CN110627833B - 一种冬凌草甲素衍生物及其制备和应用 - Google Patents
一种冬凌草甲素衍生物及其制备和应用 Download PDFInfo
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Abstract
本发明公开了一种冬凌草甲素衍生物。本发明的冬凌草甲素衍生物具有抗癌作用，可作为抗肿瘤药物应用。本发明公开了其制法。
Description
技术领域
本发明涉及冬凌草甲素的衍生物及其在制药中的应用，属于医药技术领域。
背景技术
冬凌草甲素具有抗细胞增殖、抑制癌细胞DNA、RNA和蛋白质的合成、诱导细胞凋亡、抗突变和β-受体阻断等作用，对多种癌症如食管癌、胃癌、肝癌、肺癌、鼻咽癌、结肠癌、膀胱癌、***和白血病均具有一定治疗作用。但抗癌活性尚不突出，存在很大的改进空间。
氮芥类药物抗癌活性显著，但有一定的毒性。罗氏公司用拼合方法将苯丁酸氮芥与***龙拼合成泼尼莫司汀，成功提高了对***癌的选择性，同时降低了苯丁酸氮芥的毒性。因此，拼合方法是发现疗效好的新药的重要途径。文献报道含有磷酰二胺结构的化合物代谢后的代谢物，有杀灭癌细胞的作用(J.Med.Chem.2002,45,3540.)。因此，本发明将具有抗癌活性的氮芥和亚乙基亚胺片段以磷酰二胺结构形式引入到冬凌草甲素分子中，制备了所述的冬凌草甲素衍生物，以期获得疗效好的抗癌药物。
发明内容
本发明的目的在于提供一种冬凌草甲素衍生物，其具有较好的抗癌活性。
本发明的另一目的在于提供上述冬凌草甲素衍生物的制备方法。
本发明的再一目的在于提供上述冬凌草甲素衍生物的用途。
以下对本发明进行详细描述。
本发明提供的一种冬凌草甲素衍生物，结构如下所示：
式中，R独立为H,CH2CH2Cl，但不同时为H；或者两个R共同形成CH2CH2；X独立为O,S。
所述的冬凌草甲素衍生物为：
本发明还提供了上述化合物的制备方法，如下式所示：
式中，R独立为H,CH2CH2Cl，但不同时为H；或者两个R共同形成CH2CH2；X独立为O,S。
本发明的冬凌草甲素衍生物能在制备抗癌药物中应用。
通过以下实施例进一步举例说明本发明，但应注意本发明的范围并不受这些实施例的任何限制。
具体实施方式
实施例1
化合物(1)的制备
将1g(2.72mmol)冬凌草甲素、40mL丙酮、40mg TsOH和6mL 2,2-二甲氧基丙烷混合，室温搅拌2h，减压蒸除丙酮，加入水30mL稀释，二氯甲烷萃取(3×30mL)，有机层依次用NaHCO3溶液、饱和食盐水洗涤，Na2SO4干燥，过滤，冷至0℃，然后慢慢加入511mg(5.06mmol)Et3N和348mg(3.03mmol)MsCl，室温搅拌过夜，加水20mL稀释，二氯甲烷萃取(3×25mL)，有机层依次用NaHCO3溶液、饱和食盐水洗涤，Na2SO4干燥，浓缩，柱层析纯化(乙酸乙酯：正己烷1:1)，得到中间体(I)，收率80％。
将68mg(0.14mmol)中间体(I)溶于10mL DMF中，加入36mg(0.42mmol)LiBr和30mg(0.42mmol)Li2CO3，在115℃反应2h,加入15mL水，EtOAc萃取(3×20mL)，有机层依次用NaHCO3溶液、饱和食盐水洗涤，Na2SO4干燥，浓缩，柱层析纯化(乙酸乙酯：正己烷1:4)，得到中间体(II)，收率84％。HPLC纯度99.8％(t R＝18.30min).1H NMR(400MHz,CDCl 3)δ6.16(s,1H),5.78(m,1H),5.56(s,1H),5.42(d,1H,J＝12.0Hz),5.19(dd,1H,J＝3.0Hz,10.2Hz),4.82(s,1H),3.99(d,1H,J＝10.2Hz),3.91(dd,1H,J＝8.4Hz,12.0Hz),3.81(d,1H,J＝9.6Hz),3.06(d,1H,J＝9.0Hz),2.53(m,1H),1.95(d,1H,J＝17.4Hz),1.76(m,4H),1.65(s,3H),1.56(m,1H),1.51(d,1H,J＝8.4Hz),1.35(s,3H),1.19(s,3H),1.04(s,3H)；HRMS Calcd for C23H31O5:[M+H]+387.2166；found 387.2168.
将38.6mg(0.1mmol)中间体(II)加入到10mL乙醇中，搅拌，冷却至0℃，加入23.7mg(0.15mmol)KMnO4与40mL水的溶液和0.5mg四丁基溴化铵,用4.8mg(0.12mmol)NaOH控制反应体系pH﹥12，反应4小时，过滤，蒸除乙醇，乙酸乙酯提取(3х10mL),干燥，浓缩，柱层析纯化，得到中间体(III)，收率46％。
中间体(III)溶于THF中，加入5％的HCl溶液，室温搅拌2h，蒸干，纯化，得到中间体(IV)，收率98％。
将0.45g(0.011mol)乙撑亚胺和1.11g(0.011mol)Et3N或3.89g(0.022mol)氮芥盐酸盐和2.22g(0.022mol)Et3N或0.87g(0.011mol)2-氯乙胺盐酸盐和2.22g(0.022mol)Et3N分别溶于15mL二氯甲烷中，冷至0℃，分别滴加1.52g(0.01mol)的POCl3或1.68g(0.01mol)的PSCl3与5mL二氯甲烷的溶液，滴加完毕，室温反应3小时，过滤，浓缩，减压蒸馏，分别得到乙撑亚胺磷酰二氯，乙撑亚胺硫磷酰二氯，氮芥磷酰二氯，氮芥硫磷酰二氯，2-氯乙胺磷酰二氯和2-氯乙胺硫磷酰二氯，收率依次分别为79％，81％，85％，84％，77％和78％。
将43.5mg(0.1mmol)中间体(III)溶于溶于10mL二氯甲烷中，加入22.2mg(0.22mmol)Et3N，冷至0℃，滴加28.3mg(0.11mmol)的氮芥磷酰二氯与5mL二氯甲烷的溶液，滴加完毕，室温反应7小时，过滤，滤液加入2mL5％的HCl溶液，室温搅拌2h，浓缩，柱层析纯化，得到化合物(1)，收率81％。1H NMR(400MHz,CDCl 3)δ6.17(s,1H),5.90(d,J＝11Hz,1H),5.55(s,1H),5.53(s,1H),5.46(s,1H),4.83(s,1H),4.33(d,J＝9.9Hz,1H),3.89(dd,J＝10.4,8.0Hz,1H),3.86(d,J＝9.9Hz,1H),3.68(m,4H),3.55(m,4H),3.48(d,J＝9.6Hz,1H),3.19(d,J＝9.0Hz,1H),3.07(m,1H),3.02(d,J＝9.2Hz,1H),2.39(m,1H),2.04(m,1H),1.78(m,2H),1.49(m,2H),1.17(s,6H)；MS(ESI)m/z:Calcd for C24H34Cl2NO8P:[M+H]+566.1；found 566.0.
实施例2
化合物(2)的制备
将38.1mg(0.1mmol)中间体(IV)溶于10mL二氯甲烷中，加入44.4mg(0.44mmol)Et3N，冷至0℃，滴加56.6mg(0.22mmol)的氮芥磷酰二氯与6mL二氯甲烷的溶液，滴加完毕，室温反应7小时，过滤，浓缩，柱层析纯化，制得化合物(2)，收率87％。1H NMR(400MHz,CDCl3)δ6.16(s,1H),5.89(d,J＝11Hz,1H),5.56(s,1H),4.83(s,1H),4.33(d,J＝9.9Hz,1H),3.89(dd,J＝10.4,8.0Hz,1H),3.86(d,J＝9.9Hz,1H),3.67(m,8H),3.54(m,8H),3.46(d,J＝9.6Hz,1H),3.21(d,J＝9.0Hz,1H),3.07(m,1H),3.02(d,J＝9.2Hz,1H),2.39(m,1H),2.03(m,1H),1.78(m,2H),1.49(m,2H),1.16(s,6H)；MS(ESI)m/z:Calcd forC28H40Cl4N2O9P2:[M+H]+751.1；found 751.3.
实施例3
化合物(3)的制备
用27.3mg(0.11mmol)的氮芥硫磷酰二氯代替28.3mg(0.11mmol)的氮芥磷酰二氯，其它操作同实施例1，制得化合物(3)，收率83％。1H NMR(400MHz,CDCl3)δ6.16(s,1H),5.89(d,J＝11Hz,1H),5.54(s,1H),5.52(s,1H),5.46(s,1H),4.83(s,1H),4.33(d,J＝9.9Hz,1H),3.89(dd,J＝10.4,8.0Hz,1H),3.86(d,J＝9.9Hz,1H),3.65(m,4H),3.57(m,4H),3.28(d,J＝9.6Hz,1H),3.09(d,J＝9.0Hz,1H),3.07(m,1H),3.02(d,J＝9.2Hz,1H),2.39(m,1H),2.05(m,1H),1.79(m,2H),1.49(m,2H),1.17(s,6H)；MS(ESI)m/z:Calcd forC24H34Cl2NO7PS:[M+H]+582.1；found 581.9.
实施例4
化合物(4)的制备
用54.6mg(0.22mmol)氮芥硫磷酰二氯代替56.6mg(0.22mmol)氮芥磷酰二氯，其它操作同实施例2，制得化合物(4)，收率84％。1H NMR(400MHz,CDCl3)δ6.17(s,1H),5.89(d,J＝11Hz,1H),5.56(s,1H),4.83(s,1H),4.33(d,J＝9.9Hz,1H),3.89(dd,J＝10.4,8.0Hz,1H),3.86(d,J＝9.9Hz,1H),3.66(m,8H),3.53(m,8H),3.28(d,J＝9.6Hz,1H),3.09(d,J＝9.0Hz,1H),3.07(m,1H),3.02(d,J＝9.2Hz,1H),2.39(m,1H),2.03(m,1H),1.78(m,2H),1.49(m,2H),1.17(s,6H)；MS(ESI)m/z:Calcd for C28H40Cl4N2O7P2S2:[M+H]+783.0；found783.3.
实施例5
化合物(5)的制备
用21.5mg(0.11mmol)2-氯乙胺磷酰二氯代替28.3mg(0.11mmol)的氮芥磷酰二氯，其它操作同实施例1，制得化合物(5)，收率80％。1H NMR(400MHz,CDCl3)δ6.16(s,1H),5.90(d,J＝11Hz,1H),5.54(s,1H),5.53(s,1H),5.46(s,1H),4.83(s,1H),4.33(d,J＝9.9Hz,1H),3.89(dd,J＝10.4,8.0Hz,1H),3.86(d,J＝9.9Hz,1H),3.70(m,2H),3.61(m,2H),3.28(d,J＝9.6Hz,1H),3.09(d,J＝9.0Hz,1H),3.07(m,1H),3.02(d,J＝9.2Hz,1H),2.39(m,1H),2.04(m,1H),1.78(m,2H),1.49(m,2H),1.17(s,6H)；MS(ESI)m/z:Calcd forC22H31ClNO8P:[M+H]+504.2；found504.0.
实施例6
化合物(6)的制备
用43.0mg(0.22mmol)2-氯乙胺磷酰二氯代替56.6mg(0.22mmol)氮芥磷酰二氯，其它操作同实施例2，制得化合物(6)，收率85％。1H NMR(400MHz,CDCl3)δ6.16(s,1H),5.89(d,J＝11Hz,1H),5.56(s,1H),4.83(s,1H),4.33(d,J＝9.9Hz,1H),3.89(dd,J＝10.4,8.0Hz,1H),3.86(d,J＝9.9Hz,1H),3.71(m,4H),3.64(m,4H),3.28(d,J＝9.6Hz,1H),3.09(d,J＝9.0Hz,1H),3.07(m,1H),3.02(d,J＝9.2Hz,1H),2.39(m,1H),2.03(m,1H),1.78(m,2H),1.49(m,2H),1.16(s,6H)；MS(ESI)m/z:Calcd for C24H34Cl2N2O9P2:[M+H]+627.1；found627.0.
实施例7
化合物(7)的制备
用17.5mg(0.11mmol)乙撑亚胺磷酰二氯代替28.3mg(0.11mmol)的氮芥磷酰二氯，其它操作同实施例1，制得化合物(7)，收率78％。1H NMR(400MHz,CDCl 3)δ6.17(s,1H),5.90(d,J＝11Hz,1H),5.55(s,1H),5.53(s,1H),5.46(s,1H),4.83(s,1H),4.33(d,J＝9.9Hz,1H),3.89(dd,J＝10.4,8.0Hz,1H),3.86(d,J＝9.9Hz,1H),3.28(d,J＝9.6Hz,1H),3.09(d,J＝9.0Hz,1H),3.07(m,1H),3.02(d,J＝9.2Hz,1H),2.39(m,1H),2.04(m,1H),1.78(m,2H),1.63(m,4H),1.49(m,2H),1.17(s,6H)；MS(ESI)m/z:Calcd for C22H30NO8P:[M+H]+468.1；found 468.1.
实施例8
化合物(8)的制备
用35.0mg(0.22mmol)乙撑亚胺磷酰二氯代替56.6mg(0.22mmol)氮芥磷酰二氯，其它操作同实施例2，制得化合物(8)，收率84％。1H NMR(400MHz,CDCl3)δ6.17(s,1H),5.89(d,J＝11Hz,1H),5.56(s,1H),4.83(s,1H),4.33(d,J＝9.9Hz,1H),3.89(dd,J＝10.4,8.0Hz,1H),3.86(d,J＝9.9Hz,1H),3.28(d,J＝9.6Hz,1H),3.09(d,J＝9.0Hz,1H),3.07(m,1H),3.02(d,J＝9.2Hz,1H),2.39(m,1H),2.03(m,1H),1.78(m,2H),1.64(m,8H),1.49(m,2H),1.16(s,6H)；MS(ESI)m/z:Calcd for C24H32N2O9P2:[M+H]+555.1；found 555.2.
实施例9
化合物(9)的制备
用17.5mg(0.11mmol)乙撑亚胺磷酰二氯代替27.3mg(0.11mmol)的氮芥硫磷酰二氯代替，其它操作同实施例3，制得化合物(9)，收率84％。1H NMR(400MHz,CDCl 3)δ6.17(s,1H),5.89(d,J＝11Hz,1H),5.54(s,1H),5.52(s,1H),5.46(s,1H),4.83(s,1H),4.33(d,J＝9.9Hz,1H),3.89(dd,J＝10.4,8.0Hz,1H),3.86(d,J＝9.9Hz,1H),3.28(d,J＝9.6Hz,1H),3.09(d,J＝9.0Hz,1H),3.07(m,1H),3.02(d,J＝9.2Hz,1H),2.39(m,1H),2.05(m,1H),1.79(m,2H),1.63(m,4H),1.49(m,2H),1.17(s,6H)；MS(ESI)m/z:Calcd for C22H30NO7PS:[M+H]+484.1；found484.2.
实施例10
化合物(10)的制备
用23.2mg(0.11mmol)2-氯乙胺硫磷酰二氯代替21.5mg(0.11mmol)2-氯乙胺磷酰二氯，其它操作同实施例6，制得化合物(10)，收率83％。1H NMR(400MHz,CDCl 3)δ6.17(s,1H),5.89(d,J＝11Hz,1H),5.56(s,1H),4.83(s,1H),4.33(d,J＝9.9Hz,1H),3.89(dd,J＝10.4,8.0Hz,1H),3.86(d,J＝9.9Hz,1H),3.78(m,4H),3.65(m,4H),3.28(d,J＝9.6Hz,1H),3.09(d,J＝9.0Hz,1H),3.07(m,1H),3.02(d,J＝9.2Hz,1H),2.39(m,1H),2.03(m,1H),1.75(m,2H),1.46(m,2H),1.16(s,6H)；MS(ESI)m/z:Calcd for C22H31ClNO7PS:[M+H]+520.1；found 520.2.
实施例11
化合物(11)的制备
用46.4mg(0.22mmol)2-氯乙胺硫磷酰二氯代替56.6mg(0.22mmol)氮芥磷酰二氯，其它操作同实施例2，制得化合物(11)，收率84％。1H NMR(400MHz,CDCl3)δ6.17(s,1H),5.89(d,J＝11Hz,1H),5.56(s,1H),4.83(s,1H),4.33(d,J＝9.9Hz,1H),3.89(dd,J＝10.4,8.0Hz,1H),3.86(d,J＝9.9Hz,1H),3.28(d,J＝9.6Hz,1H),3.09(d,J＝9.0Hz,1H),3.07(m,1H),3.02(d,J＝9.2Hz,1H),2.39(m,1H),2.03(m,1H),1.77(m,4H),1.46(m,4H),1.16(s,6H)；MS(ESI)m/z:Calcd for C24H34Cl2N2O7P2S2:[M+H]+659.1；found 659.1.
实施例12
化合物(12)的制备
用38.5mg(0.22mmol)乙撑亚胺硫磷酰二氯代替35.0mg(0.22mmol)乙撑亚胺磷酰二氯，其它操作同实施例8，制得化合物(12)，收率86％。1H NMR(400MHz,CDCl 3)δ6.17(s,1H),5.89(d,J＝11Hz,1H),5.56(s,1H),4.83(s,1H),4.33(d,J＝9.9Hz,1H),3.89(dd,J＝10.4,8.0Hz,1H),3.86(d,J＝9.9Hz,1H),3.28(d,J＝9.6Hz,1H),3.09(d,J＝9.0Hz,1H),3.07(m,1H),3.02(d,J＝9.2Hz,1H),2.39(m,1H),2.03(m,1H),1.78(m,2H),1.62(m,8H),1.49(m,2H),1.16(s,6H)；MS(ESI)m/z:Calcd for C24H32N2O7P2 S2:[M+H]+587.1；found587.0.
实施例13
冬凌草甲素衍生物的体外抗肿瘤活性
细胞株采用人白血病细胞K526、乳腺癌细胞MCF-7、人肝癌细胞BEL7402、人胃癌细胞MGC-803、***细胞Hela和人肺癌细胞A549。
六种细胞分别经消化、计数制成浓度为5x104个/mL的细胞悬液。96孔板中每孔加入100μL细胞悬液(每孔5x103个细胞)，置于37℃，5％CO2培养箱中培养24h，用培养基稀释药物至所需浓度(浓度10μmol/L)，每孔加100μL相应含药培养基，同时设阴性对照组和阳性对照组。然后，96孔板置于37℃，5％CO2培养箱中培养72h，每孔加入20μLMTT(5mg/mL)染色，继续培养4h，弃去培养基，每孔加150μLDMSO溶解，λ＝490nm测OD值，计算IC50值(表1)。
表1冬凌草甲素衍生物抗肿瘤活性
Claims (4)
1.一种冬凌草甲素衍生物，如下式所示：
式中，R独立为H,CH2CH2Cl，但不同时为H；或者两个R共同形成CH2CH2；X独立为O,S。
2.根据权利要求1所述的冬凌草甲素衍生物，其特征在于：所述衍生物为：
3.根据权利要求1所述的冬凌草甲素衍生物，其制备方法包括以下步骤：
式中，R独立为H,CH2CH2Cl，但不同时为H；或者两个R共同形成CH2CH2；
X独立为O,S。
4.根据权利要求1所述的冬凌草甲素衍生物在制备抗癌药物中的应用。
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| CN104188988A (zh) * | 2014-08-18 | 2014-12-10 | 深圳市健元医药科技有限公司 | 冬凌草甲素衍生物注射剂及其制备 |
| CN106866695A (zh) * | 2017-02-22 | 2017-06-20 | 石家庄学院 | 冬凌草甲素衍生物及其制备和应用 |
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| CN104188988A (zh) * | 2014-08-18 | 2014-12-10 | 深圳市健元医药科技有限公司 | 冬凌草甲素衍生物注射剂及其制备 |
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