝10.2Hz,1H),5.40(d,J＝4.0Hz,1H),5.06(d,J＝9.8Hz,1H),3.94(dt,J＝11.4,4.1Hz,1H),3.46(ddt,J＝10.2,4.9,2.5Hz,1H),3.43(s,3H),3.01(dd,J＝12.8,3.6Hz,1H),2.94(d,J＝14.8Hz,1H),2.81(t,J＝12.1Hz,1H),2.28(dd,J＝14.8,4.6Hz,1H),1.78(d,J＝1.1Hz,3H).
(2)向10mL圆底烧瓶中加入S2a(10mg,0.026mmol)，甲苯3mL，搅拌的条件下加入DBU(7.9mg,0.052mmol)，60℃搅拌反应8h。反应结束后加适量稀盐酸调节至中性，减压蒸干，加水搅拌，再经乙酸乙酯萃取三次，合并有机相，减压蒸馏除去溶剂，得到粗产物S2。再经反相半制备液相制备，流动相MeCN-H2O(45:55,v/v)，得到S2单体化合物(6.4mg,收率69.9％)，结构鉴定数据如下：m/z:[M+H]+＝353.3990,1H NMR(CDCl3,400MHz):δ8.02(d,J＝7.3Hz,2H),7.59(t,J＝7.5Hz,1H),7.47(t,J＝7.7Hz,2H),7.07(s,1H),6.34(d,J＝2.7Hz,1H),5.92(d,J＝2.3Hz,1H),5.58(t,J＝10.2Hz,1H),5.40(d,J＝4.0Hz,1H),5.06(d,J＝9.8Hz,1H),3.94(dt,J＝11.4,4.1Hz,1H),3.46(ddt,J＝10.2,4.9,2.5Hz,1H),3.01(dd,J＝12.8,3.6Hz,1H),2.94(d,J＝14.8Hz,1H),2.81(t,J＝12.1Hz,1H),2.28(dd,J＝14.8,4.6Hz,1H),1.78(d,J＝1.1Hz,3H).
实施例3：S3的制备
操作同实施例2，不同的是使用碘甲烷,流动相MeCN-H2O(40:60,v/v)，得到S3单体化合物收率64.8％，结构鉴定数据如下：m/z:[M+Na]+＝313.3224,1H NMR(CDCl3,400MHz):δ7.03(s,1H),6.42(d,J＝2.4Hz,1H),6.15(d,J＝1.5Hz,1H),5.37(d,J＝3.9Hz,1H),5.03(d,J＝9.6Hz,1H),4.24(t,J＝9.7Hz,1H),3.78(dt,J＝11.4,4.2Hz,1H),3.43(s,3H),3.07(m,1H),2.94(dd,J＝8.8,2.9Hz,1H),2.90(d,J＝7.9Hz,1H),2.72(t,J＝12.0Hz,1H),2.25(dd,J＝14.7,4.7Hz,1H),1.61(s,3H).
实施例4：S4的制备
操作同实施例2，不同的是使用4-甲氧基溴化苄，流动相MeCN-H2O(45:55,v/v)，得到S4单体化合物收率，58.7％，结构鉴定数据如下：m/z:[M+H]+＝497.4418,1H NMR(CDCl3,400MHz):δ7.97(d,J＝8.9Hz,2H),7.05(s,1H),6.94(d,J＝8.9Hz,2H),6.34(d,J＝2.7Hz,1H),5.92(d,J＝2.2Hz,1H),5.56(t,J＝10.2Hz,1H),5.40(d,J＝4.2Hz,1H),5.06(d,J＝9.7Hz,1H),3.96～3.90(m,1H),3.87(s,3H),3.45(ddt,J＝10.1,4.9,2.5Hz,1H),3.01(dd,J＝12.9,3.6Hz,1H),2.94(d,J＝14.8Hz,1H),2.85-2.78(m,1H),2.28(dd,J＝14.8,4.6Hz,1H),1.78(d,J＝1.2Hz,3H).
实施例5：S5的制备
向10mL圆底烧瓶中加入S1(17mg,0.62mmol)，丁二酸(73mg,0.62mmol)，EDCI(118mg,0.62mmol)，DMAP(7.5mg,0.062mmol)，干燥的DCM 3mL，室温搅拌反应8h。反应完全后加3mL水终止反应，将反应液置于分液漏斗中，取有机层，水相再经乙酸乙酯萃取，合并有机相，减压蒸馏除去溶剂，得到粗产物S5。再经反相半制备液相制备，流动相MeCN-H2O(50:50,v/v)，得到S5单体化合物(12.8mg,收率54.7％)，结构鉴定数据如下：m/z:[M+Na]+＝403.1151,1H NMR(CDCl3,600MHz):δ7.07(s,1H),6.38(d,J＝2.7Hz,1H),5.89(d,J＝2.3Hz,1H),5.58(t,J＝10.2Hz,1H),5.40(d,J＝4.0Hz,1H),5.06(d,J＝9.8Hz,1H),3.94(dt,J＝11.4,4.1Hz,1H),3.46(ddt,J＝10.2,4.9,2.5Hz,1H),3.01(dd,J＝12.8,3.6Hz,1H),2.94(d,J＝14.8Hz,1H),2.81(t,J＝12.1Hz,1H),2.39-2.29(m,4H),2.26(dd,J＝14.8,4.6Hz,1H),1.78(d,J＝1.1Hz,3H).
实施例6：S6的制备
操作同实施例5，不同的是使用己二酸,流动相MeCN-H2O(30:70,v/v)，得到S6单体化合物收率，88.7％，结构鉴定数据如下：m/z:[M+Na]+＝427.1363,1H NMR(CDCl3,600MHz):δ7.04(s,1H),6.40(d,J＝2.6Hz,1H),5.90(d,J＝2.0Hz,1H),5.37(d,J＝4.0Hz,1H),5.23(t,J＝10.2Hz,1H),4.90(d,J＝9.8Hz,1H),3.84(dt,J＝11.4,4.1Hz,1H),3.27(dtd,J＝7.0,4.7,2.5Hz,1H),2.96(dd,J＝12.8,3.5Hz,1H),2.92(d,J＝14.8Hz,1H),2.74(t,J＝12.1Hz,1H),2.39-2.29(m,4H),2.26(dd,J＝14.8,4.6Hz,1H),1.70(d,J＝1.0Hz,3H),1.68-1.60(m,4H).
实施例7：S7的制备
操作同实施例5，不同的是使用辛二酸,流动相MeCN-H2O(40:60,v/v)，得到S7单体化合物,收率73.7％，结构鉴定数据如下：m/z:[M+Na]+＝455.1676,1H NMR(CDCl3,600MHz):δ7.04(s,1H),6.40(d,J＝2.7Hz,1H),5.91(d,J＝1.8Hz,1H),5.38(d,J＝4.1Hz,1H),5.23(t,J＝10.2Hz,1H),4.90(d,J＝9.8Hz,1H),3.85(dt,J＝11.4,4.1Hz,1H),3.27(ddt,J＝10.2,4.8,2.5Hz,1H),2.96(dd,J＝12.8,3.6Hz,1H),2.93(d,J＝14.8Hz,1H),2.75(t,J＝12.1Hz,1H),2.36-2.24(m,6H),1.71(d,J＝1.2Hz,3H),1.64-1.57(m,4H),1.36-1.28(m,4H).
实施例8：S8的制备
操作同实施例5，不同的是使用苯甲酸,流动相MeCN-H2O(40:60,v/v)，得到S8单体化合物,收率73.7％，结构鉴定数据如下：m/z:[M+Na]+＝403.1151,1H NMR(CDCl3,400MHz):δ8.02(d,J＝7.3Hz,2H),7.59(t,J＝7.5Hz,1H),7.47(t,J＝7.7Hz,2H),7.07(s,1H),6.34(d,J＝2.7Hz,1H),5.92(d,J＝2.3Hz,1H),5.58(t,J＝10.2Hz,1H),5.40(d,J＝4.0Hz,1H),5.06(d,J＝9.8Hz,1H),3.94(dt,J＝11.4,4.1Hz,1H),3.46(ddt,J＝10.2,4.9,2.5Hz,1H),3.01(dd,J＝12.8,3.6Hz,1H),2.94(d,J＝14.8Hz,1H),2.81(t,J＝12.1Hz,1H),2.26(dd,J＝14.8,4.6Hz,1H),1.78(d,J＝1.1Hz,3H).
实施例9：S9的制备
操作同实施例5，不同的是使用4-氟苯甲酸,流动相MeCN-H2O(50:50,v/v)，得到S9单体化合物,收率52.6％，结构鉴定数据如下：m/z:[M+Na]+＝421.1058,1H NMR(CDCl3,600MHz):δ8.06-8.01(m,2H),7.15(t,J＝8.6Hz,2H),7.06(s,1H),6.35(d,J＝2.7Hz,1H),5.87(d,J＝2.2Hz,1H),5.57(t,J＝10.2Hz,1H),5.40(d,J＝4.1Hz,1H),5.06(d,J＝9.8Hz,1H),3.92(dt,J＝11.4,4.1Hz,1H),3.50-3.41(m,1H),3.01(dd,J＝12.9,3.6Hz,1H),2.94(d,J＝14.8Hz,1H),2.81(t,J＝12.0Hz,1H),2.29(dd,J＝14.8,4.6Hz,1H),1.78(d,J＝1.2Hz,3H).
实施例10：S10的制备
操作同实施例5，不同的是使用肉桂酸,流动相MeCN-H2O(50:50,v/v)，得到S10单体化合物,收率83.3％，结构鉴定数据如下：m/z:[M+Na]+＝429.1309,1H NMR(CDCl3,600MHz):δ7.69(d,J＝16.0Hz,1H),7.53(dd,J＝6.5,2.9Hz,2H),7.44-7.38(m,3H),7.05(s,1H),6.40(dd,J＝9.3,6.7Hz,2H),5.96(d,J＝2.0Hz,1H),5.45(t,J＝10.2Hz,1H),5.39(d,J＝4.1Hz,1H),5.02(d,J＝9.8Hz,1H),3.90(dt,J＝11.4,4.1Hz,1H),3.38(ddt,J＝10.1,4.8,2.5Hz,1H),3.00(dd,J＝12.9,3.6Hz,1H),2.95(d,J＝14.8Hz,1H),2.79(t,J＝12.1Hz,1H),2.28(dd,J＝14.8,4.6Hz,1H),1.76(dd,J＝1.1Hz,3H).
实施例11：S11的制备
操作同实施例5，不同的是使用4-氟肉桂酸,流动相MeCN-H2O(50:50,v/v)，得到S11单体化合物,收率64.6％，结构鉴定数据如下：m/z:[M+Na]+＝447.1224,1H NMR(CDCl3,600MHz):δ7.65(d,J＝16.0Hz,1H),7.52(dd,J＝8.6,5.4Hz,2H),7.08(dd,J＝16.1,7.5Hz,3H),6.39(d,J＝2.7Hz,1H),6.32(d,J＝16.0Hz,1H),5.94(d,J＝2.0Hz,1H),5.45(t,J＝10.2Hz,1H),5.39(d,J＝3.9Hz,1H),5.01(d,J＝9.8Hz,1H),3.90(dt,J＝11.4,4.1Hz,1H),3.37(dtd,J＝7.1,4.7,2.4Hz,1H),3.00(dd,J＝12.8,3.5Hz,1H),2.94(d,J＝14.8Hz,1H),2.78(t,J＝12.1Hz,1H),2.28(dd,J＝14.8,4.6Hz,1H),1.75(d,J＝1.0Hz,3H).
实施例12：S12的制备
操作同实施例5，不同的是使用2-萘甲酸,流动相MeCN-H2O(50:50,v/v)，得到S12单体化合物,收率93.8％，结构鉴定数据如下：m/z:[M+Na]+＝453.1309,1H NMR(CDCl3,600MHz):δ7.69(d,J＝16.0Hz,1H),7.53(dd,J＝6.5,2.9Hz,2H),7.44-7.38(m,3H),7.05(s,1H),6.40(dd,J＝9.3,6.7Hz,2H),5.96(d,J＝2.0Hz,1H),5.45(t,J＝10.2Hz,1H),5.39(d,J＝4.1Hz,1H),5.02(d,J＝9.8Hz,1H),3.90(dt,J＝11.4,4.1Hz,1H),3.38(ddt,J＝10.1,4.8,2.5Hz,1H),3.00(dd,J＝12.9,3.6Hz,1H),2.95(d,J＝14.8Hz,1H),2.79(t,J＝12.1Hz,1H),2.28(dd,J＝14.8,4.6Hz,1H),1.76(dd,J＝1.1Hz,3H).
实施例13：S13的制备
操作同实施例5，不同的是使用4-吡啶甲酸,流动相MeCN-H2O(30:70,v/v)，得到S13单体化合物,收率73.8％，结构鉴定数据如下，m/z:[M+H]+＝382.1285,1H NMR(CDCl3,600MHz):δ8.84(s,2H),7.84(d,J＝2.9Hz,2H),7.08(s,1H),6.35(d,J＝2.7Hz,1H),5.84(d,J＝2.2Hz,1H),5.58(t,J＝10.3Hz,1H),5.41(d,J＝4.0Hz,1H),5.05(d,J＝9.7Hz,1H),3.92(dt,J＝11.4,4.1Hz,1H),3.47(dtd,J＝7.0,4.7,2.5Hz,1H),3.02(dd,J＝12.9,3.5Hz,1H),2.94(d,J＝14.8Hz,1H),2.81(t,J＝12.2Hz,1H),2.30(dd,J＝14.9,4.6Hz,1H),1.79(d,J＝1.0Hz,3H).
实施例14：S14的制备
(a)向10mL圆底烧瓶中加入S1(20mg,0.07mmol)，4-溴丁酸(117mg,0.7mmol)，EDCI(138.8mg,0.7mmol)，DMAP(8.8mg,0.07mmol)，干燥的DCM 3mL，室温搅拌反应8h。反应完全后加3mL水终止反应，将反应液置于分液漏斗中，取有机层，水相再经乙酸乙酯萃取(4mL×3)，合并有机相，减压蒸馏除去溶剂，得到粗产物S14a。再经反相半制备液相制备，流动相MeCN-H2O(45:55,v/v)，得到S14a单体化合物(22.4mg,收率70.4％)，结构鉴定数据如下：m/z:[M+Na]+＝439.0560,1H NMR(CDCl3,600MHz):δ7.02(s,1H),6.42(d,J＝2.3Hz,1H),5.91(d,J＝1.7Hz,1H),5.38(d,J＝4.3Hz,1H),5.26-5.21(m,1H),4.92(d,J＝9.8Hz,1H),3.86-3.82(m,1H),3.39(t,J＝6.6Hz,2H),3.32-3.27(m,1H),2.97(dd,J＝13.0,3.8Hz,1H),2.94(d,J＝15.0Hz,1H),2.76(t,J＝12.1Hz,1H),2.34(dt,J＝11.3,7.4Hz,2H),2.27(dd,J＝14.8,4.7Hz,1H),1.88-1.85(m,2H),1.72(d,J＝1.4Hz,3H).
(b)向10mL圆底烧瓶中加入S14a(20mg,0.05mmol)，三苯基膦(39.3mg,0.15mmol)，干燥的MeCN 5mL，81℃搅拌反应8h。反应完全后，减压蒸馏除去溶剂，得到粗产物S14。再经反相半制备液相制备，流动相MeCN-H2O(65:35,v/v)，得到S14单体化合物(19.7mg,收率70.4％)，结构鉴定数据如下：m/z:[M+H]+＝688.5723,1H NMR(CDCl3,600MHz):δ7.92-7.87(m,6H),7.83-7.75(m,3H),7.68-7.63(m,6H),7.02(s,1H),6.42(d,J＝2.3Hz,1H),5.91(d,J＝1.7Hz,1H),5.63-5.45(m,2H),5.38(d,J＝4.3Hz,1H),5.26-5.21(m,1H),4.92(d,J＝9.8Hz,1H),3.86-3.82(m,1H),3.39(t,J＝6.6Hz,2H),3.32-3.27(m,1H),2.97(dd,J＝13.0,3.8Hz,1H),2.94(d,J＝15.0Hz,1H),2.76(t,J＝12.1Hz,1H),2.34(dt,J＝11.3,7.4Hz,2H),2.27(dd,J＝14.8,4.7Hz,1H),1.72(d,J＝1.4Hz,3H).
实施例15：S15的制备
操作同实施例14，不同的是使用6-溴己酸，流动相MeCN-H2O(65:35,v/v)，得到S15单体化合物,收率83.8％，结构鉴定数据如下：m/z:[M+H]+＝712.5724,1H NMR(CDCl3,600MHz):δ7.92-7.87(m,6H),7.83-7.75(m,3H),7.68-7.63(m,6H),7.02(s,1H),6.42(d,J＝2.3Hz,1H),5.91(d,J＝1.7Hz,1H),5.63-5.45(m,2H),5.38(d,J＝4.3Hz,1H),5.26-5.21(m,1H),4.92(d,J＝9.8Hz,1H),3.86-3.82(m,1H),3.39(t,J＝6.6Hz,2H),3.32-3.27(m,1H),2.97(dd,J＝13.0,3.8Hz,1H),2.94(d,J＝15.0Hz,1H),2.76(t,J＝12.1Hz,1H),2.34(dt,J＝11.3,7.4Hz,2H),2.27(dd,J＝14.8,4.7Hz,1H),1.72(d,J＝1.4Hz,3H),1.58-1.55(m,2H).
实施例16：S16的制备
操作同实施例14，不同的是使用8-溴辛酸，流动相MeCN-H2O(65:35,v/v)，得到S16单体化合物,收率73.8％，结构鉴定数据如下：m/z:[M+H]+＝736.5721,1H NMR(CDCl3,600MHz):δ7.92-7.87(m,6H),7.83-7.75(m,3H),7.68-7.63(m,6H),7.02(s,1H),6.42(d,J＝2.3Hz,1H),5.91(d,J＝1.7Hz,1H),5.63-5.45(m,2H),5.38(d,J＝4.3Hz,1H),5.26-5.21(m,1H),4.92(d,J＝9.8Hz,1H),3.86-3.82(m,1H),3.39(t,J＝6.6Hz,2H),3.32-3.27(m,1H),2.97(dd,J＝13.0,3.8Hz,1H),2.94(d,J＝15.0Hz,1H),2.76(t,J＝12.1Hz,1H),2.34(dt,J＝11.3,7.4Hz,2H),2.27(dd,J＝14.8,4.7Hz,1H),1.72(d,J＝1.4Hz,3H),1.59-1.53(m,4H).
实施例17：S17和S21的制备
(a)向10mL圆底烧瓶中加入S1(20mg,0.07mmol)，Boc-正缬氨酸(152mg,0.7mmol)，EDCI(138.8mg,0.7mmol)，DMAP(8.8mg,0.07mmol)，干燥的DCM3mL，室温搅拌反应8h。反应完全后加3mL水终止反应，将反应液置于分液漏斗中，取有机层，水相再经乙酸乙酯萃取，合并有机相，减压蒸馏除去溶剂，得到粗产物S17。再经反相半制备液相制备，流动相MeCN-H2O(40:60,v/v)，得到S17单体化合物(22.7mg,收率70.9％)，结构鉴定数据如下：m/z:[M+Na]+＝496.2098,1H NMR(CDCl3,600MHz):δ7.04(s,1H),6.42(d,J＝2.3Hz,1H),6.00(s,1H),5.37(s,1H),5.30(t,J＝10.2Hz,1H),4.87(dd,J＝15.3,9.2Hz,2H),4.21(dd,J＝13.4,8.1Hz,1H),3.83(dd,J＝7.3,4.1Hz,1H),3.33-3.26(m,1H),2.96(dd,J＝12.8,3.1Hz,1H),2.91(d,J＝14.7Hz,1H),2.75(t,J＝12.1Hz,1H),2.27(dd,J＝14.8,4.3Hz,1H),1.70(s,3H),1.56-1.48(m,1H),1.41(s,10H),1.36-1.30(m,2H),0.92(t,J＝7.3Hz,3H).
(b)向10mL圆底烧瓶中加入S17(20mg,0.04mmol)，干燥的DCM 3mL，过量的三氟乙酸(1mmol)，0℃搅拌反应8h，通过TLC确定反应完全后，加入适量饱和碳酸氢钠调节溶液至中性，减压蒸馏除去溶剂，得到粗产物S21。再经反相半制备液相制备，流动相MeCN-H2O(40:60,v/v)，得S21单体化合物(15.8mg,收率76.7％)，结构鉴定数据如下：m/z:[M+Na]+＝398.4212,1H NMR(CDCl3,600MHz):δ7.04(s,1H),6.42(d,J＝2.3Hz,1H),6.00(s,1H),5.37(s,1H),5.30(t,J＝10.2Hz,1H),4.87(dd,J＝15.3,9.2Hz,2H),4.21(dd,J＝13.4,8.1Hz,1H),3.83(dd,J＝7.3,4.1Hz,1H),3.33-3.26(m,1H),2.96(dd,J＝12.8,3.1Hz,1H),2.91(d,J＝14.7Hz,1H),2.75(t,J＝12.1Hz,1H),2.27(dd,J＝14.8,4.3Hz,1H),1.70(s,3H),1.56-1.48(m,1H),1.36-1.30(m,3H),0.92(t,J＝7.3Hz,3H).
实施例18：S18和S22的制备
(1)操作同实施例17，不同的是使用Boc-L缬氨酸，经反相半制备液相制备，流动相MeCN-H2O(50:50,v/v)，得到S18单体化合物,收率80.9％，鉴定数据如下：m/z:[M+H]+＝498.2098,1H NMR(CDCl3,600MHz):δ7.04(s,1H),6.41(d,J＝2.6Hz,1H),6.00(s,1H),5.37(d,J＝2.9Hz,1H),5.31(t,J＝10.2Hz,1H),4.88(t,J＝9.5Hz,2H),4.12(dd,J＝9.1,5.4Hz,1H),3.83(dt,J＝11.1,3.9Hz,1H),3.32-3.24(m,1H),2.96(dd,J＝12.8,3.3Hz,1H),2.91(d,J＝14.8Hz,1H),2.74(t,J＝12.1Hz,1H),2.27(dd,J＝14.8,4.6Hz,1H),2.12-2.02(m,1H),1.70(s,3H),1.41(s,9H),0.92(d,J＝6.8Hz,3H),0.84(d,J＝6.9Hz,3H).
(2)半制备液相制备，流动相MeCN-H2O(40:60,v/v)，得到S22单体化合物,收率90.9％。结构鉴定数据如下m/z:[M+H]+＝398.4213,1H NMR(CDCl3,600MHz):δ7.04(s,1H),6.41(d,J＝2.6Hz,1H),6.00(s,1H),5.37(d,J＝2.9Hz,1H),5.31(t,J＝10.2Hz,1H),4.88(t,J＝9.5Hz,2H),4.12(dd,J＝9.1,5.4Hz,1H),3.83(dt,J＝11.1,3.9Hz,1H),3.32-3.24(m,1H),2.96(dd,J＝12.8,3.3Hz,1H),2.91(d,J＝14.8Hz,1H),2.74(t,J＝12.1Hz,1H),2.27(dd,J＝14.8,4.6Hz,1H),2.12-2.02(m,1H),1.70(s,3H),0.92(d,J＝6.8Hz,3H),0.84(d,J＝6.9Hz,3H).
实施例19：S19和S23的制备
(1)操作同实施例17，不同的是使用Boc-L-甲硫氨酸，经反相半制备液相制备，流动相MeCN-H2O(40:50,v/v)，得到S19单体化合物,收率84.7％，鉴定数据如下：m/z:[M+H]+＝508.2122,1H NMR(CDCl3,600MHz):δ7.04(s,1H),6.42(d,J＝2.7Hz,1H),5.99(s,1H),5.37(s,1H),5.31(t,J＝10.2Hz,1H),5.02(d,J＝8.2Hz,1H),4.88(d,J＝9.7Hz,1H),4.37(d,J＝4.4Hz,1H),3.83(dd,J＝7.4,3.9Hz,1H),2.96(dd,J＝12.7,2.8Hz,1H),2.91(d,J＝14.7Hz,1H),2.75(t,J＝12.1Hz,1H),2.52–2.45(m,2H),2.27(dd,J＝14.7,4.1Hz,1H),2.09(s,3H),1.70(s,3H),1.42(d,J＝7.6Hz,11H).
(2)反相半制备液相制备，流动相MeCN-H2O(40:60,v/v)，得到S23单体化合物,收率93.9％，结构鉴定数据如下：m/z:[M+H]+＝408.4213,1H NMR(CDCl3,600MHz):δ7.04(s,1H),6.42(d,J＝2.7Hz,1H),5.99(s,1H),5.37(s,1H),5.31(t,J＝10.2Hz,1H),5.02(d,J＝8.2Hz,1H),4.88(d,J＝9.7Hz,1H),4.37(d,J＝4.4Hz,1H),3.83(dd,J＝7.4,3.9Hz,1H),2.96(dd,J＝12.7,2.8Hz,1H),2.91(d,J＝14.7Hz,1H),2.75(t,J＝12.1Hz,1H),2.52–2.45(m,2H),2.27(dd,J＝14.7,4.1Hz,1H),2.09(s,3H),1.70(s,3H),1.42(d,J＝7.6Hz,2H).
实施例20：S20和S24的制备
(1)操作同同实施例17，不同的是使用Boc-L-3-氟苯丙氨酸，经反相半制备液相制备，流动相MeCN-H2O(55:40,v/v)，得到S20单体化合物,收率87.4％，结构鉴定数据如下：m/z:[M+Na]+＝564.2004,1H NMR(CDCl3,600MHz):δ7.26(dd,J＝14.0,7.9Hz,1H),7.01(s,1H),6.95(td,J＝8.4,2.0Hz,1H),6.91(d,J＝7.6Hz,1H),6.78(d,J＝9.5Hz,1H),6.36(d,J＝2.7Hz,1H),5.87(s,1H),5.38(d,J＝3.4Hz,1H),5.28(t,J＝10.3Hz,1H),4.93(d,J＝8.2Hz,1H),4.71(d,J＝9.7Hz,1H),4.51(dd,J＝14.2,6.6Hz,1H),3.80(dt,J＝8.0,3.7Hz,1H),3.25-3.19(m,1H),3.02(d,J＝6.4Hz,2H),2.94(dd,J＝21.8,9.1Hz,2H),2.73(t,J＝12.1Hz,1H),2.27(dd,J＝14.8,4.6Hz,1H),1.68(s,3H),1.40(s,9H).
(2)反相半制备液相制备，流动相MeCN-H2O(55:45,v/v)，S24单体化合物,收率73.9％，结构鉴定数据分别如下：m/z:[M+Na]+＝464.4275,1H NMR(CDCl3,600MHz):δ7.26(dd,J＝14.0,7.9Hz,1H),7.01(s,1H),6.95(td,J＝8.4,2.0Hz,1H),6.91(d,J＝7.6Hz,1H),6.78(d,J＝9.5Hz,1H),6.36(d,J＝2.7Hz,1H),5.87(s,1H),5.38(d,J＝3.4Hz,1H),5.28(t,J＝10.3Hz,1H),4.93(d,J＝8.2Hz,1H),4.71(d,J＝9.7Hz,1H),4.51(dd,J＝14.2,6.6Hz,1H),3.80(dt,J＝8.0,3.7Hz,1H),3.25-3.19(m,1H),3.02(d,J＝6.4Hz,2H),2.94(dd,J＝21.8,9.1Hz,2H),2.73(t,J＝12.1Hz,1H),2.27(dd,J＝14.8,4.6Hz,1H),1.68(s,3H).
实施例21：S25的制备
向10mL圆底烧瓶中加入S1(20mg,0.07mmol)，三苯基膦(27.5mg,0.105mmol)，四溴化碳(34.8mg,0.105mmol)，干燥的DCM 3mL，室温搅拌反应8h。反应完全后减压蒸馏除去溶剂，得到粗产物S25。再经反相半制备液相制备，流动相MeCN-H2O(15:85,v/v)，得到S25单体化合物(20.4mg,收率83.3％)，结构鉴定数据如下：m/z:[M+Na]+＝362.1957,1H NMR(CDCl3,600MHz):δ6.97(s,1H),6.41(d,J＝2.4Hz,1H),6.15(d,J＝1.5Hz,1H)5.34(d,J＝3.7Hz,1H),4.99(d,J＝9.6Hz,1H),4.22(td,J＝10.2,2.3Hz,1H),3.84(m,1H),3.74(dd,J＝8.8,3.4Hz,1H),3.62(m,1H),2.97(td,J＝6.9,3.5Hz,1H),2.90(d,J＝4.0Hz,1H),2.88(d,J＝4.8Hz,1H),2.75(t,J＝11.9Hz,1H),2.57(dt,J＝10.2,6.5Hz,1H),2.21(dd,J＝14.7,4.8Hz,1H),1.59(s,3H).
实施例22：S26的制备
操作同实施例21，不同的是使用四氯化碳，流动相MeCN-H2O(15:85,v/v)，得到S26单体化合物,收率73.8％，结构鉴定数据如下：m/z:[M+Na]+＝317.7445,1H NMR(CDCl3,600MHz):δ7.03(s,1H),6.38(d,J＝2.4Hz,1H),6.16(d,J＝1.5Hz,1H),5.37(d,J＝3.9Hz,1H),5.03(d,J＝9.6Hz,1H),4.24(t,J＝9.7Hz,1H),3.78(dt,J＝11.4,4.2Hz,1H),3.07(m,1H),2.94(dd,J＝8.8,2.9Hz,1H),2.90(d,J＝7.9Hz,1H),2.72(t,J＝12.0Hz,1H),2.25(dd,J＝14.7,4.7Hz,1H),1.61(s,3H).
实施例23：S27的制备
(a)向10mL两口圆底烧瓶中加入PPh3(26.9mg,0.1mmol)，DEAD(13.6mg,0.08mmol)，干燥的THF 3mL，在氮气保护的条件下，室温搅拌反应10分钟。之后，用注射器滴加中间体1(20mg,0.065mmol)，室温搅拌反应10分钟后，再用注射器滴加DPPA(21.4mg,0.08mmol)，过夜反应。反应完全后，放置氮吹处室温吹干，得到粗产物中间体2。再经反相半制备液相制备，流动相MeCN-H2O(20:80,v/v)，得到中间体2(17.4mg,收率80.6％)，结构鉴定数据如下：m/z:[M+Na]+＝356.6434,1H NMR(CDCl3,600MHz):δ7.03(s,1H),6.42(d,J＝2.4Hz,1H),6.15(d,J＝1.5Hz,1H),5.37(d,J＝3.9Hz,1H),5.03(d,J＝9.6Hz,1H),4.24(t,J＝9.7Hz,1H),3.78(dt,J＝11.4,4.2Hz,1H),3.47(s,3H),3.07(m,1H),2.94(dd,J＝8.8,2.9Hz,1H),2.90(d,J＝7.9Hz,1H),2.72(t,J＝12.0Hz,1H),2.25(dd,J＝14.7,4.7Hz,1H),1.61(s,3H).
(b)向10mL圆底烧瓶中加入中间体2(20mg,0.060mmol)，甲苯3mL，搅拌的条件下加入DBU(18.27mg,0.12mmol)，60℃搅拌反应8h。反应结束后加适量稀盐酸调节至中性，减压蒸干，加水搅拌，再经乙酸乙酯萃取三次，合并有机相，减压蒸馏除去溶剂，得到粗产物S27。再经反相半制备液相制备，流动相MeCN-H2O(20:80,v/v)，得到S27单体化合物(12.4mg,收率68.7％)，结构鉴定数据如下：m/z:[M+H]+＝324.1337,1H NMR(CDCl3,600MHz):δ7.03(s,1H),6.42(d,J＝2.4Hz,1H),6.15(d,J＝1.5Hz,1H),5.37(d,J＝3.9Hz,1H),5.03(d,J＝9.6Hz,1H),4.24(t,J＝9.7Hz,1H),3.78(dt,J＝11.4,4.2Hz,1H),3.07(m,1H),2.94(dd,J＝8.8,2.9Hz,1H),2.90(d,J＝7.9Hz,1H),2.72(t,J＝12.0Hz,1H),2.25(dd,J＝14.7,4.7Hz,1H),1.61(s,3H).
实施例24：S28的制备
(a)向10mL圆底烧瓶中加入中间体2(20mg,0.06mmol)，碘化亚铜(9.7mg,0.06mmol)，三乙胺(60.7mg,0.6mmol)，MeCN-H2O(2:1,v/v)3mL，室温搅拌反应24h。反应完全后，过滤，放置氮吹处室温吹干，得到粗产物S28a。再经反相半制备液相制备，流动相MeCN-H2O(50:50,v/v)，得到S28a单体化合物(20.2mg,收率77.3％)，结构鉴定数据如下：m/z:[M+Na]+＝458.4818,1H NMR(CDCl3,600MHz):δ8.28(s,1H),7.96-7.90(m,2H),7.47(t,J＝7.7Hz,2H),7.39(t,J＝7.4Hz,1H),7.02(s,1H),5.65-5.58(m,1H),5.38(d,J＝4.3Hz,1H),5.06(d,J＝9.8Hz,1H),3.92(dd,J＝12.9,7.5Hz,1H),3.84(dd,J＝8.7,2.8Hz,1H),3.54(dd,J＝8.8,2.9Hz,1H),3.46(s,3H),3.08(dt,J＝11.4,5.9Hz,1H),2.93(t,J＝10.0Hz,3H),2.73(dt,J＝6.0,2.8Hz,1H),2.29(dd,J＝14.9,4.7Hz,1H),1.81(d,J＝1.3Hz,3H).
(b)向10mL圆底烧瓶中加入S28a(20mg,0.046mmol)，DBU(14mg,0.092mmol)，甲苯3mL，60℃搅拌反应4h。反应完全后，加3mL水终止反应，将反应液置于分液漏斗中，取有机层，水相再经乙酸乙酯萃取，合并有机相，减压蒸馏除去溶剂，得到粗产物S28。再经反相半制备液相制备，流动相MeCN-H2O(50:50,v/v)，得到S28单体化合物(10.2mg,收率55.1％)，结构鉴定数据如下：m/z:[M+Na]+＝426.4312,1H NMR(CDCl3,600MHz):δ8.28(s,1H),7.96-7.90(m,2H),7.47(t,J＝7.7Hz,2H),7.39(t,J＝7.4Hz,1H),7.02(s,1H),6.41(d,J＝2.7Hz,1H),5.97(d,J＝2.3Hz,1H),5.65-5.58(m,1H),5.38(d,J＝4.3Hz,1H),5.06(d,J＝9.8Hz,1H),3.92(dd,J＝12.9,7.5Hz,1H),3.84(dd,J＝8.7,2.8Hz,1H),3.54(dd,J＝8.8,2.9Hz,1H),3.08(dt,J＝11.4,5.9Hz,1H),2.93(t,J＝10.0Hz,3H),2.73(dt,J＝6.0,2.8Hz,1H),2.29(dd,J＝14.9,4.7Hz,1H),1.81(d,J＝1.3Hz,3H).
实施例25：S29的制备
操作同实施例24，不同的是使用1-戊炔，流动相MeCN-H2O(45:55,v/v)，得到S29单体化合物,收率73.8％，结构鉴定数据如下：m/z:[M+Na]+＝392.4212,1H NMR(CDCl3,600MHz):δ8.31(s,1H),7.04(s,1H),6.34(d,J＝2.7Hz,1H),5.92(d,J＝2.3Hz,1H),5.38(d,J＝4.3Hz,1H),5.06(d,J＝9.8Hz,1H),3.92(dd,J＝12.9,7.5Hz,1H),3.84(dd,J＝8.7,2.8Hz,1H),3.08(dt,J＝11.4,5.9Hz,1H),2.93(dd,J＝8.8,2.9Hz,1H),2.90(d,J＝7.9Hz,1H),2.73(m,3H),2.29(dd,J＝14.9,4.7Hz,1H),1.81(d,J＝1.3Hz,3H),1.36-1.28(m,5H).
实施例26：S30的制备
操作同实施例24，不同的是使用苯丙炔，流动相MeCN-H2O(50:50,v/v)，得到S30单体化合物,收率78.6％，结构鉴定数据如下：m/z:[M+Na]+＝440.4212,1H NMR(CDCl3,600MHz):δ8.28(s,1H),8.02(d,J＝7.3Hz,2H),7.59(t,J＝7.5Hz,1H),7.47(t,J＝7.7Hz,2H),7.02(s,1H),6.34(d,J＝2.7Hz,1H),5.92(d,J＝2.3Hz,1H),5.38(d,J＝4.3Hz,1H),5.06(d,J＝9.8Hz,1H),3.92(m,3H),3.84(dd,J＝8.7,2.8Hz,1H),3.08(dt,J＝11.4,5.9Hz,1H),2.93(dd,J＝8.8,2.9Hz,1H),2.90(d,J＝7.9Hz,1H),2.73(dt,J＝6.0,2.8Hz,1H),2.29(dd,J＝14.9,4.7Hz,1H),1.81(d,J＝1.3Hz,3H).
实施例27：S31的制备
(a)向50mL圆底烧瓶中加入中间体1(100mg,0.32mmol)，4-叠氮苯甲酸(529mg,3.2mmol)，EDCI(621.7mg,3.2mmol)，DMAP(39.6mg,0.32mmol)，干燥的DCM 25mL，室温搅拌反应8h。反应完全后加25mL水终止反应，将反应液置于分液漏斗中，取有机层，水相再经乙酸乙酯萃取，合并有机相，减压蒸馏除去溶剂，得到粗产物中间体3。再经反相半制备液相制备，流动相MeCN-H2O(50:50,v/v)，得到中间体3(112mg,收率76.2％)，结构鉴定数据如下：m/z:[M+Na]+＝476.1428,1H NMR(CDCl3,600MHz):δ7.93(d,J＝8.7Hz,2H),7.05(d,J＝8.7Hz,2H),7.03(s,1H),5.56(dd,J＝10.9,9.9Hz,1H),5.34(d,J＝4.4Hz,1H),4.98(d,J＝9.7Hz,1H),3.93-3.87(m,1H),3.79(dd,J＝8.8,2.7Hz,1H),3.47(dd,J＝8.8,3.0Hz,1H),3.41(s,3H),2.99(dt,J＝11.5,5.9Hz,1H),2.91-2.82(m,3H),2.68(dt,J＝6.0,2.8Hz,1H),2.25(dd,J＝14.8,4.7Hz,1H),1.76(d,J＝1.4Hz,3H).
(b)向10mL圆底烧瓶中加入中间体3(23mg,0.051mmol)，碘化亚铜(9.7mg,0.051mmol)，三乙胺(51.3mg,0.51mmol)，MeCN-H2O(2:1,v/v)3mL，室温搅拌反应24h。反应完全后，过滤，放置氮吹处室温吹干，得到粗产物S31a。再经反相半制备液相制备，流动相MeCN-H2O(50:50,v/v)，得到S31a单体化合物(20.2mg,收率71.7％)，结构鉴定数据如下：m/z:[M+H]+＝556.2052,1H NMR(CDCl3,600MHz):δ8.28(s,1H),8.18-8.15(m,2H),7.96-7.90(m,4H),7.47(t,J＝7.7Hz,2H),7.39(t,J＝7.4Hz,1H),7.02(s,1H),5.65-5.58(m,1H),5.38(d,J＝4.3Hz,1H),5.06(d,J＝9.8Hz,1H),3.92(dd,J＝12.9,7.5Hz,1H),3.84(dd,J＝8.7,2.8Hz,1H),3.54(dd,J＝8.8,2.9Hz,1H),3.46(s,3H),3.08(dt,J＝11.4,5.9Hz,1H),2.93(t,J＝10.0Hz,3H),2.73(dt,J＝6.0,2.8Hz,1H),2.29(dd,J＝14.9,4.7Hz,1H),1.81(d,J＝1.3Hz,3H)。
(c)向10mL圆底烧瓶中加入S31a(20mg,0.036mmol)，DBU(11mg,0.073mmol)，甲苯3mL，60℃搅拌反应4h。反应完全后，加3mL水终止反应，将反应液置于分液漏斗中，取有机层，水相再经乙酸乙酯萃取，合并有机相，减压蒸馏除去溶剂，得到粗产物S31。再经反相半制备液相制备，流动相MeCN-H2O(50:50,v/v)，得到S31单体化合物(10.2mg,收率54.1％)，结构鉴定数据如下：m/z:[M+Na]+＝546.5587,1H NMR(CDCl3,600MHz):δ8.28(s,1H),8.18-8.15(m,2H),7.96-7.90(m,4H),7.47(t,J＝7.7Hz,2H),7.39(t,J＝7.4Hz,1H),7.02(s,1H),6.40(dd,J＝9.3,6.7Hz,1H),5.96(d,J＝2.0Hz,1H),5.65-5.58(m,1H),5.38(d,J＝4.3Hz,1H),5.06(d,J＝9.8Hz,1H),3.92(dd,J＝12.9,7.5Hz,1H),3.84(dd,J＝8.7,2.8Hz,1H),3.54(dd,J＝8.8,2.9Hz,1H),3.08(dt,J＝11.4,5.9Hz,1H),2.93(t,J＝10.0Hz,3H),2.73(dt,J＝6.0,2.8Hz,1H),2.29(dd,J＝14.9,4.7Hz,1H),1.81(d,J＝1.3Hz,3H).
实施例28：S32的制备
操作同实施例27，不同的是使用1-己炔，流动相MeCN-H2O(50:50,v/v)，得到S32单体化合物,收率75.6％，结构鉴定数据如下：m/z:[M+Na]+＝526.2314,1H NMR(CDCl3,600MHz):δ8.26(s,1H),8.02(d,J＝7.3Hz,2H),7.59(t,J＝7.5Hz,1H),7.47(t,J＝7.7Hz,2H),7.07(s,1H),6.34(d,J＝2.7Hz,1H),5.92(d,J＝2.3Hz,1H),5.58(t,J＝10.2Hz,1H),5.40(d,J＝4.0Hz,1H),5.06(d,J＝9.8Hz,1H),3.94(dt,J＝11.4,4.1Hz,1H),3.46(ddt,J＝10.2,4.9,2.5Hz,1H),3.01(dd,J＝12.8,3.6Hz,1H),2.94(d,J＝14.8Hz,1H),2.81(t,J＝12.1Hz,1H),2.46-2.39(m,2H),2.26(dd,J＝14.8,4.6Hz,1H),1.92-1.89(m,2H),1.78(d,J＝1.1Hz,3H).1.36-1.28(m,5H).
实施例29：S33的制备
操作同实施例27，不同的是使用4-氟苯乙炔，流动相MeCN-H2O(50:50,v/v)，得到S33单体化合物,收率78.6％，结构鉴定数据如下：m/z:[M+Na]+＝564.2355,1H NMR(CDCl3,600MHz):δ8.28(s,1H),8.18-8.15(m,2H),7.96-7.90(m,4H),7.47(t,J＝7.7Hz,2H),7.02(s,1H),6.34(d,J＝2.7Hz,1H),5.92(d,J＝2.3Hz,1H),5.65-5.58(m,1H),5.38(d,J＝4.3Hz,1H),5.06(d,J＝9.8Hz,1H),3.92(dd,J＝12.9,7.5Hz,1H),3.84(dd,J＝8.7,2.8Hz,1H),3.54(dd,J＝8.8,2.9Hz,1H),3.08(dt,J＝11.4,5.9Hz,1H),2.93(t,J＝10.0Hz,1H),2.73(dt,J＝6.0,2.8Hz,1H),2.29(dd,J＝14.9,4.7Hz,1H),1.81(d,J＝1.3Hz,3H).
实施例30：S34的制备
操作同实施例27，不同的是使用4-甲基苯乙炔，流动相MeCN-H2O(50:50,v/v)，得到S34单体化合物,收率78.6％，结构鉴定数据如下：m/z:[M+Na]+＝564.2355,1H NMR(CDCl3,600MHz):δ8.28(s,1H),8.17-8.15(m,2H),7.98-7.91(m,4H),7.47(t,J＝7.7Hz,2H),7.02(s,1H),6.42(d,J＝2.4Hz,1H),6.15(d,J＝1.5Hz,1H),5.65-5.58(m,1H),5.38(d,J＝4.3Hz,1H),5.06(d,J＝9.8Hz,1H),3.92(dd,J＝12.9,7.5Hz,1H),3.84(dd,J＝8.7,2.8Hz,1H),3.54(dd,J＝8.8,2.9Hz,1H),3.08(dt,J＝11.4,5.9Hz,1H),2.93(t,J＝10.0Hz,1H),2.73(dt,J＝6.0,2.8Hz,1H),2.52(s,3H)；2.29(dd,J＝14.9,4.7Hz,1H),1.72(d,J＝1.3Hz,3H).
实施例31：S35的制备
向10mL圆底烧瓶中加入S1(40mg,0.14mmol)，己二酸(10.6mg,0.07mmol)，EDCI(138.8mg,0.7mmol)，DMAP(8.8mg,0.07mmol)，干燥的DCM 3mL，室温搅拌反应8h。反应完全后加3mL水终止反应，将反应液置于分液漏斗中，取有机层，水相再经乙酸乙酯萃取，合并有机相，减压蒸馏除去溶剂，得到粗产物S35。再经反相半制备液相制备，流动相MeCN-H2O(85:15,v/v)，得到S35单体化合物(25.8mg,收率55.6％)，结构鉴定数据如下：m/z:[M+Na]+＝685.2719,1H NMR(CDCl3,600MHz):7.04(s,2H),6.40(d,J＝2.6Hz,2H),5.90(d,J＝2.0Hz,2H),5.37(d,J＝4.0Hz,2H),5.23(t,J＝10.2Hz,2H),4.90(d,J＝9.8Hz,2H),3.84(dt,J＝11.4,4.1Hz,2H),3.27(dtd,J＝7.0,4.7,2.5Hz,2H),2.96(dd,J＝12.8,3.5Hz,2H),2.92(d,J＝14.8Hz,2H),2.74(t,J＝12.1Hz,2H),2.39-2.29(m,4H),2.26(dd,J＝14.8,4.6Hz,2H),1.70(d,J＝1.0Hz,6H),1.68-1.60(m,4H).
实施例32：S36的制备
操作同实施例31，不同的是使用辛二酸,流动相MeCN-H2O(85:15,v/v)，得到S36单体化合物,收率75.7％，结构鉴定数据如下：m/z:[M+Na]+＝713.2217,1H NMR(CDCl3,600MHz):δ7.04(s,2H),6.40(d,J＝2.7Hz,2H),5.91(d,J＝1.8Hz,2H),5.38(d,J＝4.1Hz,2H),5.23(t,J＝10.2Hz,2H),4.90(d,J＝9.8Hz,2H),3.85(dt,J＝11.4,4.1Hz,2H),3.27(ddt,J＝10.2,4.8,2.5Hz,2H),2.96(dd,J＝12.8,3.6Hz,2H),2.93(d,J＝14.8Hz,2H),2.75(t,J＝12.1Hz,2H),2.36-2.24(m,6H),1.71(d,J＝1.2Hz,6H),1.64-1.57(m,4H),1.36-1.28(m,4H).
实施例33：S37的制备
操作同实施例31，不同的是使用3,3’-二硫代丙二酸,流动相MeCN-H2O(85:15,v/v)，得到S37单体化合物,收率84.6％，结构鉴定数据如下：m/z:[M+Na]+＝749.6523,1H NMR(CDCl3,600MHz):δ6.97(s,2H),6.42(d,J＝3.0Hz,2H),5.97(d,J＝2.3Hz,2H),5.45(dd,J＝4.4,1.9Hz,2H),5.30(t,J＝10.1Hz,2H),4.46(d,J＝10.1Hz,2H),4.30(t,J＝6.7Hz,2H),4.17(ddd,J＝10.7,6.3,1.5Hz,2H),3.23(m,2H),3.09(ddd,J＝9.3,6.0,2.8Hz,2H),2.90(t,J＝7.2Hz,4H),2.79-2.72(m,4H),2.67(dd,J＝7.8,5.2Hz,2H),2.55(d,J＝13.4Hz,2H),1.82(d,J＝1.3Hz,6H).
实施例34：S38的制备
操作同实施例31，不同的是使用对苯二甲酸,流动相MeCN-H2O(85:15,v/v)，得到S38单体化合物,收率78.4％，结构鉴定数据如下：m/z:[M+Na]+＝705.2217,1H NMR(CDCl3,600MHz):δ8.10(d,J＝8.4Hz,2H),8.03(d,J＝8.4Hz,2H),7.07(s,2H),6.34(d,J＝2.7Hz,2H),5.87(d,J＝2.1Hz,2H),5.59(t,J＝10.2Hz,2H),5.41(d,J＝3.9Hz,2H),5.08(d,J＝9.8Hz,2H),3.93(dt,J＝11.4,4.1Hz,2H),3.48(dtd,J＝7.0,4.7,2.4Hz,2H),3.02(dd,J＝12.9,3.5Hz,2H),2.95(d,J＝14.8Hz,2H),2.82(t,J＝12.2Hz,2H),2.30(dd,J＝14.9,4.6Hz,2H),1.79(d,J＝1.0Hz,6H).
实施例35：抗肿瘤活性实验
采用MTT法检测细胞增殖活性，筛选受试38个化合物(S1-S38)的体外抗肿瘤活性。
1.实验材料：
(1)受试细胞株:人肺癌细胞A549、宫颈癌细胞HeLa、人肝癌细胞HepG2、人肝癌细胞Hep3B、人白血病细胞HL60、人乳腺癌细胞MCF-7、人乳腺癌细胞MDA-MB-231、人结肠癌细胞SW620。
(2)受试药物：本发明合成的地胆草种内酯衍生物(S1-S38)。
(3)阳性对照物：顺铂。
2.实验方法：
(1)受试药物的配制：准确称取各受试样品1mg，用DMSO配置成50μM的母液，用相应培养基配制成不同的浓度。
(2)细胞增殖抑制实验：取对数生长期细胞，接种到96孔板中，培养过夜后，分别加入不同浓度的化合物置5％CO2培养箱(37℃)作用18h，然后每孔加入20μL的MTT共孵育4h，弃上清，加入DMSO 150μL，振荡溶解10min，采用酶标仪在490nm处检测OD值，并通过软件计算IC50值。
3.活性结果如表1所示
表1地胆草种内酯衍生物对各种癌细胞的抑制活性(IC50,μM)
活性测试结果表明，筛选的化合物对多种肿瘤细胞显示出抑制活性，部分测试化合物活性优于阳性药顺铂，因此测试化合物具有用于发展为新型药物治疗癌症用途。
实施例36：抗炎活性实验
LPS可以诱导催化L-精氨酸的氧化脱氨以产生一氧化氮(NO)的诱生型一氧化氮合酶(iNOS)的mRNA或蛋白水平。一旦NO大量产生，其与超氧阴离子相互作用并产生高活性氧化剂导致细胞炎症，DNA、蛋白和组织损伤，癌变以及抗凋亡。以激活巨噬细胞释放NO为指标，在化合物中筛选对小胶质细胞活化有抑制作用的化合物。Griess法检测化合物对LPS激活巨噬细胞释放NO的抑制作用。
1.实验材料：
(1)受试细胞株：小鼠巨噬细胞RAW 264.7。
(2)受试药物：本发明合成的地胆草种内酯衍生物(S1-S13，S17-S26)。
(3)阳性对照物：米诺环素(Mino)。
2.实验方法：
(1)受试药物的配制：准确称取受试样品各1mg，用DMSO配置成50μM的母液，用相应培养基配制成不同的浓度。
(2)NO抑制实验：取对数生长期细胞，接种到96孔板中，培养24h后，加入1μg/mLLPS以及不同浓度的化合物置5％CO2培养箱(37℃)作用12h，然后每孔加入Griess A、B溶液100μL继续孵育5min，用酶联免疫检测仪测570nm波长处检测OD值，并通过软件计算IC50值。
(3)化合物对RAW 264.7胞细毒性：MTT法检测化合物对RAW 264.7细胞成活率的影响，方法同上。
3.活性结果如表2所示
表2地胆草种内酯衍生物抑制LPS诱导的RAW264.7释放NO的能力及其对RAW264.7细胞毒性(IC50,μM)
ND:Not determined.
活性测试结果表明，筛选的化合物对LPS诱导的RAW264.7释放NO具有抑制作用，部分测试化合物活性优于阳性药米诺环素，因此测试化合物具有用于发展为新型非甾体抗炎药物。
Claims (11)
1.地胆草种内酯衍生物及药学上可接受的盐：
式I中，R1为C1-8直链或支链烷基、C1-8烷氧基、未取代或取代的苄基、C1-8烷酰基、未取代或取代的苯甲酰基、未取代或取代的肉桂酰基、联苯酰基、1-萘酰基、2-萘酰基、4-吡啶甲酰基、-CO(CH2)nCOOH、-CO(CH2)mP+(Ph)3Br-，其中n和m分别为2-10之间的整数；所述的取代基为：卤素、C1-C6烷氧基、硝基、卤代C1-C6烷基、卤代C1-C6烷氧基、C1-C4酰基、二甲氨基、3，4-亚甲二氧基；
式II中，R2为C1-8直链或支链烷基、C1-8烷氧基、C1-8烷硫基、未取代或取代的苯基或苄基，R3为H、C3-6环烷基、甲基，X为H、Boc保护基；所述取代基为：卤素、C1-C6烷基，卤代C1-C6烷基、卤代C1-C6烷氧基、硝基、氨基；
式III中，R4为叠氮基、卤素、
其中R’为C1-8直链或支链烷基、C1-8烷氧基、未取代或取代的苯基或苄基；所述的取代基为：卤素、C1-C6烷基，卤代C1-C6烷基、C1-C6烷氧基、硝基；
式IV中，R5为C1-8直链或支链烷基、C1-8烷氧基、未取代或取代的苯基或苄基；所述的取代基为：卤素、C1-C6烷基，卤代C1-C6烷基、C1-C6烷氧基、硝基；
式V中，R6为
-(CH2)p-，其中p为2-10之间的整数，或-(CH2)qR”(CH2)q-，其中R”为1个或2个硫、硒原子，q为2-5之间的整数。
2.根据权利要求1所述的地胆草种内酯衍生物及药学上可接受的盐，其特征在于：n＝2-6，m＝3-7。
3.根据权利要求1或2所述的地胆草种内酯衍生物及药学上可接受的盐，其特征在于：所述R1为：C1-C4烷基、苯甲酰基、4-三氟甲基苯甲酰基、4-氟苯甲酰基、4-甲氧基苯甲酰基、4-硝基苯甲酰基、4-乙酰基苯甲酰基、肉桂酰基、4-氟肉桂酰基、4-氯肉桂酰基、4-甲氧基肉桂酰基、3-三氟甲基肉桂酰基、3，4亚甲二氧基肉桂酰基、3-甲氧基肉桂酰基、4-二甲氨基肉桂酰基、4-三氟甲基肉桂酰基、3，4-二氟肉桂酰基、2-萘甲酰基、2，2二甲基丁酰基、2-溴丁酰基、环丙甲酰基、环己甲酰基、4，4-二氟环己甲酰基、异戊酰基、己酰基、5-溴戊酰基、4-吡啶甲酰基、
苄基，4-氟苄基、4-溴苄基、4-氯苄基、4-甲氧基苄基、正戊基、异戊基、甲基、4-三氟甲基苄基、3-甲氧基苄基、3-三氟甲基苄基、4-硝基苄基、4-甲基苄基、3,4-二氟苄基、-CO(CH2)2COOH、-CO(CH2)4COOH、-CO(CH2)6COOH、-CO(CH2)3P+(Ph)3Br-、-CO(CH2)5P+(Ph)3Br-、-CO(CH2)7P+(Ph)3Br。
4.根据权利要求1或2所述的地胆草种内酯衍生物及药学上可接受的盐，其特征在于：R2为甲基、
R3为H、环戊烷、环己烷、甲基。
5.根据权利要求1或2所述的地胆草种内酯衍生物及药学上可接受的盐，其特征在于：R4为-N3、Cl、Br、
6.根据权利要求1或2所述的地胆草种内酯衍生物及药学上可接受的盐，其特征在于：R5为
7.根据权利要求1或2所述的地胆草种内酯衍生物及药学上可接受的盐，其特征在于：R6为
-(CH2)p-，其中p为4-6之间的整数，或-(CH2)qR”r(CH2)q-，其中R”为硫或硒原子，q为2-5之间的整数，r为1-2的整数。
8.如下化合物及其药学上可接受的盐：
9.一种药物组合物，其特征在于，包含权利要求1-8任何一项所述的地胆草种内酯衍生物及药学上可接受的盐和药学上可接受的载体或赋形剂。
10.权利要求1-8任何一项所述的地胆草种内酯衍生物及药学上可接受的盐或权利要求9所述的药物组合物在制备抗肿瘤药物中的应用。
11.权利要求1-8任何一项所述的地胆草种内酯衍生物及药学上可接受的盐或权利要求9所述的药物组合物在制备抗炎药物中的应用。
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