CN105693660B - Jaspine B、3‑epi Jaspine B氧代类似物、其制备方法及应用 - Google Patents

Jaspine B、3‑epi Jaspine B氧代类似物、其制备方法及应用 Download PDF

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CN105693660B
CN105693660B CN201610190265.1A CN201610190265A CN105693660B CN 105693660 B CN105693660 B CN 105693660B CN 201610190265 A CN201610190265 A CN 201610190265A CN 105693660 B CN105693660 B CN 105693660B
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jaspine
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刘宏民
张恩
高洁
王上
王铭铭
徐帅民
郑甲信
王亚娜
孙凯
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Zhengzhou University
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Abstract

本发明属于药物化学领域，公开了具有抗肿瘤活性的Jaspine B、3‑epi Jaspine B的氧代类似物、制备方法及其用途。本发明通过三步反应，简单、快速得到目标产物，其具有如下结构通式：

Description

Jaspine B、3-epi Jaspine B氧代类似物、其制备方法及应用
技术领域
本发明公开了具有抗肿瘤活性的Jaspine B、3-epi Jaspine B氧代类似物、它们的制备方法及其作为一类新的抗肿瘤药物先导化合物的应用，属于药物化学领域。
背景技术
近年来，从海洋生物中寻找活性物质是抗肿瘤药物研发的重要途径之一。JaspineB最先由Higa课题组在2002年从海绵(Pachastrissasp.)中首次分离得到，是一种脱水神经鞘氨醇类化合物(J.Nat.Prod.,2002,65,1505)。此后不久，Debitus课题组在另外一种海绵(Jaspissp.)中也分离出这个化合物(Tetrahedron Lett.,2003,44,225.)。目前有报道发现，Jaspine B对白血病细胞P388、肺癌细胞A549、结肠癌细胞HT29和黑色素瘤细胞SK-Mel28等多种癌细胞具有良好的细胞毒活性(J.Nat.Prod.,2002,65,1505)。
2009年Andrieu-Abadie等人报道Jaspine B通过调控鞘磷脂合酶的活性，进而调控神经酰胺的形成并激活caspase通路，引起细胞凋亡，在体外实验中JaspineB表现出对黑色素瘤细胞SK-Mel28时间和浓度依赖性的抑制作用。2011年Oishi等人发现Jaspine B和它的立体异构体能够抑制SphK1和SphK2，从而调控神经酰胺的形成并激活caspase通路，引起细胞凋亡(Biochem Pharmacol,2009,78,477.)。以上研究表明，Jaspine B是一种优良的鞘氨醇激酶和鞘磷脂合酶抑制剂，能够调节神经鞘胺醇含量，控制肿瘤的生长和凋亡。
Jaspine B需从Pachastrissa sp.或者Jaspissp.中分离提取，但提取工作操作繁琐，收率低。由于其独特的抗肿瘤作用机制和很高的抗肿瘤活性，研究Jaspine B及其类似物的合成方法不仅具有重要的科学意义，而且对研究构效关系，发现具有抗肿瘤活性的化合物具有重要的实际应用价值。
2011年本发明人以木糖为起始原料合成出Jaspine B关键中间体(刘宏民，赵明礼，高洁，张召，抗肿瘤活性天然产物Jaspine B和3-epi Jaspine B关键中间体的合成方法，CN102382081A)。在合成Jaspine B和3-epi jaspine的路线中需要做wittg反应，该反应需严格要求无水，并惰性环境中进行，而且还需要低温，反应条件条件苛刻，稍微出错反应产率就会大大降低。若在Jaspine B的2-C位长链上引入一个杂原子(O或N)，从而使反应条件比较温和，收率也有较大的提高，或许能筛选出与Jaspine B相当或者更好的活性化合物，值得研究和关注。
发明内容
基于上述，本发明目的之一是提供一类新的具有抗肿瘤活性的Jaspine B、3-epiJaspine B类似物；目的之二是提供该类化合物的制备方法；目的之三是提供该类化合物在制备抗肿瘤药物方面的应用。
本发明所述的Jaspine B、3-epi Jaspine B三氮唑类化合物具有以下结构通式：
其中n为6、7、8、9、11、13、15、17。
制备Jaspine B类似物4a-4h的方法通过以下步骤实现：(1)在溶剂中将化合物1还原得到化合物2，所用到的还原剂为KBH4或NaBH4，所选用的溶剂为甲醇或乙醇；(2)溶剂中，化合物2在碱性条件下与不同链长的溴代烷烃反应得到化合物3a-3h，所用的碱为K2CO3、NaOH或NaH；所选用的溶剂为四氢呋喃或N,N-二甲基甲酰胺；(3)溶剂中，化合物3a-3h在酸的作用下以及催化剂的作用下合成化合物4a-4h；所述溶剂选自甲醇，乙醇，乙酸乙酯；酸选用盐酸或三氟乙酸，催化剂选择Pd/C或Pd(OH)2；
其中n为6、7、8、9、11、13、15、17。
所选用的溴代烷烃为溴代庚烷、溴代辛烷、溴代壬烷、溴代癸烷、溴代十二烷、溴代十四烷、溴代十六烷或溴代十八烷；
制备3-epi Jaspine B类似物4'a-4'h的方法通过以下步骤实现：(1)在溶剂中将化合物1'还原得到化合物2'，所用到的还原剂为KBH4或NaBH4，所选用的溶剂为甲醇或乙醇；(2)溶剂中，化合物2'在碱性条件下与不同链长的溴代烷烃反应得到化合物3'a-3'h，所用的碱为K2CO3、NaOH或NaH；所选用的溶剂为四氢呋喃或N,N-二甲基甲酰胺；(3)溶剂中，化合物3'a-3'h在酸的作用下以及催化剂的作用下合成化合物4'a-4'h；所述溶剂选自甲醇，乙醇，乙酸乙酯；酸选用盐酸或三氟乙酸，催化剂选择Pd/C或Pd(OH)2；
其中n为6、7、8、9、11、13、15、17。
所选用的溴代烷烃为溴代庚烷、溴代辛烷、溴代壬烷、溴代癸烷、溴代十二烷、溴代十四烷、溴代十六烷或溴代十八烷；
本发明所述的Jaspine B、3-epi Jaspine B类似物4a-4h、4'a-4'h对多种肿瘤细胞表现出了抗肿瘤活性，尤其对食管癌细胞(EC9706和Eca-109)、小鼠黑色素瘤细胞(B16-F10)、乳腺癌细胞(MCF-7)四株肿瘤细胞有很明显的抑制作用，与Jaspine B做对比，部分化合物的抗肿瘤活性优于后者。因此，本发明合成的Jaspine B、3-epi Jaspine B类似物可以用于抗肿瘤药物的制备，为新型抗肿瘤药物的开发提供了筛选药物。原料简单易得，合成方法简单可行，收率较高，达70％以上，为新型抗肿瘤药物的开发提供了一条新型途径。
具体实施方式
下面结合具体实施例，进一步阐述本发明。这些实施例仅用于说明本发明而不用于限制本发明要求保护的范围。
合成化合物表征使用的仪器：NMR谱使用瑞典Bruker DPX-400型超导核磁共振仪测定，TMS为内标；高分辨质谱使用Waters-Micromass公司Q-Tof质谱仪测定。
实施例1化合物2和2'的合成通法
称取化合物1或者1'(2mmol)置于25mL圆底烧瓶中，用质量百分比95％乙醇溶解，冰浴，将硼氢化钾(3mmol)平均分成五次加入反应体系，每次间隔5分钟，然后撤去冰浴升至室温，常温搅拌1小时，TLC检测(石油醚:丙酮＝2:1)反应完全，在冰浴下加入氯化铵固体至不再有气泡为止，然后过滤除去固体，将滤液浓缩，用乙酸乙酯溶解，然后用饱和食盐水萃取，无水硫酸钠干燥，抽滤，减压蒸干得到粗品，然后用硅胶柱层析分离(石油醚:乙酸乙酯＝8:1)得纯品化合物。
化合物2，产率95％，无色油状物；1H NMR(400MHz,CDCl3,ppm)δ7.47–7.33(m,5H),4.84(d,J＝11.6Hz,1H),4.59(d,J＝11.6Hz,1H),4.37–4.28(m,1H),4.08(d,J＝5.5Hz,1H),3.99(dd,J＝9.7,6.1Hz,2H),3.95–3.90(m,1H),3.84(d,J＝4.0Hz,2H),2.31(s,1H).13C NMR(101MHz,CDCl3,ppm)δ136.98,128.71,128.33,127.94,79.95,79.56,73.86,69.38,61.83,61.22.HRMS:calcd for C12H15N3O3Na[M+Na]+272.1108,found 272.1110.
化合物2'，产率95％，无色油状物；1H NMR(400MHz,CDCl3,ppm):δ7.41–7.29(m,5H),4.60(q,J＝11.7Hz,2H),4.06–3.98(m,2H),3.98–3.88(m,3H),3.83–3.75(m,1H),3.65(ddd,J＝11.8,6.9,5.0Hz,1H),2.25(d,J＝5.5Hz,1H).13C NMR(100MHz,CDCl3,ppm):δ137.1,128.6,128.20,127.87,84.84,84.20,72.54,71.03,65.94,62.33.
实施例2化合物3a-3h和3'a-3'h的合成通法
称取化合物2或者2'(1mmol)用10mL无水N,N-二甲基甲酰胺溶解，冰浴，加入氢化钠(2.5mmol)，氮气保护，冰浴条件下搅拌1.5小时，然后称取溴代烷烃(2mmol)放入25mL三口烧瓶，用15mL无水N,N-二甲基甲酰胺溶解，用注射器缓慢加入反应体系中，再在冰浴条件下搅拌30分钟，撤掉冰浴，室温搅拌12小时，薄层检测反应(石油醚:乙酸乙酯＝1.5:1)完全后，将N,N-二甲基甲酰胺用油泵减压蒸干，然后乙酸乙酯20mL溶解，然后用饱和食盐水萃取(10mL×3)，乙酸乙酯反萃三次(50mL×3)，合并乙酸乙酯，无水硫酸钠干燥过夜，过滤浓缩，硅胶柱层析分离(石油醚:乙酸乙酯＝30:1)得到化合物3。
本实施合成了系列化合物3a-3h和3'a-3'h，如表1
表1
表1中化合物的核磁数据选择性表述如下：
3a，产率60％，淡黄色油状物；1H NMR(400MHz,CDCl3,ppm)δ7.42–7.29(m,5H),4.79(d,J＝11.6Hz,1H),4.63(d,J＝11.6Hz,1H),4.22(t,J＝5.2Hz,1H),4.12(dt,J＝6.8,5.3Hz,1H),3.98–3.92(m,2H),3.87(dd,J＝11.2,5.8Hz,1H),3.64(qd,J＝10.2,6.1Hz,2H),3.54–3.36(m,2H),1.62–1.51(m,2H),1.30(dd,J＝11.8,6.2Hz,8H),0.88(t,J＝6.8Hz,3H).13C NMR(101MHz,CDCl3,ppm)δ137.48,128.49,128.00,127.86,79.53,79.48,73.84,71.80,69.28,68.92,61.28,31.82,29.71,29.17,26.10,22.62,14.10.HRMS:calcdfor C19H29N3O3Na[M+Na]+370.2209,found 370.2207.
3b，产率60％，淡黄色油状物；1H NMR(400MHz,CDCl3,ppm)δ7.42–7.27(m,5H),4.78(d,J＝11.6Hz,1H),4.62(d,J＝11.6Hz,1H),4.21(t,J＝5.2Hz,1H),4.11(dt,J＝6.7,5.3Hz,1H),3.94(dd,J＝6.0,2.8Hz,2H),3.89–3.83(m,1H),3.63(t,J＝5.9Hz,2H),3.54–3.35(m,2H),1.71–1.39(m,2H),1.27(d,J＝4.9Hz,10H),0.87(t,J＝6.8Hz,3H).13C NMR(101MHz,CDCl3,ppm)δ137.48,128.50,128.00,127.87,79.53,79.48,73.84,71.81,69.29,68.93,61.28,31.84,29.71,29.47,29.27,26.14,22.67,14.12.HRMS:calcd forC19H29N3O3Na[M+Na]+384.2365,found 385.2364.
3c，产率62％，淡黄色油状物；1H NMR(400MHz,CDCl3,ppm)δ7.44–7.28(m,5H),4.78(d,J＝11.6Hz,1H),4.62(d,J＝11.6Hz,1H),4.21(t,J＝5.2Hz,1H),4.11(dt,J＝6.7,5.3Hz,1H),3.94(dd,J＝6.0,2.9Hz,2H),3.89–3.83(m,1H),3.63(t,J＝6.0Hz,2H),3.53–3.36(m,2H),1.63–1.51(m,2H),1.26(s,12H),0.88(t,J＝6.8Hz,3H).13C NMR(101MHz,CDCl3,ppm)δ137.49,128.49,128.00,127.87,79.53,79.48,73.84,71.81,69.28,68.92,61.28,31.90,29.71,29.57,29.52,29.29,26.14,22.69,14.13.HRMS:calcd forC21H33N3O3Na[M+Na]+398.2522,found398.2523.
3d，产率65％，淡黄色油状物；1H NMR(400MHz,CDCl3,ppm)δ7.40–7.30(m,5H),4.78(d,J＝11.6Hz,1H),4.62(d,J＝11.6Hz,1H),4.21(t,J＝5.2Hz,1H),4.11(dt,J＝10.7,5.3Hz,1H),3.94(dd,J＝6.0,2.8Hz,2H),3.90–3.82(m,1H),3.63(t,J＝5.9Hz,2H),3.44(ddd,J＝16.2,9.3,2.4Hz,2H),1.60–1.53(m,2H),1.28(d,J＝23.4Hz,14H),0.88(t,J＝6.8Hz,3H).13C NMR(101MHz,CDCl3,ppm)δ137.48,128.50,128.00,127.87,79.53,79.48,73.85,71.81,69.28,68.92,61.28,31.92,29.71,29.61,29.59,29.52,29.34,26.14,22.70,14.14.HRMS:calcd for C22H35+N3O3Na[M+Na]+412.2678,found 412.2670.
3e，产率68％，无色油状物；1H NMR(400MHz,CDCl3,ppm)δ7.41–7.28(m,5H),4.78(d,J＝11.6Hz,1H),4.62(d,J＝11.6Hz,1H),4.21(t,J＝5.2Hz,1H),4.11(dt,J＝6.8,5.3Hz,1H),3.94(dd,J＝6.0,2.6Hz,2H),3.90–3.82(m,1H),3.63(t,J＝5.9Hz,2H),3.53–3.31(m,2H),1.60–1.51(m,2H),1.27(d,J＝11.1Hz,18H),0.88(t,J＝6.8Hz,3H).13C NMR(101MHz,CDCl3,ppm)δ137.48,128.50,128.00,127.87,79.53,79.48,73.84,71.81,69.28,68.92,61.28,31.94,29.71,29.69,29.65,29.63,29.62,29.52,29.37,26.15,22.71,14.14.HRMS:calcd for C24H39N3O3Na[M+Na]+440.2991,found 440.2999.
3f，产率70％，无色油状物；1H NMR(400MHz,CDCl3,ppm)δ7.40–7.31(m,5H),4.78(d,J＝11.6Hz,1H),4.62(d,J＝11.6Hz,1H),4.21(t,J＝5.2Hz,1H),4.11(dt,J＝10.7,5.3Hz,1H),3.94(dd,J＝6.0,2.7Hz,21H),3.89–3.84(m,1H),3.63(t,J＝5.9Hz,2H),3.52–3.36(m,2H),1.60–1.52(m,2H),1.25(s,22H),0.88(t,J＝6.8Hz,3H).13C NMR(101MHz,CDCl3,ppm)δ137.48,128.49,128.00,127.87,79.53,79.48,73.85,71.81,69.28,68.92,61.28,31.94,29.71,29.70,29.69,29.68,29.64,29.62,29.52,29.38,26.15,22.71,14.14.HRMS:calcd for C26H43N3O3Na[M+Na]+468.3304,found 468.3305.
3g，产率75％，无色油状物；1H NMR(400MHz,CDCl3,ppm)δ7.47–7.33(m,5H),4.81(d,J＝11.6Hz,1H),4.65(d,J＝11.6Hz,1H),4.24(t,J＝5.2Hz,1H),4.14(dt,J＝6.8,5.3Hz,1H),3.97(dd,J＝6.0,2.5Hz,2H),3.89(dd,J＝11.2,5.8Hz,1H),3.72–3.59(m,2H),3.47(ddd,J＝16.1,9.3,2.5Hz,2H),1.60(dd,J＝13.0,6.0Hz,2H),1.28(s,26H),0.91(t,J＝6.8Hz,3H).13C NMR(101MHz,CDCl3,ppm)δ137.48,128.50,128.00,127.87,79.52,79.48,73.84,71.82,69.28,68.92,61.28,31.94,29.71,29.64,29.62,29.52,29.38,26.15,22.71,14.14.HRMS:calcd for C28H47N3O3Na[M+Na]+496.3617,found 496.36015.
3h，产率80％，无色油状物；1H NMR(400MHz,CDCl3,ppm)δ7.47–7.29(m,5H),4.78(d,J＝11.6Hz,1H),4.62(d,J＝11.6Hz,1H),4.21(t,J＝5.2Hz,1H),4.12(dd,J＝6.9,5.3Hz,1H),3.95(dd,J＝6.0,2.5Hz,2H),3.90–3.81(m,1H),3.63(t,J＝6.0Hz,2H),3.44(ddd,J＝16.1,9.2,2.4Hz,2H),1.63–1.46(m,2H),1.25(s,30H),0.88(t,J＝6.8Hz,3H).13CNMR(101MHz,CDCl3,ppm)δ137.48,128.49,128.00,127.87,79.53,79.48,73.85,71.82,69.28,68.92,61.28,31.95,29.72,29.64,29.62,29.53,29.38,26.15,22.71,14.14.HRMS:calcd for C30H51N3O3Na[M+Na]+524.3903,found 524.3909.
3'a，产率65％，淡黄色油状物；1H NMR(400MHz,CDCl3,ppm)δ7.45–7.30(m,5H),4.65(d,J＝11.8Hz,1H),4.61(d,J＝11.8Hz,1H),4.09–3.95(m,4H),3.93(d,J＝4.3Hz,1H),3.55(dd,J＝5.4,0.9Hz,2H),3.48(td,J＝6.7,1.8Hz,2H),1.61(dd,J＝12.2,5.1Hz,2H),1.31(d,J＝5.9Hz,8H),0.91(t,J＝6.8Hz,3H).13C NMR(101MHz,CDCl3,ppm)δ128.55,128.06,127.86,84.95,83.31,72.26,71.88,70.88,70.62,65.81,31.82,29.62,29.16,26.07,22.63,14.10.HRMS:calcd for C19H29N3O3Na[M+Na]+370.2209,found 370.2207.
3'b，产率68％，淡黄色油状物；1H NMR(400MHz,CDCl3,ppm)δ7.46–7.31(m,5H),4.65(d,J＝11.8Hz,1H),4.61(d,J＝11.8Hz,1H),4.07–3.96(m,4H),3.94(d,J＝4.2Hz,1H),3.56(dd,J＝5.4,1.3Hz,2H),3.48(td,J＝6.7,1.7Hz,2H),1.67–1.55(m,2H),1.33(d,J＝18.4Hz,10H),0.91(t,J＝6.8Hz,3H).13C NMR(101MHz,CDCl3,ppm)δ137.33,128.55,128.05,127.86,84.96,83.31,72.26,71.88,70.87,70.63,65.82,31.84,29.62,29.45,29.27,26.12,22.67,14.10.HRMS:calcd for C19H29N3O3Na[M+Na]+384.2365,found384.2364.
3'c，产率70％，淡黄色油状物；1H NMR(400MHz,CDCl3,ppm)δ7.43–7.31(m,5H),4.65(d,J＝11.8Hz,1H),4.61(d,J＝11.8Hz,1H),4.07–3.95(m,4H),3.94(d,J＝4.2Hz,1H),3.56(dd,J＝5.4,1.3Hz,2H),3.48(td,J＝6.7,1.7Hz,2H),1.65–1.53(m,2H),1.30(s,12H),0.91(t,J＝6.8Hz,3H).13C NMR(101MHz,CDCl3,ppm)δ137.33,128.55,128.05,127.86,84.96,83.31,72.26,71.88,70.87,70.62,65.82,31.90,29.62,29.58,29.50,29.29,26.12,22.69,14.12.HRMS:calcd for C21H33N3O3Na[M+Na]+398.2522,found398.2523.
3'd，产率70％，淡黄色油状物；1H NMR(400MHz,CDCl3,ppm)δ7.45–7.31(m,5H),4.65(d,J＝11.8Hz,1H),4.61(d,J＝11.8Hz,1H),4.08–3.96(m,4H),3.94(dd,J＝4.2,1.2Hz,1H),3.56(dd,J＝5.4,1.4Hz,2H),3.48(td,J＝6.7,1.7Hz,2H),1.64–1.56(m,2H),1.30(s,14H),0.91(t,J＝6.9Hz,3H).13C NMR(101MHz,CDCl3,ppm)δ137.33,128.55,128.05,127.86,84.96,83.31,72.26,71.88,70.87,70.62,65.82,31.92,29.62,29.60,29.50,29.35,26.12,22.70,14.12.HRMS:calcd for C22H35+N3O3Na[M+Na]+412.2678,found412.2670.
3'e，产率75％，无色油状物；1H NMR(400MHz,CDCl3,ppm)7.42–7.27(m,5H),4.62(d,J＝11.8Hz,1H),4.57(d,J＝11.8Hz,1H),4.03–3.92(m,4H),3.90(d,J＝4.3Hz,1H),3.52(dd,J＝5.4,1.1Hz,2H),3.45(td,J＝6.7,1.6Hz,2H),1.56(d,J＝7.0Hz,2H),1.26(s,18H),0.88(t,J＝6.8Hz,4H).13C NMR(101MHz,CDCl3,ppm)δ137.33,128.54,128.05,127.86,84.96,83.30,72.25,71.88,70.87,70.62,65.82,31.94,29.69,29.66,29.64,29.63,29.51,29.37,26.12,22.70,14.13.HRMS:calcd for C24H39N3O3Na[M+Na]+440.2991,found 440.2999.
3'f，产率75％，无色油状物；1H NMR(400MHz,CDCl3,ppm)δ7.42–7.31(m,5H),4.65(d,J＝11.8Hz,1H),4.61(d,J＝11.8Hz,1H),4.07–3.96(m,4H),3.94(dd,J＝4.3,1.3Hz,1H),3.56(dd,J＝5.4,1.9Hz,2H),3.48(td,J＝6.7,1.5Hz,2H),1.65–1.57(m,2H),1.29(s,22H),0.92(t,J＝6.8Hz,4H).13C NMR(101MHz,CDCl3,ppm)δ137.34,128.53,128.03,127.85,84.97,83.31,72.25,71.88,70.85,70.63,65.84,31.94,29.71,29.69,29.67,29.63,29.50,29.37,26.12,22.70,14.11.HRMS:calcd for C26H43N3O3Na[M+Na]+468.3304,found 468.3305.
3'g，产率80％，无色油状物；1H NMR(400MHz,CDCl3,ppm)δ7.41–7.28(m,5H),4.63(d,J＝11.8Hz,1H),4.58(d,J＝11.8Hz,1H),4.04–3.93(m,4H),3.91(d,J＝4.3Hz,1H),3.53(dd,J＝5.4,1.2Hz,2H),3.45(td,J＝6.7,1.7Hz,2H),1.62–1.54(m,2H),1.27(d,J＝6.9Hz,26H),0.89(t,J＝6.8Hz,3H).13C NMR(101MHz,CDCl3,ppm)δ137.33,128.54,128.04,127.86,84.96,83.31,72.25,71.88,70.86,70.62,65.82,31.95,29.72,29.68,29.65,29.63,29.51,29.38,26.13,22.71,14.13.HRMS:calcd for C28H47N3O3Na[M+Na]+496.3617,found 496.3615.
3'h，产率70％，无色油状物；1H NMR(400MHz,CDCl3)δ7.47–7.30(m,5H),4.71–4.53(m,2H),4.07–3.95(m,4H),3.94(d,J＝4.3Hz,1H),3.56(dd,J＝5.4,1.3Hz,2H),3.48(td,J＝6.7,1.6Hz,2H),1.62–1.55(m,2H),1.29(s,30H),0.91(t,J＝6.8Hz,3H).13C NMR(101MHz,CDCl3)δ137.33,128.54,128.04,127.86,84.96,83.30,72.26,71.89,70.87,70.62,65.82,31.94,29.72,29.68,29.65,29.63,29.51,29.38,26.12,22.71,14.13.HRMS:calcd for C30H51N3O3Na[M+Na]+524.3903,found 524.3909.
实施例3化合物4a-4h和4'a-4'h的合成通法
将化合物3(6.8mmol)用100mL甲醇(含1％的HCl)溶解，放入250mL的加氢瓶中，加入纯度为10％的Pd/C(118mg)，在氢化装置上在60℃温度下，以60psi压力反应8h，薄层检测反应(乙酸乙酯：甲醇＝10:1)，原料完全转化为产物后，将反应瓶从氢化装置撤下，趁热抽滤，将反应液倒入铺有硅胶的布氏漏斗上滤去Pd/C,并将滤饼回收，用二氯甲烷溶解，超声5分钟，抽滤，收集滤液，反复操作2～3次至超声后的二氯甲烷中没有产物检测出。然后将滤液减压蒸干，再进行硅胶柱层析分离(乙酸乙酯:甲醇＝13:1，每100mL洗脱剂加入1mL氨水)得化合物4。
本实施合成了系列化合物4a-4h和4'a-4'h，如表2
表2
表2中化合物的核磁数据选择性表述如下：
4a，产率70％，无色油状物；1H NMR(400MHz,CDCl3,ppm)δ4.16(t,J＝5.0Hz,1H),4.03(dd,J＝8.9,4.6Hz,1H),3.94(dd,J＝8.5,6.7Hz,1H),3.75(dd,J＝10.5,3.9Hz,1H),3.69(dd,J＝10.6,4.8Hz,1H),3.66–3.60(m,1H),3.60–3.55(m,1H),3.50(t,J＝6.8Hz,2H),2.73(s,3H),1.67–1.56(m,2H),1.38–1.13(m,8H),0.88(t,J＝6.6Hz,3H).13C NMR(101MHz,CDCl3,ppm)δ80.22,72.35,72.31,72.11,70.03,54.45,31.76,29.56,29.10,26.01,22.59,14.08.HRMS:calcd for C12H26NO3[M+H]+232.1834,found 232.1832.
4b，产率71％，无色油状物；1H NMR(400MHz,CDCl3,ppm)δ4.13(t,J＝4.9Hz,1H),4.02(dd,J＝8.8,4.7Hz,1H),3.93(dd,J＝8.4,6.5Hz,1H),3.76(dd,J＝10.6,3.9Hz,1H),3.69(dd,J＝10.6,4.9Hz,1H),3.61(dd,J＝8.3,6.8Hz,1H),3.58–3.53(m,1H),3.50(t,J＝6.8Hz,2H),1.71–1.51(m,2H),1.29(dd,J＝13.1,5.9Hz,12H),0.88(t,J＝6.8Hz,3H).13CNMR(101MHz,CDCl3,ppm)δ80.28,72.56,72.52,72.13,70.14,54.60,31.82,29.58,29.41,29.23,26.08,22.66,14.11.HRMS:calcd for C13H28NO3[M+H]+246.1991,found 246.1992.
4c，产率71％，无色油状物；1H NMR(400MHz,CDCl3,ppm)δ4.11(t,J＝4.8Hz,1H),4.02(dd,J＝9.0,4.6Hz,1H),3.93(dd,J＝8.2,6.6Hz,1H),3.76(dd,J＝10.5,3.9Hz,1H),3.68(dd,J＝10.5,5.0Hz,1H),3.63–3.57(m,1H),3.57–3.52(m,1H),3.49(t,J＝6.8Hz,2H),1.66–1.56(m,2H),1.37–1.21(m,12H),0.88(t,J＝6.8Hz,3H).13C NMR(101MHz,CDCl3,ppm)δ80.33,72.56,72.47,72.09,70.12,54.63,31.86,29.58,29.51,29.44,29.25,26.06,22.66,14.10.HRMS:calcd for C13H28NO3[M+H]+260.2147,found 260.2148.
4d，产率75％，无色油状物；1H NMR(400MHz,CDCl3,ppm)δ4.19(t,J＝4.5Hz,1H),4.04(dd,J＝8.9,4.5Hz,1H),3.98–3.90(m,1H),3.75(dd,J＝10.4,3.7Hz,1H),3.69(dd,J＝10.4,4.3Hz,1H),3.66–3.61(m,1H),3.58(d,J＝7.7Hz,1H),3.50(t,J＝6.7Hz,2H),1.67–1.56(m,2H),1.26(s,14H),0.88(t,J＝6.6Hz,3H).13C NMR(101MHz,CDCl3,ppm)δ80.15,72.29,72.27，72.14,69.99,54.35,31.90,29.56,29.50,29.45,29.32,26.06,22.68,14.12.HRMS:calcd for C14H30NO3[M+H]+274.2304,found 274.2314.
4e，产率74％，淡黄色油状物；1H NMR(400MHz,CDCl3,ppm)δ4.13(t,J＝4.8Hz,1H),4.02(dd,J＝8.8,4.6Hz,1H),3.93(dd,J＝8.2,6.6Hz,1H),3.76(dd,J＝10.5,3.9Hz,1H),3.69(dd,J＝10.4,5.0Hz,1H),3.65–3.58(m,1H),3.58–3.53(m,1H),3.49(t,J＝6.8Hz,2H),1.66–1.55(m,2H),1.25(s,18H),0.88(t,J＝6.8Hz,3H).13C NMR(101MHz,CDCl3,ppm)δ80.28,72.51,72.50,72.13,70.13,54.59,31.92,29.66,29.64,29.61,29.58,29.46,29.36,26.08,22.70,14.13.HRMS:calcd for C16H34NO3[M+H]+302.2617,found 302.2623.
4f，产率80％，淡黄色油状物；1H NMR(400MHz,CDCl3,ppm)δ4.19(t,J＝4.8Hz,1H),4.04(dd,J＝8.8,4.6Hz,1H),3.92(dd,J＝8.2,6.6Hz,1H),3.76(dd,J＝10.5,3.9Hz,1H),3.69(dd,J＝10.4,5.0Hz,1H),3.65–3.58(m,1H),3.58–3.53(m,1H),3.49(t,J＝6.8Hz,2H),1.60–1.52(m,2H),1.25(s,22H),0.88(t,J＝6.8Hz,3H).13C NMR(101MHz,CDCl3,ppm)δ80.28,72.51,72.50,72.13,70.13,54.59,31.92,29.66,29.64,29.61,29.58,29.46,29.36,26.08,22.70,14.13.HRMS:calcd for C18H38NO3[M+H]+330.2930,found 330.2933.
4g，产率78％，淡黄色油状物；1H NMR(400MHz,CDCl3,ppm)δ4.16(s,1H),4.04(dd,J＝8.7,4.4Hz,1H),3.96(dd,J＝11.6,6.4Hz,1H),3.78(dd,J＝10.5,3.8Hz,1H),3.71(dd,J＝10.6,4.7Hz,1H),3.64(dd,J＝8.9,4.3Hz,1H),3.61–3.56(m,1H),3.52(t,J＝6.8Hz,2H),1.61(d,J＝7.1Hz,2H),1.43–1.24(m,26H),0.90(t,J＝6.8Hz,3H).13C NMR(101MHz,CDCl3,ppm)δ80.24,72.50,72.49 72.15,70.10,54.55,31.93,29.69,29.66,29.61,29.45,29.36,26.07,22.69,14.11.HRMS:calcd for C20H42NO3[M+H]+358.3243,found 358.3229.
4h，产率80％，淡黄色油状物；1H NMR(400MHz,CDCl3,ppm)δ4.12(t,J＝4.9Hz,1H),4.02(dd,J＝8.8,4.7Hz,1H),3.93(dd,J＝8.3,6.5Hz,1H),3.76(dd,J＝10.6,3.9Hz,1H),3.69(dd,J＝10.5,4.9Hz,1H),3.60(dd,J＝8.2,6.9Hz,1H),3.57–3.52(m,1H),3.49(t,J＝6.8Hz,2H),1.70–1.53(m,2H),1.29(d,J＝33.0Hz,30H),0.88(t,J＝6.8Hz,3H).13C NMR(101MHz,CDCl3,ppm)δ80.31,72.59,72.54,72.13,70.14,54.62,31.93,29.71,29.67,29.62,29.59,29.46,29.37,26.08,22.70,14.13.HRMS:calcd for C22H46NO3[M+H]+386.3556,found 386.3567.
4'a，产率90％，淡黄色油状物；1H NMR(400MHz,CDCl3,ppm)δ4.04(dd,J＝9.2,5.0Hz,1H),3.97–3.89(m,1H),3.83(dd,J＝7.7,4.0Hz,1H),3.68–3.62(m,2H),3.59(dd,J＝10.4,4.1Hz,1H),3.55–3.39(m,2H),3.32–3.24(m,1H),1.66–1.52(m,2H),1.35–1.18(m,8H),0.88(t,J＝6.7Hz,3H).13C NMR(101MHz,CDCl3,ppm)δ84.64,79.42,74.66,71.97,70.96,60.09,31.77,29.57,29.12,26.03,22.60,14.07.HRMS:calcd for C12H26NO3[M+H]+232.1834,found 232.1832.
4'b，产率91％，淡黄色油状物；1H NMR(400MHz,CDCl3,ppm)δ4.03(ddd,J＝9.1,4.9,1.8Hz,1H),3.93(d,J＝2.2Hz,1H),3.83(d,J＝3.1Hz,1H),3.69–3.64(m,1H),3.64–3.61(m,1H),3.60(dd,J＝3.9,1.9Hz,1H),3.47(ddd,J＝8.9,8.0,4.5Hz,2H),3.32–3.25(m,1H),1.64–1.52(m,2H),1.26(s,12H),0.87(dd,J＝6.8,5.7Hz,3H).13C NMR(101MHz,CDCl3,ppm)δ84.70,79.28,74.51,71.97,70.93,60.06,31.81,29.56,29.42,29.23,26.06,22.63,14.08.HRMS:calcd for C13H28NO3[M+H]+246.1991,found 246.1992.
4'c，产率89％，无色油状物；1H NMR(400MHz,CDCl3,ppm)δ4.04(dd,J＝9.2,5.1Hz,1H),3.98–3.88(m,1H),3.83(dd,J＝7.9,4.1Hz,1H),3.65(dd,J＝6.3,2.9Hz,1H),3.63(d,J＝3.5Hz,1H),3.59(dd,J＝10.4,4.2Hz,1H),3.48(ddd,J＝13.6,9.3,2.4Hz,2H),3.33–3.20(m,1H),1.67–1.52(m,2H),1.26(s,12H),0.88(t,J＝6.8Hz,3H).13C NMR(101MHz,CDCl3,ppm)δ84.68,79.38,74.65,71.97,70.96,60.10,31.85,29.57,29.53,29.47,29.27,26.06,22.65,14.09.HRMS:calcd for C14H30NO3[M+H]+260.2147,found 260.2148.
4'd，产率89％，无色油状物；1H NMR(400MHz,CDCl3,ppm)δ4.04(dd,J＝9.2,5.1Hz,1H),3.97–3.86(m,1H),3.83(q,J＝3.8Hz,1H),3.68–3.64(m,1H),3.63(d,J＝3.5Hz,1H),3.60(dd,J＝10.3,4.1Hz,1H),3.56–3.39(m,2H),3.28(dd,J＝4.7,2.9Hz,1H),1.67–1.53(m,2H),1.26(s,14H),0.88(t,J＝6.6Hz,3H).13C NMR(101MHz,CDCl3,ppm)δ84.59,79.72,74.78,71.98,71.02,60.20,31.90,29.59,29.48,29.32,26.10,22.68,14.12.HRMS:calcdfor C15H32NO3[M+H]+274.2304,found 274.2314.
4'e，产率90％，无色油状物；1H NMR(400MHz,CDCl3,ppm)δ4.04(dd,J＝9.2,5.2Hz,1H),3.97–3.88(m,1H),3.82(dd,J＝8.3,4.1Hz,1H),3.67–3.63(m,1H),3.62(d,J＝3.3Hz,1H),3.61–3.57(m,1H),3.48(qt,J＝9.3,6.8Hz,2H),3.29(dt,J＝5.3,3.3Hz,1H),1.57(dd,J＝14.2,7.0Hz,2H),1.27(d,J＝9.9Hz,18H),0.88(t,J＝6.8Hz,3H).13C NMR(101MHz,CDCl3,ppm)δ84.52,79.88,74.73,71.99,71.06,60.18,31.92,29.67,29.64,29.60,29.49,29.35,26.10,22.69,14.12.HRMS:calcd for C17H36NO3[M+H]+302.2617,found 302.2623.
4'f，产率87％，无色油状物；1H NMR(400MHz,CDCl3,ppm)δ4.06(dd,J＝9.3,5.0Hz,1H),4.01–3.95(m,1H),3.86(dd,J＝7.6,3.8Hz,1H),3.70(dd,J＝9.3,3.0Hz,1H),3.63(qd,J＝10.4,3.6Hz,2H),3.50(tdd,J＝16.2,9.3,6.9Hz,2H),3.35(d,J＝2.7Hz,1H),1.73–1.49(m,2H),1.28(d,J＝11.2Hz,22H),0.89(t,J＝6.8Hz,3H).13C NMR(101MHz,CDCl3,ppm)δ84.55,79.32,74.01,72.01,70.96,59.82,31.92,29.69,29.67,29.65,29.60,29.55,29.48,29.35,26.07,22.68,14.10.HRMS:calcd for C19H40NO3[M+H]+330.2930,found 330.2933.
4'g，产率89％，无色油状物；1H NMR(400MHz,CDCl3,ppm)δ4.05(dd,J＝9.4,5.0Hz,1H),4.02–3.95(m,1H),3.85(dd,J＝7.6,3.8Hz,1H),3.71(dd,J＝9.4,3.0Hz,1H),3.69–3.56(m,5H),3.55–3.42(m,2H),3.41–3.35(m,1H),1.57(dd,J＝13.8,6.9Hz,2H),1.27(d,J＝11.2Hz,26H),0.88(t,J＝6.8Hz,3H).13C NMR(101MHz,CDCl3,ppm)δ84.48,79.29,73.72,72.02,70.96,59.68,31.92,29.70,29.68,29.66,29.64,29.60,29.54,29.48,29.36,26.06,22.69,14.11.HRMS:calcd for C21H44NO3[M+H]+358.3243,found 358.3229.
4'h，产率87％，无色油状物；1H NMR(400MHz,CDCl3,ppm)δ4.06(dd,J＝9.4,4.9Hz,1H),4.03–3.98(m,1H),3.87(dd,J＝7.5,3.8Hz,1H),3.73(dd,J＝9.2,2.6Hz,4H),3.66(dd,J＝10.4,3.2Hz,1H),3.61(dd,J＝10.4,3.9Hz,1H),3.57–3.43(m,2H),3.38(s,1H),1.65–1.56(m,2H),1.39–1.21(m,32H),0.89(t,J＝6.8Hz,3H).13C NMR(101MHz,CDCl3,ppm)δ84.51,79.36,73.94,72.02,70.97,59.78,31.92,29.70,29.66,29.60,29.55,29.48,29.36,26.07,22.68,14.11.HRMS:calcd for C21H44NO3[M+H]+386.3556,found 386.3567.
应用例1上述化合物对肿瘤细胞活性检测
1.实验方法：
样品为实施例所合成的上述化合物、纯化而得；样品储备液：称取3-5mg样品置于1.5mL EP管中，然后用DMSO配制成浓度是10mM的溶液，4℃保存放置，实验时根据所需浓度利用培养基稀释。
2.筛选：
取对数生长期的细胞，消化计数后，用培养基调整细胞密度，以4000-8000个cell/孔接种至96孔板中，每孔100μL，培养24h后，弃去培养基，加入用培养基稀释好的药物，每个浓度设3个复孔，另设空白对照组及阳性对照组。药物作用72h后，每孔加入20μLMTT溶液，继续培养4h后，吸去液体，加入150μL的DMSO，振荡均匀，酶标仪490nm处检测吸光度值，计算抑制率，计算公式如下：
抑制率(％)＝(1-给药组吸光度值/空白组吸光度值)×100％
试验结果采用SPSS软件计算IC50值和相关系数，结果如下表3所示。
3.实验结果
表3上述部分优选化合物对食管癌细胞(EC9706和Eca-109)、小鼠黑色素瘤细胞(B16-F10)、乳腺癌细胞(MCF-7)抗肿瘤活性评价数据：
表3
化合物 Eca109 Ec9706 B16-F10 MCF-7
4a >120 >120 >120 >120
4b >120 >120 >120 >120
4c >120 78.71±5.0 25.20±3.1 117.20±5.7
4d 53.53±4.2 48.93±4.1 10.87±1.7 41.13±3.8
4e 29.12±3.1 26.27±3.0 6.55±0.9 22.39±2.8
4f 16.45±2.2 21.00±2.5 4.88±0.6 15.81±2.2
4g 17.01±2.2 20.05±2.4 2.0±0.4 6.22±1.0
4h 13.33±1.8 26.24±2.6 3.43±0.3 15.94±2.0
4'a >120 >120 >120 >120
4'b >120 >120 >120 >120
4'c 119.23±5.7 113.55±5.7 28.52±3.4 40.20±3.7
4'd 61.10±4.5 33.96±3.5 25.62±3.1 18.62±2.6
4'e 19.05±2.5 26.60±3.0 12.85±1.7 65.76±4.3
4'f 28.38±2.8 28.69±3.0 10.89±1.7 2.5±0.1
4'g 35.10±3.1 44.81±3.3 4.55±0.6 7.76±2.8
4'h 62.70±2.6 35.48±3.0 13.70±1.9 26.46±2.6
Jasping B 15.63±2.2 31.39±0.9 5.08±0.6 8.24±1.3

Claims (2)

1.一种Jaspine B氧代类似物的制备方法，其特征在于，通过以下步骤实现：（1）在溶剂中将化合物1还原得到化合物2，所用到的还原剂为KBH4或NaBH4，所选用的溶剂为甲醇或乙醇；（2）溶剂中，化合物2在碱性条件下与不同链长的溴代烷烃反应得到化合物3a-3h，所用的碱为K2CO3、NaOH或NaH；所选用的溶剂为四氢呋喃或N,N-二甲基甲酰胺；（3）溶剂中，化合物3a-3h在酸作用下及催化剂作用下合成化合物4a-4h；所述溶剂选自甲醇，乙醇，乙酸乙酯；酸选用盐酸或三氟乙酸，催化剂选择Pd/C或Pd(OH)2；
其中n为6、7、8、9、11、13、15或17；
所选用的溴代烷烃为溴代庚烷、溴代辛烷、溴代壬烷、溴代癸烷、溴代十二烷、溴代十四烷、溴代十六烷或溴代十八烷。
2.一种3-epi Jaspine B 氧代类似物的制备方法，通过以下步骤实现：（1）在溶剂中将化合物1'还原得到化合物2'，所用到的还原剂为KBH4或NaBH4，所选用的溶剂为甲醇或乙醇；（2）溶剂中，化合物2'在碱性条件下与不同链长的溴代烷烃反应得到化合物3'a-3'h，所用的碱为K2CO3、NaOH或NaH；所选用的溶剂为四氢呋喃或N,N-二甲基甲酰胺；（3）溶剂中，化合物3'a-3'h在酸作用下及催化剂作用下合成化合物4'a-4'h；所述溶剂选自甲醇，乙醇，乙酸乙酯；酸选用盐酸或三氟乙酸，催化剂选择Pd/C或Pd(OH)2；
其中n为6、7、8、9、11、13、15或17；
所选用的溴代烷烃为溴代庚烷、溴代辛烷、溴代壬烷、溴代癸烷、溴代十二烷、溴代十四烷、溴代十六烷或溴代十八烷。
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