CN113387808A - Tagalsin C二萜衍生物及其制备和用途 - Google Patents

Tagalsin C二萜衍生物及其制备和用途 Download PDF

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CN113387808A
CN113387808A CN202110853692.4A CN202110853692A CN113387808A CN 113387808 A CN113387808 A CN 113387808A CN 202110853692 A CN202110853692 A CN 202110853692A CN 113387808 A CN113387808 A CN 113387808A
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申丽
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Abstract

本发明涉及一种tagalsin C二萜衍生物及其制备和用途。具体地，本发明公开了结构如式1所示的二萜化合物，定义详见说明书。本发明还公开了包含该化合物的药物组合物，以及它们在预防和/或治疗癌症中的用途。

Description

Tagalsin C二萜衍生物及其制备和用途
技术领域
本发明属于医药领域，具体涉及tagalsin C类二萜衍生物及其制备和用途。
技术背景
据报道，从角果木属植物中分离得到的次生代谢产物以二萜类化合物居多，主要有dolabrane型二萜、松香烷型二萜、海松烷型二萜、罗汉松烷型二萜、贝壳杉烷型二萜、贝叶烷型二萜、半日花烷型二萜以及二萜二聚体。其中，dolabrane型二萜仅在红树植物C.tagal中分离得到，是C.tagal的标志性组分。Tagalsin C是分离自我国海南角果木的dolabrane型二萜，虽然已经被报道对多种肿瘤细胞株的增殖具有抑制作用，然而，其抑制效果仍然有所欠缺。
发明内容
本发明的目的是提供一类结构全新的且对多种癌细胞具有良好抑制效果的二萜类化合物。具体地，本发明的发明人对tagalsin C进行了结构修饰，得到了一系列抑癌效果显著提高的衍生物。
本发明第一方面提供了如式1所示的化合物或其药学上可接受的盐，
Figure BDA0003183312750000011
其中，R1为取代或未取代的C6-C10芳基、取代或未取代的5元至10元杂芳基、取代或未取代的C3-C6环烷基或取代或未取代的5元至10元杂环基；所述取代是指上述基团上的一个或多个(例如一个或两个或三个)氢原子被选自下组的取代基所取代：硝基、氰基、卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、氨基、-C(＝O)-C1-C6烷基、-C(＝O)-C1-C6烷氧基。
在一实施例中，R1为取代或未取代的苯基、取代或未取代的吡啶、取代或未取代的嘧啶、取代或未取代的呋喃、取代或未取代的噻吩、取代或未取代的吡咯、取代或未取代的咪唑、取代或未取代的吡唑、取代或未取代的哌嗪、或取代或未取代的哌啶；所述取代是指上述基团上的一个或多个(例如一个或两个或三个)氢原子被选自下组的取代基所取代：硝基、氰基、卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、氨基、-C(＝O)-C1-C6烷基、-C(＝O)-C1-C6烷氧基。
在一实施例中，R1为取代或未取代的苯基、取代或未取代的吡啶、取代或未取代的嘧啶、取代或未取代的呋喃、取代或未取代的噻吩、取代或未取代的吡咯、取代或未取代的咪唑、取代或未取代的吡唑、取代或未取代的哌嗪、或取代或未取代的哌啶；所述取代是指上述基团上的一个或多个(例如一个或两个或三个)氢原子被选自下组的取代基所取代：硝基、卤素、甲基、三氟甲基、甲氧基、氨基、-C(＝O)-甲基。
在一实施例中，R1选自下组：
Figure BDA0003183312750000021
Figure BDA0003183312750000031
在一实施例中，所述化合物选自下组：
Figure BDA0003183312750000032
Figure BDA0003183312750000041
本发明第二方面提供了一种药物组合物，所述药物组合物包含本发明第一方面所述的化合物或其药学上可接受的盐以及药学上可接受的载体。
本发明第三方面提供了如本发明第一方面所述的化合物或其药学上可接受的盐或如本发明第二方面所述的药物组合物在制备用于预防和/或治疗癌症的药物中的用途。
在一实施例中，所述癌症选自下组的一种或多种：结肠癌、胃癌细胞、肺癌细胞、乳腺癌(例如三阴性乳腺癌)。
本发明第四方面提供了如本发明第一方面所述的化合物或其药学上可接受的盐的制备方法，其中，所述方法包括步骤：将化合物tagalsin C与有机酸R1COOH进行酯化反应，从而形成式1化合物；
Figure BDA0003183312750000051
各式中R1的定义同前。
具体实施方式
如本文所用，术语“C6-C10芳基”是指具有6-10个碳原子作为环原子的芳基，例如苯基、萘基等类似基团。
如本文所用，术语“5元至10元杂芳基”是指具有5-10个环原子的杂芳基，其中，所述环原子包括碳原子和至少1个或多个(例如2个或3个)杂原子，所述杂原子选自下组：N、O或S。例如，吡啶、嘧啶、吡唑、吡咯、噻吩、呋喃、咪唑等类似基团。
如本文所用，术语“C3-C6环烷基”是指具有3-6个碳原子作为环原子的环烷基，例如，环丙基、环丁基、环戊基、环己基等类似基团。
如本文所用，术语“5元至10元杂环基”是指具有5-10个环原子的杂环基，其中，所述环原子包括碳原子和至少1个或多个(例如2个或3个)杂原子，所述杂原子选自下组：N、O或S。例如，哌啶、哌嗪、四氢呋喃等类似基团。
如本文所用，术语“卤素”是指氟、氯、溴、碘。
如本文所用，术语“C1-C6烷基”是指具有1-6个碳原子的烷基，例如，甲基、乙基、丙基、丁基、戊基、己基等类似基团。
如本文所用，术语“卤代C1-C6烷基”指C1-C6烷基上的氢原子被一个或多个卤素取代，所述C1-C6烷基定义同前，例如，卤代甲基(例如，三氟甲基等)、卤代乙基(例如三氟乙基、五氟乙基等)、卤代丙基、卤代丁基、卤代戊基、卤代己基等类似基团。
如本文所用，术语“C1-C6烷氧基”是指具有1-6个碳原子的烷氧基，例如，甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基等类似基团。
如本文所用，本发明化合物为式1所示的化合物或其药学上可接受的盐。
如本文所用，“药学上可接受的盐”包括例如本发明化合物与无机酸形成的盐和与有机酸形成的盐。另外，如果本文所述的化合物作为酸加成盐获得，则游离碱可通过碱化所述酸加成盐的溶液而获得。相反地，如果所述产物是游离碱，则可根据用于从碱性化合物制备酸加成盐的常规方法，通过将所述游离碱溶解于适当的有机溶剂中并且用酸处理所述溶液制得加成盐，特别是药学上可接受的加成盐。本领域的技术人员将会认识到可用于制备无毒的药学上可接受的加成盐的各种合成方法。可以由无机酸和有机酸制备药学上可接受的酸加成盐。衍生自无机酸的盐包括盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等。衍生自有机酸的盐包括乙酸盐、丙酸盐、乙醇酸盐、丙酮酸盐、草酸盐、苹果酸盐、丙二酸盐、琥珀酸盐、马来酸盐、富马酸盐、酒石酸盐、柠檬酸盐、苯甲酸盐、肉桂酸盐、扁桃酸盐、甲磺酸盐、乙磺酸盐、对甲苯磺酸盐、水杨酸盐等。
本发明化合物具有抑制癌细胞生长的功能。据此，本发明化合物或以及含有该化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解与癌症，例如胃癌、结肠癌、乳腺癌等。
本发明的药物组合物包含安全有效量范围内的本发明化合物作为活性成分以及药学上可以接受的载体。
所述的“安全有效量”指的是：活性成分的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg活性成分/剂，更佳地，含有5-200mg活性成分/剂。较佳地，所述的“一剂”为一个胶囊或药片。
所述的“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组分能和活性成分以及它们之间相互掺和，而不明显降低活性成分的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
Figure BDA0003183312750000061
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明活性成分或含有该活性成分的药物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性成分与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性成分的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性成分也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性成分外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性成分外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。用于局部给药的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明活性成分可以单独给药，或者与其他药学上可接受的化合物联合给药。
使用药物组合物时，是将安全有效量的本发明活性成分适用于需要治疗的受试者，例如哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选5～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
如本文所用，“治疗”是用于获得有益或所需结果(包括临床结果)的方法。有益的或所需的临床结果可包括以下中的一个或多个：a)抑制疾病或病状(例如，减少由疾病或病状导致的一种或多种症状和/或减轻疾病或病状的程度)；b)减缓或阻止与疾病或病状相关的一种或多种临床症状的发展(例如，稳定疾病或病状、预防或延迟疾病或病状的恶化或进展和/或预防或延迟疾病或病状的扩散(例如，转移)；和/或c)缓解疾病，即引起临床症状的消退(例如，改善疾病状态、提供疾病或病状的部分或全部缓解、增强另一种药物的作用、延迟疾病的进展、提高生活质量和/或延长存活)。
如本文所用，“预防”意指导致疾病或病状的临床症状不发展的疾病或病状的任何治疗。在某些实施方案中，活性成分可施用于处于风险或者具有疾病或病状家族史的受试者(包括人)。
如本文所用，“受试者”是指已经或将要成为治疗、观察或实验对象的动物，诸如哺乳动物(包括人)。本文所述的方法可用于人疗法和/或兽医应用。在某些实施方案中，受试者是哺乳动物。在某些实施方案中，受试者是人。
合成方法1：
Figure BDA0003183312750000081
合成方法1可包括步骤：将tagalsin C与有机酸R1COOH进行酯化反应(例如在缩合试剂存在下，例如，在DCC和DMAP存在下)，从而形成式1化合物。各式中，R1为取代或未取代的C6-C10芳基、取代或未取代的5元至6元杂芳基、取代或未取代的C3-C6环烷基或取代或未取代的5元至6元杂环基；所述取代是指上述基团上的一个或多个(例如一个或两个或三个)氢原子被选自下组的取代基所取代：硝基、氰基、卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、氨基、-C(＝O)-C1-C6烷基、-C(＝O)-C1-C6烷氧基。
合成方法2：
Figure BDA0003183312750000091
合成方法2可包括步骤：将tagalsin C与卤代烃R2X进行醚化反应(例如在碱存在下，例如，在碳酸钾或碳酸铯等存在下)，从而形成式2化合物。各式中，R2为取代或未取代的C6-C10芳基、取代或未取代的5元至6元杂芳基、取代或未取代的C3-C6环烷基或取代或未取代的5元至6元杂环基；所述取代是指上述基团上的一个或多个(例如一个或两个或三个)氢原子被选自下组的取代基所取代：硝基、氰基、卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、氨基、-C(＝O)-C1-C6烷基、-C(＝O)-C1-C6烷氧基。X为卤素。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
缩写说明：DCC：N,N'-二环己基碳二亚胺；DMAP：4-二甲氨基吡啶；DMF：N,N-二甲基甲酰胺；MTT：3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐；ATP：腺嘌呤核苷三磷酸；TCA：三氯醋酸。
本发明中所使用的化合物tagalsin C可以市售获得也可以根据已有文献方法获得，例如从海南角果木中分离得到。
实施例1合成TC-001
Figure BDA0003183312750000101
在干燥的10mL圆底烧瓶中，将化合物Tagalsin C(5.0mg，0.015mmol)溶于2.0mL无水二氯甲烷，然后加入DCC(2.0equiv.)和DMAP(1.0equiv.)振摇，最后加入苯甲酸(有机酸R1COOH，其中R1为苯基，2.0equiv.)，密封反应器并在室温下搅拌0.5小时。TLC监测反应完成后，挥干反应溶剂。将所得残余物溶于丙酮或乙腈中，离心沉淀不溶物质。取上清液通过制备型HPLC(柱型号：YMC,ODS-A,250×10mm i.d.5μm,12nm；流动相：乙腈/水)进行纯化，得到相应酯化产物TC-001。采用质谱(ESIMS)和核磁共振谱(NMR)对该化合物结构进行确认。
化合物TC-001：
Figure BDA0003183312750000102
白色固体，收率：92.1％,1H NMR(400MHz,CDCl3):δ8.15(d,J＝7.2Hz,2H),7.61(t,J＝7.4,14.8Hz,1H),7.48(t,J＝7.8,15.4Hz,2H),6.75(d,J＝6.8Hz,1H),6.25(br s,1H),5.80(dd,J＝17.4,10.8Hz,1H),5.41(br s,1H),4.94(d,J＝17.6Hz,1H),4.89(d,J＝10.8Hz,1H),2.24(m,1H),2.20(d,J＝6.8Hz),1.57(m,1H),1.54(m,1H),1.51(m,1H),1.43(m,1H),1.40(m,1H),1.39(m,1H),1.36(m,1H),1.34(m,1H),1.32(m,1H),1.28(s,3H),1.25(m,1H),1.10(m,1H),1.15(m,1H),1.08(s,3H),0.79(s,3H)；13C NMR(100MHz,CDCl3):δ182.1,165.1,150.7,149.4,146.0,135.7,133.6,130.3,128.9,128.5,118.8,109.0,56.4,41.1,40.8,40.7,39.3,36.5,36.4,35.4,33.6,31.6,25.4,22.9,12.1；HR-ESIMS:[M+Na]+m/z 427.2247.
实施例2至实施例18
按照TC-001的方法依次合成得到衍生物TC-002～TC-018。不同点在于具体反应条件参见表1所示的条件。
表1酯化反应
Figure BDA0003183312750000111
采用质谱(ESIMS)和核磁共振谱(NMR)对上述化合物结构进行确认。
化合物TC-002：
Figure BDA0003183312750000112
白色固体，收率：89.6％,1H NMR(400MHz,CDCl3):δ8.33(重叠峰,4H),6.80(d,J＝6.8Hz,1H),6.25(br s,1H),5.80(dd,J＝17.4,10.8Hz,1H),5.45(br s,1H),4.94(d,J＝17.8Hz,1H),4.87(d,J＝11.0Hz,1H),2.27(m,1H),2.23(d,J＝6.8Hz),1.58(m,1H),1.54(m,1H),1.51(m,1H),1.43(m,1H),1.40(m,1H),1.39(m,1H),1.36(m,1H),1.34(m,1H),1.27(m,1H),1.12(m,1H),1.15(s,3H),1.12(m,1H),1.12(s,3H),0.79(s,3H)；13C NMR(100MHz,CDCl3):δ181.7,163.2,150.9,150.6,149.1,145.7,136.1,134.4,131.4,131.4,123.7,123.7,119.3,109.1,56.4,41.1,40.8,40.8,39.3,36.5,36.4,35.4,33.5,31.6,25.3,22.9,12.1；LR-ESIMS:[M+H]+m/z 450.01.
化合物TC-003：
Figure BDA0003183312750000121
白色固体，收率：82.0％,1H NMR(400MHz,CDCl3):δ8.27(s,1H),8.26(s,1H),7.75(s,1H),7.74(s,1H),6.55(d,J＝6.8Hz,1H),6.26(br s,1H),5.80(dd,J＝17.4,10.8Hz,1H),5.43(br s,1H),4.94(d,J＝17.8Hz,1H),4.87(d,J＝11.0Hz,1H),2.27(m,1H),2.22(d,J＝6.7Hz),1.57(m,1H),1.55(m,1H),1.54(m,1H),1.46(m,1H),1.43(m,1H),1.40(m,1H),1.37(m,1H),1.34(m,1H),1.27(m,1H),1.28(s,3H),1.14(m,1H),1.08(s,3H),0.79(s,3H)；13C NMR(100MHz,CDCl3):δ181.9,163.9,150.7,150.6,149.2,145.8,136.0,135.6,132.2,130.7,130.6,125.6,125.5,119.1,109.1,56.4,41.1,40.8,40.7,39.3,36.5,36.4,35.4,33.5,31.6,25.4,22.9,12.1；LR-ESIMS:[M+H]+m/z 473.17.
化合物TC-004：
Figure BDA0003183312750000122
白色固体，收率：75.2％,1H NMR(400MHz,CDCl3):δ8.33(d,J＝6.8Hz,1H),7.50(d,J＝6.8Hz,1H),7.42(br s,1H),6.76(d,J＝6.6Hz,1H),6.25(br s,1H),5.80(dd,J＝17.4,10.6Hz,1H),5.42(br s,1H),4.94(d,J＝17.8Hz,1H),4.85(d,J＝11.0Hz,1H),3.99(s,3H),2.26(m,1H),2.20(d,J＝7.0Hz),1.56(m,1H),1.53(m,1H),1.50(m,1H),1.47(m,1H),1.45(m,1H),1.42(m,1H),1.37(m,1H),1.33(m,1H),1.26(s,3H),1.22(m,1H),1.12(m,1H),1.08(s,3H),0.78(s,3H)；13C NMR(100MHz,CDCl3):δ181.6,164.9,150.7,150.6,149.2,147.8,145.7,139.0,135.9,119.1,116.1,111.8,109.1,56.4,54.0,41.1,40.8,40.7,39.3,36.5,36.4,35.4,33.5,31.6,25.4,22.9,12.1；LR-ESIMS:[M+H]+m/z 436.12.
化合物TC-005：
Figure BDA0003183312750000131
白色固体，收率：67.0％,1H NMR(400MHz,CDCl3):δ8.60(dd,J＝5.2,0.7Hz,1H),8.01(m,1H),7.87(dd,J＝5.2,1.4Hz,1H),6.80(d,J＝6.8Hz,1H),6.26(br s,1H),5.79(dd,J＝17.4,10.8Hz,1H),5.44(br s,1H),4.94(d,J＝17.8Hz,1H),4.85(d,J＝11.0Hz,1H),2.26(m,1H),2.23(d,J＝6.8Hz),1.53(m,1H),1.52(m,1H),1.51(m,1H),1.47(m,1H),1.42(m,1H),1.40(m,1H),1.36(m,1H),1.34(m,1H),1.27(m,1H),1.26(s,3H),1.12(m,1H),1.08(s,3H),0.78(s,3H)；13C NMR(100MHz,CDCl3):δ181.5,162.3,152.6,150.7,150.6,149.0,145.5,139.1,136.3,124.5,122.0,119.4,109.1,56.4,54.0,41.1,40.8,40.8,39.3,36.5,36.4,35.4,33.5,31.6,25.3,22.9,12.1；LR-ESIMS:[M+H]+m/z 440.08.
化合物TC-006：
Figure BDA0003183312750000132
白色固体，收率：91.7％,1H NMR(400MHz,CDCl3):δ8.56(d,J＝5.2Hz,2H),7.97(d,J＝5.6Hz,2H),6.80(d,J＝6.8Hz,1H),6.26(br s,1H),5.80(dd,J＝17.4,10.8Hz,1H),5.44(br s,1H),4.92(d,J＝17.4Hz,1H),4.86(d,J＝10.6Hz,1H),2.26(m,1H),2.22(d,J＝6.8Hz),1.57(m,1H),1.51(m,1H),1.50(m,1H),1.46(m,1H),1.42(m,1H),1.39(m,1H),1.36(m,1H),1.34(m,1H),1.27(s,3H),1.26(m,1H),1.13(m,1H),1.08(s,3H),0.79(s,3H)；13CNMR(100MHz,CDCl3):δ181.6,163.5,152.6,150.6,150.4,149.1,145.7,136.5,136.1,123.4,119.2,109.1,56.4,41.1,40.8,40.8,39.3,36.5,36.4,35.4,33.5,31.6,25.3,22.9,12.1；LR-ESIMS:[M+H]+m/z 406.14.
化合物TC-007：
Figure BDA0003183312750000141
白色固体，收率：77.8％,1H NMR(400MHz,CDCl3):δ7.93(d,J＝3.8Hz,1H),7.64(d,J＝4.8Hz,1H),7.14(t,J＝4.0,8.8Hz,1H),6.80(d,J＝6.8Hz,1H),6.24(br s,1H),5.80(dd,J＝17.6,10.8Hz,1H),5.40(br s,1H),4.91(d,J＝17.4Hz,1H),4.86(d,J＝10.8Hz,1H),2.25(m,1H),2.19(d,J＝6.8Hz),1.56(m,1H),1.54(m,1H),1.54(m,1H),1.49(m,1H),1.44(m,1H),1.40(m,1H),1.37(m,1H),1.34(m,1H),1.26(s,3H),1.21(m,1H),1.13(m,1H),1.07(s,3H),0.78(s,3H)；13C NMR(100MHz,CDCl3):δ182.0,160.4,150.7,150.4,149.3,145.6,135.9,134.8,133.6,132.2,127.9,118.9,109.0,56.4,41.1,40.8,40.7,39.3,36.5,36.4,35.4,33.5,31.6,25.4,23.0,12.1；LR-ESIMS:[M+H]+m/z 411.07；[M+Na]+m/z433.16.
化合物TC-008：
Figure BDA0003183312750000142
白色固体，收率：79.4％,1H NMR(400MHz,CDCl3):δ7.70(s,1H),7.55(s,1H),6.76(d,J＝6.6Hz,1H),6.26(br s,1H),5.81(dd,J＝17.4,10.4Hz,1H),5.40(br s,1H),4.90(d,J＝17.6Hz,1H),4.86(d,J＝10.8Hz,1H),2.23(dt,2.6,14.2Hz,1H),2.16(d,J＝6.6Hz),1.54(m,1H),1.51(m,1H),1.50(m,1H),1.49(m,1H),1.42(重叠峰,2H),1.38(m,1H),1.35(m,1H),1.33(m,1H),1.25(s,3H),1.12(m,1H),1.07(s,3H),0.76(s,3H)；13C NMR(100MHz,CDCl3):δ182.0,160.6,150.8,149.5,145.7,138.8,135.7,132.6,132.2,127.2,118.6,109.0,56.4,41.1,40.8,40.7,39.3,36.5,36.4,35.3,33.9,33.6,31.6,25.4,23.0,12.1；LR-ESIMS:[M+H]+m/z 409.29；[M+Na]+m/z 431.07.
化合物TC-009：
Figure BDA0003183312750000151
白色固体，收率：57.3％,1H NMR(400MHz,CDCl3):δ6.61(d,J＝6.8Hz,1H),6.20(brs,1H),5.81(dd,J＝17.6,10.8Hz,1H),5.40(br s,1H),4.91(d,J＝17.4Hz,1H),4.85(d,J＝10.6Hz,1H),4.31(m,1H),3.83(m,1H),3.24(m,1H),3.06(m,1H),2.80(m,1H),2.23(m,1H),2.15(d,J＝6.8Hz),2.10(s,1H),2.01(重叠峰,2H),1.86(重叠峰,2H),1.54(m,1H),1.50(m,1H),1.48(m,1H),1.43(m,1H),1.42(m,1H),1.39(m,1H),1.35(m,1H),1.33(m,1H),1.27(m,1H),1.21(s,3H),1.12(m,1H),1.07(s,3H),0.71(s,3H)；13C NMR(100MHz,CDCl3):δ182.0,172.7,168.9,150.7,149.2,118.9,109.1,56.3,45.4,41.1,40.8,40.7,40.2,39.3,36.5,36.4,35.3,33.5,31.6,28.5,27.6,25.4,23.0,21.4,12.1；LR-ESIMS:[M+H]+m/z454.19；[M+Na]+m/z 476.22.
化合物TC-010：
Figure BDA0003183312750000152
白色固体，收率：55.5％,1H NMR(400MHz,CDCl3):δ9.36(s,1H),8.84(d,J＝4.0Hz,1H),8.45(dt,J＝1.8,8.0Hz,1H),7.49(dd,J＝4.8,7.8Hz,1H),6.79(d,J＝6.8Hz,1H),6.26(br s,1H),5.80(dd,J＝17.6,10.8Hz,1H),5.43(br s,1H),4.92(d,J＝17.4Hz,1H),4.86(d,J＝10.6Hz,1H),2.23(m,1H),2.14(d,J＝17.6Hz),1.57(m,1H),1.53(m,1H),1.50(m,1H),1.46(m,1H),1.43(m,1H),1.39(m,1H),1.37(m,1H),1.34(m,1H),1.28(s,3H),1.27(m,1H),1.13(m,1H),1.08(s,3H),0.79(s,3H)；13CNMR(100MHz,CDCl3):δ181.8,163.9,153.1,150.7,149.2,145.7,138.4,136.1,123.7,119.2,109.1,56.4,41.1,40.8,40.8,39.3,36.5,36.4,35.4,33.5,31.6,25.4,23.0,12.1；LR-ESIMS:[M+H]+m/z 406.20.
化合物TC-011：
Figure BDA0003183312750000161
白色固体，收率：37.6％,1H NMR(400MHz,CDCl3):δ9.11(d,J＝2.2Hz,1H),8.34(dd,J＝2.2,8.2Hz,1H),7.46(d,J＝8.4Hz,1H),6.80(d,J＝6.6Hz,1H),6.25(br s,1H),5.80(dd,J＝17.4,10.8Hz,1H),5.43(br s,1H),4.94(d,J＝17.4Hz,1H),4.87(d,J＝10.8Hz,1H),2.26(t,J＝2.2,14.2Hz,1H),2.22(d,J＝6.8Hz),1.55(m,1H),1.54(m,1H),1.51(m,1H),1.50(m,1H),1.42(m,1H),1.40(m,1H),1.37(m,1H),1.34(m,1H),1.26(s,3H),1.24(m,1H),1.14(m,1H),1.08(s,3H),0.78(s,3H)；13C NMR(100MHz,CDCl3):δ181.3,162.9,156.3,151.8,150.6,149.1,145.6,140.1,136.1,124.3,119.2,109.1,56.4,41.1,40.8,40.8,39.3,36.5,36.4,35.4,33.5,31.6,25.4,23.0,12.1；LR-ESIMS:[M+H]+m/z440.09.
化合物TC-012：
Figure BDA0003183312750000162
黄色油状液体，收率：75.4％,1H NMR(400MHz,CDCl3):δ9.29(s,1H),8.65(d,J＝5.0Hz,1H),7.49(d,J＝5.4Hz,1H),6.80(d,J＝6.8Hz,1H),6.26(br s,1H),5.80(dd,J＝17.4,10.8Hz,1H),5.44(br s,1H),4.94(d,J＝17.6Hz,1H),4.86(d,J＝10.8Hz,1H),2.27(m,1H),2.22(d,J＝6.8Hz),1.57(m,1H),1.56(m,1H),1.53(m,1H),1.50(m,1H),1.42(m,1H),1.40(m,1H),1.37(m,1H),1.34(m,1H),1.28(s,3H),1.22(m,1H),1.14(m,1H),1.08(s,3H),0.78(s,3H)；13C NMR(100MHz,CDCl3):δ181.6,161.7,152.8,152.7,150.7,149.1,145.7,145.5,136.2,126.2,119.2,109.1,56.4,41.1,40.8,40.7,39.3,36.5,36.4,35.4,33.6,31.6,25.3,22.9,12.2；LR-ESIMS:[M+H]+m/z 440.15.
化合物TC-013：
Figure BDA0003183312750000171
黄色油状液体，收率：43.7％,1H NMR(400MHz,CDCl3):δ8.41(d,J＝8.2Hz,1H),7.40(d,J＝8.2Hz,1H),6.80(d,J＝6.6Hz,1H),6.25(br s,1H),5.80(dd,J＝17.4,10.6Hz,1H),5.44(br s,1H),4.91(d,J＝17.8Hz,1H),4.86(d,J＝10.6Hz,1H),2.26(m,1H),2.22(d,J＝6.4Hz),1.56(m,1H),1.53(m,1H),1.51(m,1H),1.49(m,1H),1.45(m,1H),1.42(m,1H),1.36(m,1H),1.33(m,1H),1.27(m,1H),1.26(s,3H),1.14(m,1H),1.08(s,3H),0.76(s,3H)；13C NMR(100MHz,CDCl3):δ181.7,161.7,153.7,150.6,149.1,145.5,143.3,136.3,124.0,122.9,119.3,109.1,56.4,41.1,40.8,40.8,39.3,36.5,36.4,35.4,33.6,31.6,25.3,23.0,12.2；LR-ESIMS:[M+H]+m/z 474.11.
化合物TC-014：
Figure BDA0003183312750000172
黄色油状液体，收率：62.8％,1H NMR(400MHz,CDCl3):δ8.62(d,J＝2.4Hz,1H),8.55(d,J＝8.2Hz,1H),6.80(d,J＝6.6Hz,1H),6.26(br s,1H),5.81(dd,J＝17.4,10.4Hz,1H),5.45(br s,1H),4.94(d,J＝17.4Hz,1H),4.87(d,J＝10.6Hz,1H),2.26(m,1H),2.23(d,J＝6.4Hz),1.57(m,1H),1.56(m,1H),1.53(m,1H),1.49(m,1H),1.42(m,1H),1.40(m,1H),1.37(m,1H),1.33(m,1H),1.26(s,3H),1.14(m,1H),1.08(s,3H),0.77(s,3H)；13C NMR(100MHz,CDCl3):δ181.6,161.7,153.4,150.6,149.2,149.1,145.5,143.3,136.4,126.5,119.4,118.7,109.1,56.4,41.1,40.8,40.8,39.3,36.5,36.4,35.4,33.6,31.6,25.3,22.9,12.2；LR-ESIMS:[M+H]+m/z 540.41.
化合物TC-015：
Figure BDA0003183312750000173
白色固体，收率：87.3％,1H NMR(400MHz,CDCl3):δ8.84(d,J＝1.4Hz,1H),8.10(dd,J＝2.0,8.6Hz,1H),6.80(d,J＝6.8Hz,1H),6.50(d,J＝8.6Hz,1H),6.24(br s,1H),5.80(dd,J＝17.4,10.6Hz,1H),5.40(br s,1H),4.89(d,J＝17.6Hz,1H),4.86(d,J＝10.8Hz,1H),2.26(m,1H),2.19(d,J＝6.8Hz),1.56(m,1H),1.54(m,1H),1.53(m,1H),1.50(m,1H),1.44(m,1H),1.40(m,1H),1.37(m,1H),1.34(m,1H),1.27(s,3H),1.24(m,1H),1.13(m,1H),1.07(s,3H),0.78(s,3H)；13C NMR(100MHz,CDCl3):δ182.3,164.2,161.4,152.4,150.7,149.4,145.9,139.4,135.7,118.8,115.1,109.1,107.4,56.4,41.1,40.8,40.7,39.3,36.5,36.4,35.3,33.6,31.6,25.4,23.0,12.1；LR-ESIMS:[M+H]+m/z 421.24.
化合物TC-016：
Figure BDA0003183312750000181
白色固体，收率：94.0％,1H NMR(400MHz,CDCl3):δ8.90(d,J＝2.0Hz,1H),8.41(d,J＝2.0Hz,1H),6.82(d,J＝6.8Hz,1H),6.25(br s,1H),5.80(dd,J＝17.4,10.8Hz,1H),5.41(br s,1H),4.91(d,J＝17.8Hz,1H),4.85(d,J＝11.0Hz,1H),2.26(m,1H),2.20(d,J＝6.6Hz),1.56(m,1H),1.50(m,1H),1.49(m,1H),1.44(m,1H),1.39(m,1H),1.38(m,1H),1.36(m,1H),1.33(m,1H),1.27(s,3H),1.24(m,1H),1.13(m,1H),1.07(s,3H),0.80(s,3H)；13CNMR(100MHz,CDCl3):δ181.7,159.3,153.6,150.7,149.3,145.6,136.1,129.1,118.9,109.0,56.4,41.1,40.8,40.7,39.3,36.5,36.4,35.3,33.6,31.6,25.4,22.9,12.0；LR-ESIMS:[M+H]+m/z 412.28；[2M+Na]+m/z845.43.
化合物TC-017：
Figure BDA0003183312750000182
白色固体，收率：72.3％,1H NMR(400MHz,CDCl3):δ9.31(s,1H),7.10(m,1H),7.01(m,1H),6.74(d,J＝6.8Hz,1H),6.31(dd,J＝2.6,6.2Hz,1H),6.25(br s,1H),5.80(dd,J＝17.4,10.8Hz,1H),5.43(br s,1H),4.91(d,J＝17.8Hz,1H),4.85(d,J＝11.0Hz,1H),2.26(m,1H),2.20(d,J＝6.6Hz),1.56(m,1H),1.53(m,1H),1.49(m,1H),1.44(m,1H),1.40(m,1H),1.38(m,1H),1.36(m,1H),1.33(m,1H),1.26(s,3H),1.23(m,1H),1.10(m,1H),1.07(s,3H),0.77(s,3H)；13C NMR(100MHz,CDCl3):δ182.4,159.1,150.7,149.4,145.2,136.0,124.0,121.3,118.8,117.1,110.9,109.0,56.4,41.1,40.8,40.7,39.3,36.5,36.4,35.3,33.6,31.6,25.4,22.9,12.1；LR-ESIMS:[M+Na]+m/z 416.26；[2M+Na]+m/z 809.46.
化合物TC-018：
Figure BDA0003183312750000191
白色固体，收率：75.0％,1H NMR(400MHz,CDCl3):δ9.43(s,1H),9.39(重叠峰,2H),6.82(d,J＝6.8Hz,1H),6.25(br s,1H),5.80(dd,J＝17.4,10.8Hz,1H),5.45(br s,1H),4.91(d,J＝17.8Hz,1H),4.85(d,J＝11.0Hz,1H),2.26(m,1H),2.23(d,J＝6.6Hz),1.56(m,1H),1.53(m,1H),1.50(m,1H),1.43(m,1H),1.40(m,1H),1.39(m,1H),1.36(m,1H),1.34(m,1H),1.27(s,3H),1.23(m,1H),1.12(m,1H),1.08(s,3H),0.79(s,3H)；13C NMR(100MHz,CDCl3):δ181.6,162.0,161.9,158.5,150.6,149.0,145.4,136.5,123.4,119.4,109.1,56.4,41.1,40.8,40.7,39.3,36.5,36.4,35.3,33.5,31.6,25.3,22.9,12.1；LR-ESIMS:[M+H]+m/z 407.19.
实施例19合成TC-019
Figure BDA0003183312750000192
在干燥的10mL圆底烧瓶中，将化合物tagalsin C(5.0mg，0.015mmol)，溶于2.0mL无水DMF，然后加入无水碳酸钾(0.5equiv.)或者无水碳酸铯(0.5equiv.)振摇，最后加入苄溴(卤代烃R2X，其中，R2为苄基，X为溴，2.0equiv.)，密封反应器并在室温下搅拌30min。TLC监测反应完成后，减压蒸干反应溶剂。将所得残余物溶于丙酮或乙腈中，离心沉淀不溶物质。取上清液通过制备型HPLC(柱型号：YMC,ODS-A,250×10mm i.d.5μm,12nm；流动相：乙腈/水)进行纯化，得到相应醚化产物TC-019。采用质谱(ESIMS)和核磁共振谱(NMR)对该化合物结构进行确认。
化合物TC-019：
Figure BDA0003183312750000201
棕黄色油状物，收率：86.5％,1H NMR(400MHz,CDCl3):δ7.38(重叠峰,2H),7.36(重叠峰,2H),7.32(m,1H),6.23(br s,1H),5.85(d,J＝6.8Hz,1H),5.78(dd,J＝17.4,10.8Hz,1H),5.31(br s,1H),5.12(ABq,J＝12.8Hz),4.89(d,J＝17.4Hz,1H),4.85(d,J＝10.6Hz,1H),2.20(dt,J＝2.4,14.4Hz,1H),1.95(d,J＝6.8Hz),1.45(m,1H),1.43(m,1H),1.40(m,1H),1.37(m,1H),1.36(m,1H),1.34(m,1H),1.27(m,1H),1.23(m,1H),1.19(m,1H),1.10(m,1H),1.07(s,3H),1.01(s,3H),0.42(s,3H)；13CNMR(100MHz,CDCl3):δ184.3,151.0,150.2,149.9,136.7,128.7,127.9,127.2,119.8,118.3,109.0,69.8,55.8,40.9,40.4,40.4,39.5,36.7,36.6,35.2,33.9,31.6,25.5,23.0,11.9；HR-ESIMS:[M+Na]+m/z 413.2456；
实施例20至实施例21
按照TC-019的方法依次合成得到衍生物TC-020～TC-030。不同点在于具体反应条件参见表2所示的条件。
表2醚化反应
Figure BDA0003183312750000202
采用质谱(ESIMS)和核磁共振谱(NMR)对上述化合物结构进行确认。
化合物TC-020：
Figure BDA0003183312750000211
棕黄色油状物，收率：76.9％,1H NMR(400MHz,CDCl3):δ8.23(d,J＝8.8Hz,2H),7.59(d,J＝8.8Hz,2H),7.32(m,1H),6.26(br s,1H),5.90(d,J＝6.8Hz,1H),5.78(dd,J＝17.4,10.8Hz,1H),5.37(br s,1H),5.12(ABq,J＝13.6Hz),4.90(d,J＝17.4Hz,1H),4.86(d,J＝10.6Hz,1H),2.20(dt,J＝2.4,14.4Hz,1H),2.02(d,J＝6.8Hz,1H),1.47(m,1H),1.46(m,1H),1.44(m,1H),1.43(m,1H),1.37(m,1H),1.34(m,1H),1.29(m,1H),1.20(m,1H),1.17(m,1H),1.10(m,1H),1.10(s,3H),1.03(s,3H),0.52(s,3H)；13C NMR(100MHz,CDCl3):δ183.8,150.6,149.9,149.8,147.5,144.1,127.5,123.8,119.8,118.7,109.0,68.6,55.6,40.8,40.4,40.3,39.3,36.5,36.4,35.4,33.7,31.4,25.5,22.9,12.0；LR-ESIMS:[M+H]+m/z 436.12.
化合物TC-021：
Figure BDA0003183312750000212
棕黄色油状物，收率：75.7％,1H NMR(400MHz,CDCl3):δ7.23(m,1H),6.94(br s,1H),6.92(d,J＝1.6Hz,1H),6.79(m,1H),6.23(br s,1H),5.84(d,J＝6.8Hz,1H),5.75(dd,J＝17.4,10.6Hz,1H),5.31(br s,1H),5.09(d,J＝13.0Hz,1H),4.92(d,J＝13.0Hz,1H),4.87(d,J＝17.4Hz,1H),4.82(d,J＝10.8Hz,1H),3.77(s,3H),2.15(dt,J＝2.4,14.2Hz,1H),1.95(d,J＝6.8Hz,1H),1.47(m,1H),1.46(m,1H),1.44(m,1H),1.42(m,1H),1.37(m,1H),1.32(m,1H),1.29(m,1H),1.20(m,1H),1.14(m,1H),1.10(m,1H),1.07(s,3H),1.01(s,3H),0.42(s,3H)；13C NMR(100MHz,CDCl3):δ184.1,160.0,150.9,150.1,149.7,138.2,129.6,119.8,119.3,118.2,113.6,112.2,108.9,69.5,55.7,55.3,40.8,40.3,40.3,39.3,36.5,36.5,35.1,33.8,31.5,25.4,22.9,11.7；LR-ESIMS:[M+H]+m/z 421.18；[M+Na]+m/z443.14.
测试例1抗肿瘤活性实验
1.仪器：
倒置显微镜(Leica DM IL LED，徕卡显微系统贸易有限公司)，
Figure BDA0003183312750000221
Luminescent发光法细胞活力检测试剂盒(Promega生物技术有限公司)，化学发光酶标仪(LumiStation 1800型，上海闪谱生物科技公司)
2.试剂：
胎牛血清(Hyclone，广州泰勒生物科技有限公司)，
Figure BDA0003183312750000222
Luminescent发光法细胞活力检测试剂(10mL，Promega生物技术有限公司)，磷酸盐缓冲液(PBS，Hyclone，广州泰勒生物科技有限公司)，DMEM培养基(Life Technologies，广州泰勒生物科技有限公司)，胰蛋白酶(上海麦克林生化科技有限公司)，苔盼蓝染色液(Biofer，上海跃腾生物技术有限公司)
HCT-116(购买厂家中国医学科学院基础医学研究所细胞资源中心，货号1101HUM-PUMC000158)
BGC-823(购买厂家中国科学院上海生命科学研究院细胞资源中心，货号BGC-823TCHu 11)
NCI-H460(购买厂家中国医学科学院基础医学研究所细胞资源中心，货号1101HUM-PUMC000355)
MDA-MB-231(购买厂家中国医学科学院基础医学研究所细胞资源中心，货号1101HUM-PUMC000014)
MDA-MB-453(购买厂家中国医学科学院基础医学研究所细胞资源中心，货号1101HUM-PUMC000016)
3.实验方法
3.1细胞复苏及培养：将冻存细胞在37℃温水中融化。在超净工作台内，将细胞悬液转移到离心管中进行离心。离心结束后，移液枪吸取上清液倒掉，在离心管底部沉积的细胞中加入细胞培养液。随后将细胞悬液转移至DMEM培养基中，置于CO2恒温培养箱(培养条件：37℃、5％CO2、相对湿度90％)培养，待细胞铺满瓶底后进行传代培养。
3.2检测试剂准备：
Figure BDA0003183312750000223
Luminescent发光法细胞活力检测试剂，按照96孔板，每孔100μL的用量，取适量测试剂平衡至室温备用。
3.3细胞活力测试
a)：取在对数生长周期的细胞，加入适量浓度为0.25％的胰蛋白酶溶液在37℃下进行消化，通过显微镜观察，当细胞逐渐收缩变圆，相互之间不再连接成片，停止消化。
b)：消化后，加入含10％胎牛血清的DMEM培养液，不断吹打细胞，使其成为细胞悬液，然后转移至离心管中；加入4％三氯醋酸(TCA)提取ATP
c)：2％苔盼蓝染色之后进行细胞计数，用以分析活细胞数和发光强度的关系。根据细胞数目，调整细胞密度为每毫升1×105个细胞。
d)：根据细胞数目，调整细胞密度为每毫升1×105个细胞，按每孔0.5mL细胞悬液，0.5mL培养液接种于96孔培养板中，置于CO2恒温培养箱(37℃、5％二氧化碳，90％湿度)培养24h，观察到细胞生长良好时设置加药组和对照组，按药物浓度重复3个复孔，每孔加入含有药物的培养基100μL，继续培养24h。
e)：24h药物刺激结束后，取出培养箱中的细胞加入4％三氯醋酸(TCA)提取ATP。
f)：提取的待测ATP上清液置于96孔板中，每孔加入100μL
Figure BDA0003183312750000232
Luminescent发光法细胞活力检测试剂。
g)：室温振荡2min以促进细胞裂解；然后在室温下孵育10min。
h)：取用多功能酶标仪进行发光检测。
i)：根据化学发光读数直接计算细胞相对活力。
j)：用Bliss法细胞毒性曲线计算抑制50％细胞生长所需要的浓度(IC50值/μM)。
3.4荧光素酶-ATP检测结果
选取底物Tagalsin C及本发明化合物(TC-001～TC-021)进行癌细胞株毒性测试，顺铂(Cisplatin)作为阳性对照药，测试结果如下表3。
表3
Figure BDA0003183312750000231
Figure BDA0003183312750000241
活性结果显示，C-2位羟基进行酯化修饰的18个衍生物绝大多数对肿瘤细胞系有显著抑制活性，部分化合物比先导物tagalsin C活性更强，11个衍生物的IC50值达到1μM以下，表明对tagalsin C的C-2位的酯化修饰有利于提高抗肿瘤活性。C-2位羟基醚化修饰的3个衍生物(TC-019～TC-021)对所有测试细胞株均没有显著抑制活性，表明对C-2位的醚化修饰降低tagalsin C的抗肿瘤活性。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (9)

1.如式1所示的化合物或其药学上可接受的盐，
Figure FDA0003183312740000011
其中，R1为取代或未取代的C6-C10芳基、取代或未取代的5元至10元杂芳基、取代或未取代的C3-C6环烷基或取代或未取代的5元至10元杂环基；所述取代是指上述基团上的一个或多个氢原子被选自下组的取代基所取代：硝基、氰基、卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、氨基、-C(＝O)-C1-C6烷基、-C(＝O)-C1-C6烷氧基。
2.如权利要求1所述的化合物或其药学上可接受的盐，其中，R1为取代或未取代的苯基、取代或未取代的吡啶、取代或未取代的嘧啶、取代或未取代的呋喃、取代或未取代的噻吩、取代或未取代的吡咯、取代或未取代的咪唑、取代或未取代的吡唑、取代或未取代的哌嗪、或取代或未取代的哌啶；所述取代是指上述基团上的一个或多个(例如一个或两个或三个)氢原子被选自下组的取代基所取代：硝基、氰基、卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、氨基、-C(＝O)-C1-C6烷基、-C(＝O)-C1-C6烷氧基。
3.如权利要求1所述的化合物或其药学上可接受的盐，其中，R1为取代或未取代的苯基、取代或未取代的吡啶、取代或未取代的嘧啶、取代或未取代的呋喃、取代或未取代的噻吩、取代或未取代的吡咯、取代或未取代的咪唑、取代或未取代的吡唑、取代或未取代的哌嗪、或取代或未取代的哌啶；所述取代是指上述基团上的一个或多个(例如一个或两个或三个)氢原子被选自下组的取代基所取代：硝基、卤素、甲基、三氟甲基、甲氧基、氨基、-C(＝O)-甲基。
4.如权利要求1所述的化合物或其药学上可接受的盐，其中，R1选自下组：
Figure FDA0003183312740000012
Figure FDA0003183312740000021
5.如权利要求1所述的化合物或其药学上可接受的盐，其中，所述化合物选自下组：
Figure FDA0003183312740000022
Figure FDA0003183312740000031
Figure FDA0003183312740000041
6.一种药物组合物，所述药物组合物包含如权利要求1所述的化合物或其药学上可接受的盐以及药学上可接受的载体。
7.如权利要求1所述的化合物或其药学上可接受的盐或如权利要求6所述的药物组合物在制备用于预防和/或治疗癌症的药物中的用途。
8.如权利要求7所述的用途，其中，所述癌症选自下组的一种或多种：结肠癌、胃癌细胞、肺癌细胞、乳腺癌。
9.如权利要求1所述的化合物或其药学上可接受的盐的制备方法，其中，所述方法包括步骤：将化合物tagalsin C与有机酸R1COOH进行酯化反应，从而形成式1化合物；
Figure FDA0003183312740000042
各式中R1的定义同权利要求1。
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