CN103509021A - 金雀花碱衍生物及其制备方法和抗癌作用研究 - Google Patents
金雀花碱衍生物及其制备方法和抗癌作用研究 Download PDFInfo
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- CN103509021A CN103509021A CN201210206301.0A CN201210206301A CN103509021A CN 103509021 A CN103509021 A CN 103509021A CN 201210206301 A CN201210206301 A CN 201210206301A CN 103509021 A CN103509021 A CN 103509021A
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- 238000011160 research Methods 0.000 title abstract description 3
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- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 claims abstract description 26
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- 239000004575 stone Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
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- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/18—Bridged systems
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- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
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Abstract
本发明涉及金雀花碱衍生物及其制备方法和抗癌作用研究,主要解决该类化合物较少的技术问题。该类化合物具有的结构通式如I和II所示:
Description
技术领域
本发明涉及金雀花碱衍生物及其制备方法和抗癌作用研究。
背景技术
金雀花碱是一类具有α-吡啶酮的三环结构的生物碱,大多分布于豆科、小檗科植物中。临床上金雀花碱可用于肌肉或静脉注射,抢救因手术和各种创伤引起的反射性呼吸暂停、休克及新生儿窒息等。近期的一些研究表明,该类生物碱还具有抗心率失常、抗感染等多方面的生物活性。其中卤代的金雀花碱与烟碱乙酰胆碱受体亲和力较强,在中枢神经方面表现出较强的生物活性;硫代的金雀花碱对烟碱乙酰胆碱受体中枢神经的α4β2位点有较强的选择性。
发明内容
本发明目的是提供一种金雀花碱衍生物及其制备方法和抗癌作用研究。主要解决目前金雀花碱衍生物较少的技术问题。
本发明金雀花碱衍生物具有式I或式II的结构:
其中,
R1 = O或S;
R2,R4 =
H,F,Cl,Br,I中的一种;
R3 = H;
R5,R6 = 烷基,芳香环,杂环中的一种。
优选:式I和II中R5,R6涉及的烷基代表1-8个碳原子的直链、支链或环烷基;烷基上连有杂原子、芳香环或杂环的取代基;或烷基上连有取代的芳香环或杂环;
a.1-8个碳原子的直链、支链或环烷基是指甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基丙基、叔丁基、正戊基、异戊基、叔戊基、正己基、正庚基、正辛基、环丙基、环丁基、环戊基、环己基、环庚基或环辛基中的一种;
b.烷基上的杂原子是指O、N、S或F中的一种;
c.芳香环或杂环是指苯环、吡啶、吡咯、呋喃、噻吩、噻唑、苯并噻唑或吲哚中的一种;
d.取代的芳香环或杂环的取代基是指:-F、-Cl、-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、-NH2、-CF3、-OCF3、-OCH3、-OCH2CH3、-OCH2CH2CH3、-OCH(CH3)2或-OCH2CH2CH2CH3中的一种。
本发明的优选化合物是具有下述结构的化合物:
本发明公开的金雀花碱衍生物可有以下反应路线获得:
路线1:
路线2:
化合物1的制备方法,制备过程如下式:
以金雀花碱为原料,叔丁氧羰基保护氨基得到化合物17,然后与劳森试剂反应得到化合物18,脱去保护基得到化合物19,然后还原胺化得到化合物1。
化合物2的制备方法,制备过程如下式:
以金雀花碱为原料,叔丁氧羰基保护氨基得到化合物17,然后与劳森试剂反应得到化合物18,脱去保护基得到化合物19,然后还原胺化得到化合物3。
化合物3的制备方法,制备过程如下式:
以金雀花碱为原料,叔丁氧羰基保护氨基得到化合物17,然后与劳森试剂反应得到化合物18,脱去保护基得到化合物19,然后还原胺化得到化合物4。
化合物4的制备方法,制备过程如下式:
以金雀花碱为原料,叔丁氧羰基保护氨基得到化合物17,然后与劳森试剂反应得到化合物18,脱去保护基得到化合物19,然后还原胺化得到化合物5。
化合物5的制备方法,制备过程如下式:
以金雀花碱为原料,叔丁氧羰基保护氨基得到化合物17,然后与劳森试剂反应得到化合物18,脱去保护基得到化合物19,然后酸胺缩合得到化合物6。
化合物6的制备方法,制备过程如下式:
以金雀花碱为原料,叔丁氧羰基保护氨基得到化合物17,然后与劳森试剂反应得到化合物18,脱去保护基得到化合物19,然后酸胺缩合得到化合物7。
化合物7的制备方法,制备过程如下式:
以金雀花碱为原料,叔丁氧羰基保护氨基是得到化合物17,然后与劳森试剂反应得到化合物18,脱去保护基得到化合物19,然后酸胺缩合得到化合物8。
化合物8的制备方法,制备过程如下式:
以金雀花碱为原料,叔丁氧羰基保护氨基得到化合物17,然后与劳森试剂反应得到化合物18,脱去保护基得到化合物19,然后酸胺缩合得到化合物9。
化合物9的制备方法,制备过程如下式:
以金雀花碱为原料在碱性条件下用叔丁氧羰基保护氨基得到化合物17,然后通过N-溴代丁二酰亚胺 (NBS)溴代得到化合物20。化合物20在与劳森试剂反应得到化合物21,去保护基得到化合物22,然后还原胺化得到化合物10。
化合物10的制备方法,制备过程如下式:
以金雀花碱为原料在碱性条件下用叔丁氧羰基保护氨基得到化合物17,然后通过N-溴代丁二酰亚胺(NBS)溴代得到化合物20。化合物20在与劳森试剂反应得到化合物21,去保护基得到化合物22,然后还原胺化得到化合物11。
化合物11的制备方法,制备过程如下式:
以金雀花碱为原料在碱性条件下用叔丁氧羰基保护氨基得到化合物17,然后通过N-溴代丁二酰亚胺(NBS)溴代得到化合物20。化合物20在与劳森试剂反应得到化合物21,去保护基得到化合物22,然后还原胺化得到化合物12。
化合物12的制备方法,制备过程如下式:
本发明的有益效果:本发明涉及的金雀花碱衍生物及其制备方法是通过在金雀花碱的1位、3位和5位引入不同的官能团,以此改变该类化合物的物化性质,并且有利于提高药物的选择性和有效性。经测试,本发明优选的化合物1-12均具有较好的抑制肺癌细胞的活性,为进一步研制抗癌药物打下基础。本发明所述工艺条件温和,操作简单,试剂便宜,且易于利用“组合化学”在短时间内合成大量的金雀花碱衍生物,建立化合物库,这对快捷便利筛选生物活性更好的先导化合物提供了非常有力的支持。
具体实施方式
实施例1
化合物17的合成
在1 L的圆底烧瓶中,金雀花碱(40 g,0.21 mol)溶于500 mL四氢呋喃中,再加入二碳酸二叔丁酯(55 g,0.23 mol)和碳酸钠(27 g,0.31 mol)。室温搅拌过夜,过滤取滤液,浓缩得到化合物17(65 g,收率:92%)。ESI-MS:290.9 [M+1]。
1)化合物18的合成
在1 L的圆底烧瓶中,劳森试剂(80 g,0.2 mol)悬浮于甲苯中,110 ℃回流至全部溶解,再加入化合物17(29 g,0.1 mol)。反应于110 ℃下搅拌2 h。真空旋干溶液,加入乙酸乙酯和饱和的碳酸氢钠溶液,搅拌1 h,分液,收集有机相,干燥、旋干,硅胶柱纯化得到化合物18(20 g,收率:66%)。ESI-MS:306.9 [M+1]。1H NMR (d-DMSO,400 MHz), d = 7.39 (s, 1H), 7.26(s, 1H), 6.75(d, J
= 6.8 Hz, 1H), 4.45-4.43 (m, 1H), 4.14-3.91 (m, 3H), 3.20-3.13 (m, 4H), 1.92
(s, 2H), 1.13 (d, 9H)。
2)化合物19的合成
在100 mL的圆底烧瓶中,化合物18(2 g,6.5 mmol)溶于10 mL乙酸乙酯中,加入10 mL的盐酸-乙酸乙酯。室温搅拌2 h,抽滤取滤饼,干燥得化合物19(1.5 g,95%)。ESI-MS:207.1 [M+1]。1H NMR (CD3OD,400 MHz), d = 7.67-7.65 (m, 1H), 7.41-7.37
(m, 1H), 6.94-6.92 (m, 1H), 4.67-4.33 (m, 2H), 3.56-3.40 (m, 5H), 2.90 (s, 1H),
2.17 (m, 2H)。
3)化合物1的合成
在8 mL的反应瓶中,化合物19 (100 mg,0.41 mmol)溶于2 mL甲醇中,加入三乙胺(62 mg,0.62 mmol),对甲氧基苯甲醛(84 mg,0.62 mmol)和氰基硼氢化钠(51 mg,0.62 mmol)。室温搅拌过夜,经高效液相色谱纯化得到化合物1(50 mg, 收率:37%)。ESI-MS:327.1 [M+1]。1H NMR (d-DMSO,400 MHz), d = 7.44-7.41 (m, 1H), 7.26-7.22 (m,
1H), 6.82-6.80 (m, 2H), 6.71-6.69 (m, 2H), 6.63-6.61 (m, 1H), 4.37-3.94 (m,
2H), 3.66 (s, 3H), 3.29-3.25 (m, 2H), 3.14-3.13 (m, 1H), 2.78 (dd, J = 5.4 Hz,
2H), 2.26-2.25 (m, 2H), 2.23-2.22 (m, 2H)。
实施例2
1) 化合物2的合成
在8 mL的反应瓶中,化合物19 (100 mg,0.41 mmol)溶于2 mL甲醇中,加入三乙胺(62 mg,0.62 mmol),环戊酮(52 mg,0.62 mmol)和氰基硼氢化钠(51 mg,0.62 mmol)。室温搅拌过夜,经高效液相色谱纯化得到化合物2(45 mg, 收率:40%)。ESI-MS:275.1 [M+1]。1H NMR (d-DMSO,400 MHz), d = 7.36-7.34 (m, 1H), 7.26-7.22 (m,
1H), 6.68-6.66 (m, 1H), 4.20-3.98 (m, 2H), 3.13 (s, 1H), 2.97-2.84 (m, 2H),
2.42-2.41 (m, 1H), 2.25-2.15 (m, 2H), 1.82-1.69 (m, 2H), 1.61-1.35 (m, 7H),
1.13-0.95 (m, 2H)。
实施例3
1)化合物3的合成
在8 mL的反应瓶中,化合物19(100 mg,0.41 mmol)溶于2 mL甲醇中,加入三乙胺(62 mg,0.62 mmol),3-噻吩甲醛(70 mg,0.62 mmol)和氰基硼氢化钠(51 mg,0.62 mmol)。室温搅拌过夜,经高效液相色谱纯化得到化合物3(45 mg, 收率:36%)。ESI-MS:303.0 [M+1]。1H NMR
(d-DMSO,400 MHz), d = 7.43-7.40 (m, 1H),
7.36-7.34 (m, 1H), 7.27-7.23 (m, 1H), 6.97-6.96 (m, 1H), 6.66-6.64 (m, 1H),
6.59-6.58 (m, 1H), 4.37-3.94 (m, 2H), 3.43-3.34 (m, 3H), 3.14-3.13 (m, 1H),
2.89-2.73 (m, 2H), 2.27-2.24 (m, 2H), 1.86-1.68 (m, 2H)。
实施例4
1)化合物4的合成
在8 mL的反应瓶中,化合物19 (100 mg,0.41 mmol)溶于2 mL甲醇中,加入三乙胺(62 mg,0.62 mmol),4-甲酰基苯硼酸(93 mg,0.62 mmol)和氰基硼氢化钠(51 mg,0.62 mmol)。室温搅拌过夜,经高效液相色谱纯化得到化合物1(40 mg, 收率:28%)。ESI-MS:333.2 [M+1]。1H NMR
(d-DMSO,400 MHz), d = 7.92 (s, 1H), 7.56
(d, J = 8 Hz, 1H), 7.46-7.44 (m, 1H), 7.28-7.24 (m, 1H), 6.84 (d, J = 8 Hz, 1H),
6.64-6.62 (m, 1H), 4.42-4.35 (m, 1H), 4.10-4.06 (m, 1H), 3.42-3.30 (m, 2H),
3.14 (d, J = 4.8 Hz, 2H), 2.27-2.28 (m, 2H), 1.90-1.68 (m, 2H)。
实施例5
1)化合物5的合成
在8 mL的反应瓶中,3-乙酰氨基苯甲酸(89 mg,0.50 mmol)溶于2 mL DMF中,加入三乙胺(62 mg,0.62 mmol),EDCI(119 mg,0.62 mmol)和HOBt(84 mg,0.62 mmol)。室温搅拌5h,加入化合物19(100 mg,0.41 mmol)。室温反应过夜,反应液经高效液相色谱纯化得到化合物5(50 mg, 收率:33%)。ESI-MS:368.1 [M+1]。1H NMR (d-DMSO,400 MHz), d = 10.06 (s, 1H), 7.52-7.49 (m, 3H),
7.266 (t, J = 6.89 Hz, 1H), 6.84-6.70 (m, 3H), 4.51-4.47 (m, 1H), 3.91 (brs,
1H), 3.66 (s, 3H), 3.30 (s, 3H), 2.47-2.46 (m, 2H), 2.01 (s, 3H), 1.98 (m, 2H)。
实施例6
1)化合物6的合成
在8 mL的反应瓶中,2-乙基丁酸(58 mg,0.50 mmol)溶于2 mL DMF中,加入三乙胺(62 mg,0.62 mmol),EDCI(119 mg,0.62 mmol)和HOBt(84 mg,0.62 mmol)。室温搅拌5h,加入化合物19(100 mg,0.41 mmol)。室温反应过夜,反应液经高效液相色谱纯化得到化合物6(50 mg, 收率:40%)。ESI-MS:305.1 [M+1]。1H NMR (CDCl3,400 MHz), d = 7.65-7.59 (m, 1H), 7.11 (t, J = 7.6
Hz, 1H), 6.56-6.55 (m, 1H), 4.91-4.78 (m, 1H), 4.69-4.68 (m, 1H), 4.25-4.09 (m,
2H), 3.38-3.31 (m, 1H), 3.22-3.19 (m, 1H), 2.90-2.90 (m, 1H), 2.65 (m, 1H),
2.46-2.14 (m, 1H), 2.07 (m, 2H), 1.52-1.27 (m, 4H), 0.83-0.78 (m, 3H),
0.49-0.28 (m, 3H)。
实施例7
1)化合物7的合成
在8 mL的反应瓶中,3-(1H-苯并咪唑-2-基)丙酸(95 mg,0.50 mmol)溶于2 mL DMF中,加入三乙胺(62 mg,0.62 mmol),EDCI(119 mg,0.62 mmol)和HOBt(84 mg,0.62 mmol)。室温搅拌5h,加入化合物19(100 mg,0.41 mmol)。室温反应过夜,反应液经高效液相色谱纯化得到化合物7(50 mg, 收率:32%)。ESI-MS:379.1 [M+1]。1H NMR (d-DMSO,400 MHz), d = 7.44-7.34 (m, 3H), 7.27-7.20 (m,
1H), 7.11-7.07 (m, 1H), 6.85-6.75 (m, 1H), 4.62-4.51 (m, 1H), 4.37-4.27 (m,
1H), 4.14-3.93 (m, 2H), 3.43-3.40 (m, 2H), 2.88-2.77 (m, 3H), 2.71-2.63 (m,
2H), 2.57 (m, 1H), 1.96 (s, 2H)。
实施例8
1)化合物8的合成
在8 mL的反应瓶中,吡唑并[1,
5-a]吡啶-3-羧酸(81 mg,0.50 mmol)溶于2 mL DMF中,加入三乙胺(62 mg,0.62 mmol),EDCI(119 mg,0.62 mmol)和HOBt(84 mg,0.62 mmol)。室温搅拌5h,加入化合物19(100 mg,0.41 mmol)。室温反应过夜,反应液经高效液相色谱纯化得到化合物8(60 mg, 收率:41%)。ESI-MS:379.1 [M+1]。1H NMR (d-DMSO,400 MHz), d = 8.67 (d, J = 7.2 Hz, 1H), 7.86 (s,
1H), 7.47 (d, J = 8.8 Hz, 1H), 7.36-7.27 (m, 2H), 7.12 (t, J = 8 Hz, 1H),
6.98-6.94 (m, 1H), 6.68 (d, J = 6.8 Hz, 1H), 4.53-4.45 (m, 2H), 4.28-4.25 (m,
1H), 3.93-3.87 (m, 1H), 3.40-3.13 (m, 3H), 2.57 (m, 1H), 2.06-1.97 (m, 2H)。
实施例9
1)化合物20的合成
在1 L的圆底烧瓶中,化合物17(10 g,0.34 mol)溶于150 mL二氯甲烷中,再加入N-溴代丁二酰亚胺(7.3 g,0.41 mol)。室温搅拌过夜,移出溶剂,通过柱纯化得到化合物20(6.5 g,收率:30 %)。ESI-MS:370.8 [M+1]。1H NMR (CDCl3,400 MHz), d = 7.42 (d, J = 9.6 Hz, 1H), 6.38 (d, J
= 8.4 Hz, 1H), 4.38-4.14 (m, 3H), 3.83 (dd, J1 = 1.6 Hz, J2
= 16 Hz, 1H), 3.46-3.39 (m, 1H), 3.15-2.98 (m, 2H), 2.41 (m, 1H), 1.98 (m, 2H),
1.32 (d, 9H)。
2)化合物21的合成
在1 L的圆底烧瓶中,劳森试剂(4.4 g,0.01 mol)悬浮于甲苯中,110 ℃回流至全部溶解,再加入化合物20(2 g,0.054 mol)。反应于110 ℃下搅拌2 h。真空旋干溶液,加入乙酸乙酯和饱和的碳酸氢钠溶液,搅拌1 h,分液,收集有机相,干燥、旋干,硅胶柱纯化得到化合物21(1.6 g,收率:80 %)。ESI-MS:386.8 [M+1]。
3) 化合物22的合成
在100 mL的圆底烧瓶中,化合物21(1 g,3.52 mmol)溶于10 mL乙酸乙酯中,加入10 mL的盐酸-乙酸乙酯。室温搅拌2 h,抽滤取滤饼,干燥得化合物22(0.8 g,95%)。ESI-MS:286.9 [M+1]。1H NMR (CD3OD,400 MHz), d = 7.50-7.45 (m, 2H), 4.56-4.52 (m,
1H), 4.36-4.29 (m, 1H), 3.85-3.84 (m, 1H), 3.50-3.35 (m, 4H), 2.84 (m, 1H),
2.23-2.17 (m, 1H), 2.09-2.03 (m, 1H)。
3)化合物9合成
在8 mL的反应瓶中,化合物22 (100
mg, 0.35 mmol)溶于2 mL甲醇中,加入三乙胺(53 mg,0.53 mmol),2-苯基丙醛(71 mg,0.53 mmol)和氰基硼氢化钠(33 mg,0.53 mmol)。室温搅拌过夜,经高效液相色谱纯化得到化合物9(50 mg, 收率:35%)。ESI-MS:404.1 [M+1]。1H NMR
(CDCl3,400 MHz), d
= 7.48-7.40 (m, 1H), 7.22-7.05 (m, 4H), 6.99-6.97 (m, 1H), 6.90-6.88 (m, 1H),
4.39-4.15 (m, 2H), 3.45-3.44 (m, 1H), 3.06-2.97 (m, 1H), 2.91-2.83 (m, 1H),
2.77-2.66 (m, 1H), 2.48-2.21 (m, 5H), 1.83-1.81 (m, 2H), 1.03-0.92 (m, 3H)。
实施例10
1)化合物10的合成
在8 mL的反应瓶中,化合物22 (100
mg, 0.35 mmol)溶于2 mL甲醇中,加入三乙胺(53 mg,0.53 mmol),苯甲醛(56 mg,0.53 mmol)和氰基硼氢化钠(33 mg,0.53 mmol)。室温搅拌过夜,经高效液相色谱纯化得到化合物10 (60 mg, 收率:45%)。ESI-MS:377.1 [M+1]。1H NMR (CDCl3,400 MHz), d = 7.85 (d, J = 9.2 Hz, 1H), 7.29 (d, J
= 9.2 Hz, 1H), 7.20-7.18 (m, 3H), 6.96-6.93 (m, 2H), 4.54 (m, 1H), 4.28-4.22
(m, 1H), 3.55-3.53 (m, 1H), 3.44 (d, J = 1.6 Hz, 2H), 3.06-2.93 (m, 2H),
2.53-2.50 (m, 1H), 2.38-2.26 (m, 2H), 1.90-1.89 (m, 2H)。
实施例11
1)化合物11合成
在8 mL的反应瓶中,化合物22 (100
mg, 0.35 mmol)溶于2 mL甲醇中,加入三乙胺(53 mg,0.53 mmol),环己基甲醛(60 mg,0.53 mmol)和氰基硼氢化钠(33 mg,0.53 mmol)。室温搅拌过夜,经高效液相色谱纯化得到化合物11 (60 mg, 收率:37%)。ESI-MS:383.1 [M+1]。1H NMR (CDCl3,400 MHz), d = 7.51 (d, J = 9.2 Hz, 1H), 7.27 (d, J
= 9.2 Hz, 1H), 4.52-4.21 (m, 2H), 3.53-3.51 (m, 1H), 3.04-2.88 (m, 2H),
2.50-2.48 (m, 1H), 2.32-2.18 (m, 2H), 2.01 (d, J = 7.6 Hz, 2H), 1.88-1.86 (m,
2H), 1.60-1.41 (m, 2H), 1.29-1.22 (m, 2H), 0.69-0.56 (m, 2H)。
实施例12
1)化合物12合成
在8 mL的反应瓶中,化合物22 (100
mg, 0.35 mmol)溶于2 mL甲醇中,加入三乙胺(53 mg,0.53 mmol),2-吡咯甲醛(50 mg,0.53 mmol)和氰基硼氢化钠(33 mg,0.53 mmol)。室温搅拌过夜,经高效液相色谱纯化得到化合物12 (60 mg, 收率:47%)。ESI-MS:366.0 [M+1]。1H NMR (CDCl3,400 MHz), d = 7.80 (brs, 1H), 7.57 (d, J = 8 Hz,
1H), 7.31 (d, J = 8.8 Hz, 1H), 6.64-6.62 (m, 1H), 6.06-6.04 (m, 1H), 5.94-5.93
(m, 1H), 4.52 (m, 1H), 4.26-4.20 (m, 1H), 3.58-3.56 (m, 1H), 3.46-3.38 (m, 2H),
3.03-2.89 (m, 2H), 2.54-2.52 (m, 1H), 2.30-2.26 (m, 2H), 1.91-1.89 (m, 2H)。
本发明合成的化合物具有抗肿瘤作用,其抑制人肺癌细胞株(A-549)的实验结果如下:
(一)抑制人肺癌细胞株(A-549)的实验方法
1.DMSO溶解化合物至浓度10
mM, -20 ℃ 保存;
2.收集细胞并计数,5 x 103个 A-549悬浮于100 mL培养基中,铺入96孔板,每孔3个平行,96孔板中细胞过夜培养;
3.第二天,每孔加入50 mL化合物处理细胞,终浓度30,10, 3.33,1,0.33 mM,总体积150 mL。另外,对照组有细胞但不加药处理,空白组既无细胞也不加药处理;
4.化合物处理2天后,用美国普洛麦格(Promega)公司试剂盒CellTiter-Glo®来检测细胞活力;
5.取出处理好的96孔板放置室温平衡30分钟;
6.提前解冻CellTiter-Glo® 试剂,平衡至室温;
7.在96孔板中每孔加入80 mL
CellTiter-Glo® 试剂;
8.将96孔板置于水平摇床上混匀,让CellTiter-Glo®
试剂充分裂解细胞;
9.将96孔板室温静置10分钟以稳定荧光信号;
10.读数,并计算得到 IC50。
(二)实验结果
体外抗肿瘤试验结果见下表
化合物编号 | 抑制人肺癌细胞株(A-549)活性 IC50(μM) | 化合物编号 | 抑制人肺癌细胞株(A-549)活性 IC50(μM) |
1 | 10.8 | 7 | 18.4 |
2 | 5.5 | 8 | 4.5 |
3 | 3.2 | 9 | 2.8 |
4 | 4.3 | 10 | 5.9 |
5 | 2.5 | 11 | 3.8 |
6 | 9.8 | 12 | 2.3 |
上述活性实验结果表明本发明所述化合物具有较好的抗肿瘤活性,可用于制备新的抗肿瘤药物;另外,该类化合物制备方法简单易行,原料廉价易得,易于放大制备,因此具有很好的应用前景。
Claims (17)
2.根据权利要求1所述的金雀花碱衍生物,其特征是式I和II中R5,R6涉及的烷基代表1-8个碳原子的直链、支链或环烷基;所述的烷基上连有杂原子、芳香环或杂环的取代基;或所述的烷基上连有取代的芳香环或杂环。
3.根据权利要求2所述的金雀花碱衍生物,其特征是:
a.1-8个碳原子的直链、支链或环烷基是指甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基丙基、叔丁基、正戊基、异戊基、叔戊基、正己基、正庚基、正辛基、环丙基、环丁基、环戊基、环己基、环庚基或环辛基中的一种;
b.烷基上的杂原子是指O、N、S或F中的一种;
c.芳香环或杂环是指苯环、吡啶、吡咯、呋喃、噻吩、噻唑、苯并噻唑或吲哚中的一种;
d.取代的芳香环或杂环的取代基是指:-F、-Cl、-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、-NH2、-CF3、-OCF3、-OCH3、-OCH2CH3、-OCH2CH2CH3、-OCH(CH3)2或-OCH2CH2CH2CH3中的一种。
8.权利要求4所述化合物3的制备方法,其特征是以金雀花碱为原料在碱性条件下用叔丁氧羰基保护氨基得到化合物17,然后与劳森试剂反应得到化合物18,脱去保护基得到化合物19,然后还原胺化得到化合物3,反应式如下:
。
11.权利要求4所述化合物6的制备方法,其特征是以金雀花碱为原料在碱性条件下用叔丁氧羰基保护氨基得到化合物17,然后与劳森试剂反应得到化合物18,脱去保护基得到化合物19,然后酸胺缩合得到化合物6,反应式如下:
。
16.权利要求4所述化合物11的制备方法,其特征是以金雀花碱为原料在碱性条件下用叔丁氧羰基保护氨基得到化合物17,然后通过N-溴代丁二酰亚胺溴代得到化合物20,化合物20在与劳森试剂反应得到化合物21,去保护基得到化合物22,然后还原胺化得到化合物11,反应式如下:
。
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Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2018033742A3 (en) * | 2016-08-19 | 2018-05-17 | The University Of Bristol | Cytisine derivatives for the treatment of addiction |
CN108503640A (zh) * | 2018-01-31 | 2018-09-07 | 广西田园生化股份有限公司 | 金雀花碱衍生物及其制备方法和在农药中的运用 |
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US10300050B2 (en) | 2016-02-05 | 2019-05-28 | Achieve Pharma Uk Limited | Succinate salt of cytisine and use thereof |
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Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007056155A1 (en) * | 2005-11-03 | 2007-05-18 | Chembridge Research Laboratories, Inc. | Heterocyclic compounds as tyrosine kinase modulators |
-
2012
- 2012-06-21 CN CN201210206301.0A patent/CN103509021B/zh active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007056155A1 (en) * | 2005-11-03 | 2007-05-18 | Chembridge Research Laboratories, Inc. | Heterocyclic compounds as tyrosine kinase modulators |
Non-Patent Citations (4)
Title |
---|
ANNA K. PRZYBYL ET AL.: "A comparative study of dynamic NMR spectroscopy in analysis of selected N-alkyl-,N-acyl-, and halogenated cytisine derivatives", 《JOURNAL OF MOLECULAR STRUCTURE》 * |
BRUNO TASSO ET AL.: "Synthesis, Binding, and Modeling Studies of New Cytisine Derivatives, as Ligands for Neuronal Nicotinic Acetylcholine Receptor Subtype", 《J. MED. CHEM.》 * |
PETER IMMING ET AL.: "Syntheses and evaluation of halogenated cytisine derivatives and of bioisosteric thiocytisine as potent and selective nAChR ligands", 《EUR. J. MED. CHEM.》 * |
REGESRY: "1360070-70-7", 《STN COLUMBUS》 * |
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