CN110642740A - 异斯特维醇酰胺衍生物及其制备方法 - Google Patents
异斯特维醇酰胺衍生物及其制备方法 Download PDFInfo
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/52—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C233/58—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C233/61—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
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Abstract
本发明提出了一类如结构式I‑IV所示异斯特维醇酰胺衍生物及其药学上可接受的盐，
Description
技术领域
本发明属于药物化学领域，具体而言，涉及异斯特维醇酰胺衍生物及其制备方法。
背景技术
癌症已严重威胁人类健康，其造成的死亡率仅次于心脑血管疾病，全球位列第二。目前，癌症治疗方法主要有放射治疗、手术治疗和药物治疗，其中药物治疗依然是治疗癌症的最重要方法。因此，开发高效、低毒的抗癌新药成为研发的重点，并已取得了重大进展。伴随对抗癌新药研发的不断深入，从动、植物中寻找毒性低、疗效高的抗癌活性成分，以及在天然药物有效成分上进行进一步的结构修饰，半合成一些抗癌活性更好的衍生物的研究策略，已是国内外科研工作者的共识。
异斯特维醇是由天然产物甜菊苷酸性条件下水解得到的具有贝叶烷骨架的四环二萜类化合物。早期研究结果表明：异斯特维醇具有降血压、降血糖、心肌和脑的保护作用等功效。近年来，随着对其研究的深入，大量的异斯特维醇衍生物被设计和合成，新的性能也被开发，如：小分子催化性能、材料凝胶性能、超分子自组装性能等。尤其是部分衍生物展现出比其自身更为重要的抗肿瘤功效，促使研究者更进一步设计新型衍生物以期在抗癌新药开发领域有更深层次的突破。
酰胺类化合物是一类非常重要的化合物，广泛地应用于农药、医药、有机合成以及染料、香料、塑料、轻纺等领域。在酰胺键中，羰基的氧原子具有较大的电负性，致使正极在碳的一边，这一偶极的存在使酰胺结构中的羰基可以充当氢键的受体；同时，酰胺键中氮原子上的孤对电子与羰基双键形成p-π共轭，使得氮原子上的电子云密度降低，与之相连的氢原子变得较为活泼，特别是氮原子再连有吸电子取代基，其能显示弱酸性，可以作为氢键的给体。酰胺结构这一特性极易与体内的靶标分子结合，因此，它成为一个极其重要的新药开发源。现有的药物化学分析数据库数据显示：有超过25％的药物分子中含有酰胺结构，比如：用于治疗呼吸道感染、脑膜炎、败血症的头孢哌酮钠，治疗糖尿病的巴格列酮，治疗高血压、心脏病的多卡巴胺，治疗胃肠道基质细胞瘤、急性淋巴细胞白血病的尼罗替尼以及对结直肠癌、乳腺癌具有强抑制能力的甾体和萜类抗肿瘤活性分子等，这些化合物分子中均含有酰胺亚结构单元。
虽然酰胺结构单元表现出如此广谱的活性，然而在异斯特维醇分子骨架上引入酰胺亚结构单元的报道并不多见。
因此，通过对异斯特维醇分子结构修饰，在不同的活性部位引入酰胺亚结构单元合成异斯特维醇酰胺衍生物，并通过体外抗肿瘤活性测试筛选出具有应用价值的先导分子具有重要意义。
发明内容
本发明正是基于上述技术问题至少之一，本发明将酰胺亚结构单元引入到异斯特维醇分子骨架上，通过异斯特维醇16位羰基、19位羧基的结构修饰以及D环开环、扩环反应合成出含有酰胺片段的新型异斯特维醇衍生物，另一目的是提供该类化合物的合成方法及其在抗肿瘤性能方面的应用。
有鉴于此，本发明提出了一类如结构式I-IV所示异斯特维醇酰胺衍生物及其药学上可接受的盐，
其中，式I结构中--表示单键，且具有朝内、外两个构型；R1选C2H5或C6H5；R2选H、CH2OH或CH2OCOC2H5；式II结构中R3选 CH2NHCOC2H5、CH2NHCOC6H5或CONH2；式III结构中R4选COOC2H5或CH2OH。
其中结构式I型异斯特维醇酰胺衍生物选自：
其中结构式II型异斯特维醇酰胺衍生物选自：
其中结构式III型异斯特维醇酰胺衍生物选自：
其中结构式IV型异斯特维醇酰胺衍生物选自：
根据本发明的第二方面，提出了制备异斯特维醇酰胺衍生物的方法，包括以下步骤；
(1)室温条件下，吡啶溶剂中，化合物4、8、12、14与丙酸酐反应，反应结束后体系中加入过量的蒸馏水，析出固体，过滤、重结晶得化合物I-1～I-5和II-9。化合物4、8、12、14与丙酸酐的摩尔比选 1:1.1～2.2，优选1:1.1和1:2.2；重结晶溶剂选甲醇、乙醇、异丙醇、乙酸乙酯、乙腈、DMF中的一种或几种，优选乙醇；
(2)有机溶剂中，缚酸剂条件下，化合物4、8、12、14与苯甲酰氯室温反应，反应结束后，溶剂蒸干、水洗、乙酸乙酯萃取，有机相干燥、过滤、减压蒸馏后柱层析分离，得到化合物I-6～I-8和II-10；有机溶剂选DMF、二氯甲烷、氯仿、四氢呋喃或乙腈；缚酸剂选自三乙胺、N,N-二异丙基乙胺(DIPEA)或4-二甲氨基吡啶(DMAP)；
(3)有机溶剂中，催化剂作用下，化合物7回流反应，反应结束后，溶剂蒸干、水洗、乙酸乙酯萃取，有机相干燥、过滤、减压蒸馏后柱层析分离，得到化合物III-12；有机溶剂选甲苯或丙酮；催化剂选三氟化硼乙醚溶液或浓硫酸；
室温条件下，四氢呋喃溶剂中，化合物III-12经氢化铝锂还原，反应结束后，溶剂蒸干、加稀盐酸水溶液调节PH＝7，二氯甲烷萃取，有机相干燥、过滤、减压蒸馏，重结晶得到化合物III-13；重结晶溶剂选甲醇、乙醇、异丙醇、乙酸乙酯、乙腈中的一种或几种，优选乙酸乙酯。
(4)有机溶剂中，酰氯化试剂作用下，化合物1和15经DMF催化反应，反应结束后，溶剂蒸干，得到化合物16,17粗品，不经分离直接进行下一步反应。所述的有机溶剂选甲苯、二氯甲烷；酰氯化试剂选二氯亚砜、草酰氯。
有机溶剂中，化合物16,17粗品与氨/胺反应，反应结束后，溶剂蒸干、水洗、二氯甲烷萃取，有机相干燥、过滤、减压蒸馏，重结晶得到化合物IV-14和II-11。有机溶剂选二氯甲烷、氯仿、四氢呋喃、乙腈、二氧六环或甲苯；氨/胺选氨水溶液或N,N-二(异丙基)乙二胺；反应温度 0～-25℃，优选0℃；重结晶溶剂选乙酸乙酯、甲醇、乙醇、乙腈中的一种或几种，优选乙酸乙酯。
为实现本发明的目的，本发明以异斯特维醇为原料制备目标化合物，在具体操作步骤中对反应底物、反应温度、反应时间、催化剂、溶剂以及纯化方法等进行了实验和优化，找到了操作方便，收率较高，选择性较好，反应条件温和的合成方法。
根据本发明的第三方面，异斯特维醇酰胺衍生物在制备抑制人结肠癌细胞株HCT-116和人套细胞淋巴瘤细胞株JEKO-1活性药物中的应用。
1.本发明对异斯特维醇16位羰基、19位羧基、D环开环、扩环等多活性点进行结构修饰，提供了一种结构新颖的异斯特维醇酰胺衍生物，丰富了四环二萜类化合物的结构类型；
2.本发明提供的异斯特维醇酰胺衍生物制备方法简单，原料廉价易得，反应条件温和，后处理简单，收率高，且溶剂可回收利用，利于产业化生产；
3.本发明在异斯特维醇骨架上引入酰胺活性亚结构单元，大大提高其抗肿瘤活性，获得了多个抗肿瘤活性较高的异斯特维醇酰胺衍生物，为抗癌新药开发提供研究基础和先导化合物，具有较好应用前景。
具体实施方式
为了能够更清楚地理解本发明的上述目的、特征和优点，下面结合具体实施方式对本发明进行进一步的详细描述。需要说明的是，在不冲突的情况下，本发明的实施例及实施例中的特征可以相互组合。
在下面的描述中阐述了很多具体细节以便于充分理解本发明，但是，本发明还可以采用其他不同于在此描述的其他方式来实施，因此，本发明的保护范围并不受下面公开的具体实施例的限制。
实施例1化合物I-1～I-3、II-9制备的通用方法
称取化合物4、8、12、14(10mmol)和丙酸酐(11mmol)溶于100 mL吡啶溶液中，室温下搅拌反应，TLC检测至反应完毕。向体系中加入大量的蒸馏水，白色固体析出，过滤，水洗固体至中性，得到粗品化合物，乙醇重结晶，得相应的白色固体化合物I-1～I-3和II-9。
其中，化合物4、8、12、14(合成条件参考论文European Journal of MedicinalChemistry 115(2016)26-40)。
化合物I-1：收率：89％；1H NMR(400MHz,CDCl3,ppm):δ5.51(d,J＝8.6Hz,1H),4.12–4.00(m,2H),2.22(q,J＝7.6Hz,2H),2.16(d,J＝13.3Hz,1H), 1.91–1.77(m,3H),1.70–1.54(m,6H),1.40–1.29(m,5H),1.24(t,J＝7.1Hz,3H), 1.16(t,J＝7.6Hz,3H),1.15(s,3H),1.10–0.90(m,5H),0.88(s,3H),0.71(s,3H)；13C NMR(100MHz,CDCl3,ppm):δ177.5,173.8,59.9,57.0,56.8,56.0,55.6,43.7, 42.3,41.5,41.4,41.1,40.0,38.0,34.2,29.9,28.9,24.9,21.7,20.7,18.9,14.1,13.4, 10.1；HRMS(ESI,m/z)calcd for C25H42NO3[M+H]+404.3165.Found:404.3165。
化合物I-2：收率：94％；1H NMR(400MHz,CDCl3,ppm):δ5.79(d,J＝ 9.0Hz,1H),5.56(d,J＝11.3Hz,1H),4.11–3.98(m,2H),3.78(td,J＝10.8,3.5Hz, 1H),3.59(dd,J＝9.1,5.1Hz,1H),3.49(t,J＝11.0Hz,1H),2.28(q,J＝7.6Hz,2H), 2.15(d,J＝13.4Hz,1H),1.95–1.29(m,13H),1.24(t,J＝7.2Hz,3H),1.17(t,J＝ 7.6Hz,3H),1.15(s,3H),1.11–0.93(m,5H),0.89(s,3H),0.75(s,3H)；13C NMR (100MHz,CDCl3,ppm):δ177.3,175.3,64.5,63.9,60.1,57.4,57.0,54.8,51.1, 43.6,43.4,40.5,39.7,38.2,38.0,34.6,33.8,29.9,28.8,24.8,21.8,19.7,18.8,14.1, 13.4,9.9；HRMS(ESI,m/z)calcd for C26H43NO4Na[M+Na]+456.3090.Found: 456.3083。
化合物I-3：收率：91％；1H NMR(400MHz,CDCl3,ppm):δ7.06(s,1H), 4.29(t,J＝9.4Hz,1H),4.08(q,J＝7.1Hz,2H),3.95(dd,J＝10.9,3.4Hz,1H), 3.78(dd,J＝10.9,2.6Hz,1H),2.45(s,1H),2.37(d,J＝9.0Hz,1H),2.25(q,J＝ 7.6Hz,2H),2.15(d,J＝13.4Hz,1H),2.09(d,J＝14.1Hz,1H),1.86–1.61(m,7H), 1.42–1.31(m,5H),1.24(t,J＝7.1Hz,3H),1.17(t,J＝7.4Hz,3H),1.16(s,3H), 1.09(dd,J＝11.7,2.1Hz,1H),0.99(td,J＝13.3,3.9Hz,1H),0.88(dd,J＝12.2, 3.7Hz,1H),0.83(s,3H),0.69(s,3H)；13C NMR(100MHz,CDCl3,ppm):δ177.4, 173.9,61.1,60.0,58.6,57.6,57.2,55.3,45.3,44.7,43.7,41.5,39.7,39.3,38.3, 37.8,35.1,30.2,29.0,22.0,19.5,19.0,14.1,13.5,10.2；HRMS(ESI,m/z)calcd for C26H43NO4Na[M+Na]+456.3090.Found:456.3083。
化合物II-9：收率：93％；1H NMR(400MHz,CDCl3,ppm):δ6.47(dd,J＝ 17.7,11.2Hz,1H),5.47(d,J＝6.4Hz,1H),5.12–5.06(m,2H),4.08–4.03(m,2H), 3.52(dd,J＝14.0,9.3Hz,1H),2.75(dd,J＝13.9,3.8Hz,1H),2.17(q,J＝7.6Hz, 2H),2.11(d,J＝13.2Hz,1H),1.90–1.41(m,10H),1.22(t,J＝7.1Hz,3H),1.14(s, 3H),1.12(t,J＝7.6Hz,3H),1.08–0.81(m,6H),0.77(s,3H),0.66(s,3H)；13C NMR(100MHz,CDCl3,ppm):δ177.3,173.6,145.3,110.8,59.9,58.8,57.8,55.0, 45.2,43.8,41.6,40.9,39.6,38.1,38.1,38.1,34.7,30.1,29.6,28.8,20.0,19.1,17.2, 14.0,13.6,10.0；HRMS(ESI,m/z)calcdfor C26H44NO3[M+H]+418.3321.Found: 418.3322。
实施例2化合物I-4和I-5制备的通用方法
称取化合物8、12(10mmol)和丙酸酐(22mmol)溶于100mL吡啶溶液中，室温下搅拌反应，TLC检测至反应完毕。向体系中加入大量的蒸馏水，白色固体析出，过滤，水洗固体至中性，得到粗品化合物，乙醇重结晶，得相应的白色固体化合物I-4和I-5。
化合物I-4：收率：97％；1H NMR(400MHz,CDCl3,ppm):δ5.41(d,J＝ 9.8Hz,1H),4.28(dd,J＝10.9,5.7Hz,1H),4.13–4.04(m,3H),3.95(dd,J＝9.8, 6.0Hz,1H),2.33–2.27(m,2H),2.23–2.14(m,3H),2.05–2.01(m,1H),1.87–1.67 (m,6H),1.57(d,J＝11.6Hz,2H),144–1.29(m,2H),1.25(t,J＝7.1Hz,3H),1.16 (t,J＝8.0Hz,3H),1.15(s,3H),1.12(t,J＝7.7Hz,3H),1.08–0.90(m,6H),0.88(s, 3H),0.76(s,3H)；13C NMR(100MHz,CDCl3,ppm):δ177.3,174.5,173.1,65.7, 61.3,60.0,57.3,57.0,54.9,46.2,43.6,43.0,40.9,39.7,38.2,37.9,34.7,33.6,30.0, 28.9,27.5,24.8,22.0,20.0,18.9,14.1,13.3,10.1,9.0；HRMS(ESI,m/z)calcd for C29H48NO5[M+H]+490.3532.Found:490.3534。
化合物I-5：收率：91％；1H NMR(400MHz,CDCl3,ppm):δ5.82(d,J＝ 10.8Hz,1H),4.31(t,J＝9.8Hz,2H),4.09(q,J＝7.1Hz,2H),4.03(dd,J＝11.6, 3.9Hz,1H),2.68–2.63(m,1H),2.34(q,J＝7.9Hz,2H),2.19–2.13(m,3H),1.86– 1.59(m,7H),1.52(dd,J＝11.6,2.0Hz,1H),1.39–1.30(m,2H),1.25(t,J＝7.1Hz, 3H),1.17–1.08(m,9H),1.06–0.85(m,6H),0.83(s,3H),0.75(s,3H)；13C NMR (100MHz,CDCl3,ppm):δ177.2,174.2,172.9,62.8,60.0,57.4,57.4,57.0,54.9, 44.8,43.6,42.1,41.2,39.7,39.1,38.2,37.9,34.7,30.0,28.9,27.7,22.3,21.8,19.3, 18.9,14.1,13.4,10.0,9.1；HRMS(ESI,m/z)calcd forC29H48NO5[M+H]+ 490.3532.Found:490.3539。
实施例3化合物I-6～I-8、II-10制备的通用方法
称取化合物4、8、12、14(10mmol)溶解于100mL二氯甲烷中，分别加入1mL缚酸剂DIPEA和苯甲酰氯(1.6g,11mmol)，室温下搅拌反应2 小时，TLC检测，反应完毕。减压蒸去溶剂后，加入乙酸乙酯和饱和食盐水萃取，饱和食盐水洗涤有机相3次，有机相用无水硫酸钠干燥，过滤、浓缩、炒样、柱层析分离，得到相应的白色固体化合物I-6～I-8和II-10。
化合物I-6：收率：92％；1H NMR(400MHz,CDCl3,ppm):δ7.75(d,J＝ 7.0Hz,2H),7.50(t,J＝7.3Hz,1H),7.44(t,J＝7.2Hz,1H),6.10(d,J＝8.4Hz,1H), 4.26–4.20(m,1H),4.13–3.99(m,2H),2.16(d,J＝13.2Hz,1H),2.00(dd,J＝14.1, 11.6Hz,1H),1.84–1.59(m,8H),1.51–1.29(m,5H),1.23(t,J＝7.1Hz,3H),1.16(s, 3H),1.12–0.98(m,4H),0.96(s,3H),0.88(td,J＝13.3,4.1Hz,1H),0.72(s,3H)；13C NMR(100MHz,CDCl3,ppm):δ177.5,167.6,135.1,131.3,128.6,128.6, 126.8,126.8,60.0,57.5,57.0,56.1,55.6,43.7,42.5,41.8,41.4,41.2,40.0,38.0, 34.4,28.9,25.0,21.7,20.8,18.9,14.1,13.4；HRMS(ESI,m/z)calcd for C29H42NO3[M+H]+452.3165.Found:452.3159。
化合物I-7：收率：91％；1H NMR(400MHz,CDCl3,ppm):δ7.75(d,J＝ 7.2Hz,2H),7.53(t,J＝7.3Hz,1H),7.45(t,J＝7.4Hz,2H),6.45(d,J＝9.1Hz,1H), 4.66(d,J＝11.2Hz,1H),4.12–3.97(m,2H),3.86(dd,J＝11.1,3.8Hz,1H),3.80 (dd,J＝9.0,5.0Hz,1H),3.58(t,J＝10.9Hz,1H),2.16(d,J＝13.2Hz,1H),2.07– 1.67(m,8H),1.59–1.32(m,4H),1.23(t,J＝7.1Hz,3H),1.16(s,3H),1.14–0.99 (m,4H),0.97(s,3H),0.88(td,J＝13.3,4.2Hz,1H),0.75(s,3H)；13C NMR (100MHz,CDCl3,ppm):δ177.3,168.8,134.2,131.9,128.7,128.7,127.0,127.0, 64.5,64.4,60.1,57.5,57.0,54.9,51.4,43.6,43.6,40.8,39.7,38.2,38.0,34.7,34.0, 28.8,25.0,21.8,19.8,18.8,14.1,13.4；HRMS(ESI,m/z)calcd for C30H44NO4 [M+H]+482.327.Found:482.3266。
化合物I-8：收率：90％；1H NMR(400MHz,CDCl3,ppm):δ7.93(s,1H), 7.81(d,J＝7.0Hz,2H),7.46(t,J＝7.3Hz,1H),7.40(t,J＝7.3Hz,2H),4.53(t,J＝ 9.5Hz,1H),4.07(q,J＝7.1Hz,2H),4.03(s,1H),3.88(d,J＝10.7Hz,1H),2.45(d, J＝9.1Hz,1H),2.37(s,1H),2.19–2.15(m,2H),1.89–1.64(m,7H),1.44–1.32(m, 4H),1.23(t,J＝7.1Hz,3H),1.17(s,3H),1.12–0.92(m,3H),0.89(s,3H),0.87– 0.84(m,2H),0.71(s,3H)；13C NMR(100MHz,CDCl3,ppm):δ177.4,167.0, 135.1,131.1,128.5,128.5,126.9,126.9,61.4,60.0,59.3,57.6,57.3,55.5,45.5, 44.7,43.7,42.1,39.8,39.4,38.3,37.8,35.2,29.0,22.2,22.1,19.6,19.0,14.1,13.5； HRMS(ESI,m/z)calcd for C30H44NO4[M+H]+482.327.Found:482.3264。
化合物II-10：收率：95％；1H NMR(400MHz,CDCl3,ppm):δ7.70(d,J＝ 6.9Hz,2H),7.48(t,J＝7.3Hz,1H),7.42(t,J＝7.3Hz,2H),6.58(dd,J＝17.8, 11.1Hz,1H),6.24(d,J＝6.0Hz,1H),5.22–4.02(m,4H),3.73(dd,J＝13.9,9.4Hz, 1H),2.97(dd,J＝14.0,3.7Hz,1H),2.15(d,J＝13.1Hz,1H),1.89–1.42(m,10H), 1.22(t,J＝7.1Hz,3H),1.15(s,3H),1.13–0.88(m,6H),0.85(s,3H),0.68(s,3H)；13C NMR(100MHz,CDCl3,ppm):δ177.3,167.2,145.8,135.1,131.2,128.6, 128.6,126.7,126.7,110.8,59.9,58.8,57.9,54.9,53.4,45.6,43.8,41.6,41.0,39.6, 38.2,38.1,35.1,29.8,28.8,20.0,19.1,17.2,14.0,13.7；HRMS(ESI,m/z)calcd for C30H44NO3[M+H]+466.3321.Found:466.3317。
实施例4化合物III-12的制备方法
称取化合物7(3.9g,10mmol)溶解于50mL干燥的甲苯溶剂中，向体系中加入0.2mL三氟化硼乙醚溶液，油浴条件下，搅拌回流反应12个小时，反应完毕。减压蒸去溶剂后，加入乙酸乙酯和饱和食盐水萃取，饱和食盐水洗涤有机相3次，有机相用无水硫酸钠干燥，过滤、浓缩、炒样、柱层析分离，得到白色固体化合物III-12；
化合物III-12：收率：81％；1H NMR(400MHz,CDCl3,ppm):δ6.29(s,1H), 4.13–4.08(m,2H),4.02(dd,J＝10.0,4.2Hz,1H),3.67(t,J＝9.4Hz,1H),2.81(dd, J＝8.0,4.0Hz,1H),2.16(d,J＝13.6Hz,1H),1.90–1.29(m,11H),1.28–1.25(m, 6H),1.18(s,3H),1.17–0.85(m,7H),0.81(s,3H)；13C NMR(100MHz,CDCl3, ppm):δ177.3,177.0,62.1,60.4,60.2,59.3,57.7,51.5,47.0,44.5,43.7,40.1,40.0, 38.5,38.3,37.8,36.8,28.7,28.6,21.0,20.1,18.9,17.8,14.2；HRMS(ESI,m/z) calcd for C23H37NO4Na[M+Na]+414.2620.Found:414.2622。
实施例5化合物III-13的制备方法
称取化合物III-12(3.9g，10mmol)溶解至50mL干燥的四氢呋喃中，向体系中加入氢化铝锂(0.5g,12mmol)，搅拌回流反应7个小时，TLC检测，反应完毕。减压蒸去溶剂，二氯甲烷和稀盐酸水溶液萃取，饱和食盐水洗涤有机相3次至中性，有机相用无水硫酸钠干燥后，过滤、浓缩、乙酸乙酯重结晶，即得白色固体化合物III-13；
化合物III-13：收率：94％；1H NMR(400MHz,CDCl3,ppm):δ6.66–6.59 (m,1H),3.94(dd,J＝10.2,4.6Hz,1H),3.69–3.59(m,2H),3.44(d,J＝10.8Hz, 1H),2.84–2.81(dd,J＝8.0,4.6Hz,1H),1.82–1.26(m,12H),1.25(s,3H),1.15(s, 3H),1.08–0.97(m,4H),0.94(s,3H),0.91–0.81(m,4H)；13C NMR(100MHz, CDCl3,ppm):δ177.6,65.3,62.1,59.9,57.9,51.5,46.9,44.2,39.9,39.8,38.9,38.6, 37.9,36.9,35.7,29.7,28.4,27.1,18.9,18.0,17.6,16.8；HRMS(ESI,m/z)calcd for C21H35NO3Na[M+Na]+372.2515.Found:372.2514。
实施例6化合物IV-14、II-11制备的通用方法
称取化合物1、15(30mmol)加入到50mL的二氯甲烷中，搅拌溶解，室温条件下，缓慢滴加草酰氯(90mmol)，反应3个小时，缓慢滴加0.5mL 催化量的DMF，体系继续反应至无气泡溢出，反应完毕。减压蒸干溶剂，得到相应的灰白色粗产品固体化合物16、17。粗产品化合物不经纯化进一步反应。将化合物16、17加入到50mL干燥的四氢呋喃溶液中，搅拌溶解，冰浴条件下，迅速向体系中加入取代的胺(60mmol)，搅拌反应，TLC检测至反应完毕。减压蒸去溶剂四氢呋喃后，加入二氯甲烷和饱和食盐水萃取，饱和食盐水洗涤有机相3次，有机相用无水硫酸钠干燥，过滤、浓缩、乙酸乙酯重结晶，得到相应的白色固体IV-14和II-11。
化合物II-11：收率：92％；1H NMR(400MHz,CDCl3,ppm):δ6.18(dd,J＝ 17.6,11.1Hz,1H),5.50(s,1H),5.01(t,J＝14.9Hz,1H),4.15–3.99(m,2H),2.41 (d,J＝13.2Hz,1H),2.19–1.58(m,10H),1.44–1.31(m,4H),1.23(t,J＝8.5Hz, 3H),1.15(s,3H),1.11(s,3H),1.04–0.76(m,5H),0.60(s,3H)；13C NMR (100MHz,CDCl3,ppm):δ180.4,177.3,142.1,111.4,59.9,59.0,57.8,56.1,43.8, 40.9,39.8,39.1,38.2,38.1,36.6,31.8,28.7,19.8,19.2,18.1,14.0,13.5；HRMS (ESI,m/z)calcd for C23H38NO3[M+H]+376.2852.Found:376.2855。
化合物IV-14：收率：90％；1H NMR(400MHz,CDCl3,ppm):δ6.44(s,1H), 3.20–3.18(m,2H),3.06–2.99(m,2H),2.67–2.62(m,2H),2.05(d,J＝14.2Hz,1H), 1.97–1.33(m,14H),1.28–1.20(m,2H),1.17(s,3H),1.14–1.10(m,2H),1.02(s, 6H),1.00(s,6H),0.97(s,3H),0.93–0.89(m,1H),0.76(s,3H)；13C NMR (100MHz,CDCl3,ppm):δ222.6,176.6,57.5,54.7,54.3,48.7,48.4,46.9,43.6, 42.1,41.7,40.2,39.5,38.1,37.3,37.2,30.2,22.3,20.9,20.6,20.3,19.9,19.2,13.4； HRMS(ESI,m/z)calcd for C28H49N2O2[M+H]+445.3794.Found:445.3791。
实施例7癌细胞体外抑制活性测试
细胞种板：HCT-116为1000个/孔，JEKO-1为5000个/孔。37℃， 5％CO2培养箱过夜。样品及对照品稀释：样品用培养基稀释，30mM稀释100倍到300μM(10μl样品+990μl培养基)，再进行3倍系列稀释(300、 100、33.3、11.1、3.7、1.23、0.41、0.13μM)8个梯度；对照品用培养基稀释，5mM稀释100倍到300μM(60μl顺铂+942μl培养基)，再进行3倍系列稀释(300、100、33.3、11.1、3.7、1.23、0.41、0.13μM)8个梯度。另设空白对照组。之后，将稀释好的样品和对照品转移至细胞孔中，100μl/孔，2个复孔。96孔板边缘加200μlPBS。用封口膜包好，放入培养箱3天。3天后，避光加入5mg/ml的MTT溶液，20μl/孔，继续培养4h。对HCT-116细胞，可直接小心弃上清，加DMSO，150μl/孔；而JEKO-1细胞，在加DMSO之前，需3000rpm，离心10min。离心后用移液枪吸弃上清。加入DMSO试剂 150μl/孔，微孔板振荡器振荡10min。酶标仪测吸光度值。最后将数据输入 Soft Pro软件制作四参数图，利用寇式法计算出样本的IC50值，如表1所示。
表1化合物对癌细胞株的IC50值
表中数据显示：所有新型异斯特维醇酰胺衍生物对二株肿瘤细胞的抑制活性均好于初始原料异斯特维醇，其中HCT-116细胞对化合物的敏感度优于 JEKO-1细胞，这说明异斯特维醇酰胺衍生物对肿瘤细胞的抑制活性具有一定的选择性。对人结肠癌细胞HCT-116的抑制活性结果显示：19位修饰酰胺取代物IV-14表现出最好的抗肿瘤效果，该化合物对HCT-116的抑制活性IC50值高达7.66±0.21μM；16位修饰酰胺取代物仅表现出一般的抑制效果(I-1, I-6)，而15位羟甲基的引入能明显提高化合物的抗肿瘤活性(I-1vs I-2,I-6 vsI-7)，当羟基被进一步酰化后，其抗肿瘤功效明显下降(I-2vs I-4)，说明羟基的引入也有利于抗肿瘤活性的提升。总之，脂肪族酰胺的抗肿瘤效果优于芳香族酰胺化合物(I-1vs I-6,I-2vs I-7,I-3vs I-8)，D-环扩环的内酰胺衍生物(III-12,III-13)却表现出最差的抑制活性。
对人套细胞淋巴瘤细胞JEKO-1的抑制活性结果显示：所有化合物对 JEKO-1细胞表现出相对一般的抗肿瘤功效，其中，异斯特维醇D-环扩环的内酰胺(III-12,III-13)表现出相对较差的抑制效果，尤其是化合物III-13活性最差，其IC50大于100μM。15、16位反式取代的酰胺类化合物(I-2,I-4, I-7)同样也表现出相对较差的抗肿瘤活性，而15、16位顺式取代的酰胺类化合物(I-3,I-5,I-8)具有相对较好的活性，这说明手性因素也对化合物的抗肿瘤效果起着非常重要的作用。D-环开环的酰胺取代物(II-9,II-10)展现出最好的抑制效果，特别是化合物II-10对JEKO-1细胞的抑制活性IC50值为 10.59±0.85μM，但D-环开环的酰胺取代物II-11却表现出相对较差的抑制活性(IC50＝43.86±2.65μM)，说明D-环开环的异斯特维醇分子中，与酰胺的连接顺序对抗肿瘤效果也具有较大的影响。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (7)
1.一类如结构式I-IV所示异斯特维醇酰胺衍生物及其药学上可接受的盐，
其中，式I结构中--表示单键，且具有朝内、外两个构型；R1选C2H5或C6H5；R2选H、CH2OH或CH2OCOC2H5；式II结构中R3选CH2NHCOC2H5、CH2NHCOC6H5或CONH2；式III结构中R4选COOC2H5或CH2OH。
2.根据权利要求1所述的异斯特维醇酰胺衍生物，其特征在于，所述结构式I型异斯特维醇酰胺衍生物选自：
3.根据权利要求1所述的异斯特维醇酰胺衍生物，其特征在于，所述结构式II型异斯特维醇酰胺衍生物选自：
4.根据权利要求1所述的异斯特维醇酰胺衍生物，其特征在于，所述结构式III型异斯特维醇酰胺衍生物选自：
5.根据权利要求1所述的异斯特维醇酰胺衍生物，其特征在于，所述结构式IV型异斯特维醇酰胺衍生物选自：
6.制备权利要求2-5所述异斯特维醇酰胺衍生物的方法，其特征在于，包括以下步骤：
(1)将化合物4、8、12、14与丙酸酐按照摩尔比为1:1.1～2.2的比例反应后，析出固体，重结晶后得化合物I-1～I-5和II-9；
(2)缚酸剂条件下，化合物4、8、12、14与苯甲酰氯室温反应处理后，进行蒸馏后柱层析分离，得到化合物I-6～I-8和II-10；
(3)在催化剂作用下，化合物7进行回流反应，处理后减压蒸馏后柱层析分离，得到化合物III-12；将所述化合物III-12经氢化铝锂还原处理后，重结晶得到化合物III-13；
(4)有机溶剂中，酰氯化试剂作用下，化合物1和15经DMF催化反应，得到化合物16,17粗品；所述化合物16,17粗品与氨/胺反应处理后，重结晶得到化合物IV-14和II-11；
7.如权利要求2～5所示的异斯特维醇酰胺衍生物在制备抑制人结肠癌细胞株HCT-116和人套细胞淋巴瘤细胞株JEKO-1活性药物中的应用。
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| 王婷婷等: "异甜菊醇衍生物的生物活性及构效关系研究进展", 《药学进展》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111229312A (zh) * | 2020-03-13 | 2020-06-05 | 河南牧业经济学院 | 一种无溶剂催化剂及其制备方法和应用 |
| CN114933554A (zh) * | 2022-06-01 | 2022-08-23 | 新乡医学院 | 一种基于异斯特维醇的可注射型超分子水凝胶及其制备方法与应用 |
| CN114933554B (zh) * | 2022-06-01 | 2023-09-29 | 新乡医学院 | 一种基于异斯特维醇的可注射型超分子水凝胶及其制备方法与应用 |
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| CN110642740B (zh) | 2022-06-14 |
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