CN110964032B - 毛栲利素硫化氢供体衍生物及其制备方法和用途 - Google Patents
毛栲利素硫化氢供体衍生物及其制备方法和用途 Download PDFInfo
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Abstract
本发明涉及天然药物及药物化学领域，涉及毛栲利素硫化氢供体衍生物及其制备方法和在抗肿瘤方面的用途。本发明所述的毛栲利素硫化氢供体衍生物及其药学上可接受的盐结构如下通式Ⅰ所示，其中，n1及n2如权利要求书和说明书中所述。
Description
技术领域
本发明涉及天然药物及药物化学领域，具体涉及毛栲利素硫化氢供体衍生物及其制备方法和在抗肿瘤方面的用途。本发明还公开了这些化合物的组合物及在制备抗肿瘤药物中的应用。
背景技术
从古至今，天然产物为疾病治愈和药物研发做出了极大的贡献，它们为新型药物的设计提供了宝贵思路，为新型药物的合成提供了丰富的结构骨架，为创新型药物提供了坚实的基础。
从唇形科(Labtea)香茶菜属(Rabdosia)植物中，人们发现了名为冬凌草甲素(oridonin)的对映贝壳杉烷二萜化合物。该化合物具有新颖的结构骨架、复杂的环系统以及手性中心，引起了人们的广泛关注。通过相关药理实验发现，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、诱导细胞调亡、抗突变以及β-受体阻断等作用。30年来随着对其研究的深入，国内外学者发现冬凌草甲素能够调控肿瘤细胞的细胞周期，使肿瘤细胞阻滞于某一细胞分裂期内而无法完成肿瘤细胞的异常增殖。此外还发现冬凌草甲素主要能够通过caspase途径和线粒体途径诱导肿瘤细胞的凋亡。
本发明以冬凌草甲素为先导化合物，设计并合成了1-位乙酰化冬凌草甲素(毛栲利素)14-位硫化氢供体衍生物，并测试了合成衍生物在抗肿瘤方面的生物活性。
发明内容
发明要解决的技术问题是寻找抗肿瘤活性好的毛栲利素硫化氢供体衍生物及其药学上可接受的盐，并进一步提供一种药物组合物。
为解决上述技术问题，本发明提供如下技术方案：
本发明所述的毛栲利素硫化氢供体衍生物及其药学上可接受的盐具有如Ⅰ的结构通式：
其中，n1、n2为1-8的整数。
优选地，n1、n2为2-6的整数。
优选地，n1为2-6的整数，n2为2-3的整数。
更优选地，n1为2、3或6；n2为2或3。
本发明还具体公开了结构如下所示的毛栲利素硫化氢供体衍生物及其药学上可接受的盐：
本发明的衍生物可用下列方法制备得到：
二硫杂环化合物5-(4-羟基苯基)-3H-1,2-二硫杂环戊烯-3-硫酮(ADT-OH，1)与溴代醇(2-溴乙醇、3-溴-1-丙醇、6-溴-1-己醇)反应，得到ADT-OH衍生物2a-c；
从冬凌草甲素3出发，经过7,14-位丙酮叉保护4，1-位乙酰化5，再脱去丙酮叉保护，得到1-O-乙酰基冬凌草甲素即毛栲利素6；
将毛栲利素6溶于二氯甲烷，依次加入三乙胺、DMAP和二酸酐(丁二酸酐或戊二酸酐)，室温反应得到相应的化合物7a及7b；
化合物7a或7b溶于二氯甲烷中，分别与ADT-OH衍生物2a-c经酯化反应得到目标化合物8a-f。
本发明进一步提供了一种药物组合物，包含所述的毛栲利素硫化氢供体衍生物及其药学上可接受的盐和药学上可接受的载体或赋形剂。
药理试验证明，本发明的毛栲利素硫化氢供体衍生物及其药学上可接受的盐或其药物组合物具有很好的抗肿瘤作用，可以用于进一步制备抗肿瘤药物。
具体实施方式：
实施例1
将45mg ADT-OH(0.2mmol)溶于无水丙酮中，加入43μL 2-溴乙醇(0.6mmol)、83mg碳酸钾(0.6mmol)，回流8h，反应完成后抽滤，滤液旋干硅胶柱层析(石油醚:乙酸乙酯＝4:1)得橘红色化合物2a。将冬凌草甲素145.6mg(0.4mmol)溶解于丙酮中，加入对甲苯磺酸(43.1mg,0.2mmol)，DMAP(30.5mg,0.2mmol)和2,2-二甲氧基丙烷(1.2mL)，TLC监测反应，反应完全后蒸干溶剂得到7,14-位丙酮叉保护冬凌草甲素型衍生物4，之后将其溶于二氯甲烷中，加入0.4mL三乙胺、0.6mL乙酸酐和催化量DMAP。TLC监测反应，反应完全后加入约20ml水，用二氯甲烷萃取三次，每次10ml，合并有机相，再用饱和食盐水洗两次，无水硫酸钠干燥，过滤、浓缩得带有丙酮叉保护的1-位乙酰化衍生物5。将其溶于四氢呋喃中，加入10％盐酸溶液，室温搅拌2h。TLC监测反应，待反应完全后减压蒸除四氢呋喃，加入约15ml水，用二氯甲烷萃取三次，每次10ml，合并有机相，再用饱和食盐水洗两次，无水硫酸钠干燥，过滤、浓缩，硅胶柱层析(二氯甲烷:甲醇＝60:1)得1-O-乙酰基冬凌草甲素即毛栲利素6。将82.2mg 1-位乙酰化冬凌草甲素衍生物6(0.2mmol)溶于6ml无水二氯甲烷中，加入40mg丁二酸酐(0.40mmol)、139μL三乙胺(1.0mmol)、催化量的DMAP，室温搅拌8h。TLC监测反应，待反应完全或不继续进行时，停止反应。水洗后分液，有机相用饱和食盐水洗，再用无水硫酸钠干燥、过滤、浓缩得化合物7a。将59.1mg化合物7a(0.12mmol)溶于无水二氯甲烷中，依次加入EDCI(69.0mg，0.36mmol)、催化量DMAP以及ADT-OH衍生物2a(32.4mg，0.12mmol)，室温搅拌10h。TLC监测反应，待反应完全后加入约15ml水，用二氯甲烷萃取三次，每次10ml，合并有机相，再用饱和食盐水洗两次，无水硫酸钠干燥，过滤、浓缩，硅胶柱层析(二氯甲烷:甲醇＝200:1)得橘红色目标化合物8a，产率38.8％。1H NMR(CDCl3,400MHz),δ(ppm):7.63,7.00(each 2H,d,JA＝JB＝8.6Hz,Ar-H),7.40(1H,s,8”-CH),6.16(1H,s,17-CH2),6.07(1H,d,J＝10.8Hz,6-OH),5.88(1H,s,14-CH),5.53(1H,s,17-CH2),4.62(1H,dd,J＝11.2,5.5Hz,1-CH),4.46(2H,m,5'-CH2),4.28,4.18(each 1H,d,JA＝JB＝10.6Hz,20-CH2),4.23(2H,t,J＝4.6Hz,6'-CH2),3.77(1H,m,6-CH),3.14(1H,d,J＝9.2Hz,13-CH),2.65(2H,m,2'-CH2),2.61(4H,m,-CH2),2.00(3H,s,-CH3),1.13(6H,s,18,19-CH3)；13C NMR(CDCl3,100MHz),δ(ppm):215.42,206.31,171.93,170.86,169.84,161.69,149.44,134.82,128.63(×2),124.69,120.64,115.58(×2),95.92,76.07,75.94,75.38,74.19,66.10,63.53,62.78,61.63,59.98,53.79,41.14,39.75,38.15,33.57,32.44,30.24,29.70,29.51,28.78,25.16,21.62,21.53,18.10；HRMS(ESI)m/z calcd for C37H42O11S3[M-H]-757.1811,found757.1839。
实施例2
参照实施例1的合成方法制备得化合物8b，橘红色固体,产率39.0％。1H NMR(CDCl3,400MHz),δ(ppm):7.62,6.98(each 2H,d,JA＝JB＝8.6Hz,Ar-H),7.40(1H,s,8”-CH),6.15(1H,s,17-CH2),6.08(1H,d,J＝10.8Hz,6-OH),5.88(1H,s,14-CH),5.52(1H,s,17-CH2),4.62(1H,dd,J＝11.2,5.4Hz,1-CH),4.28(3H,m,20-CH2,5'-CH2),4.18(1H,d,J＝10.6Hz,20-CH2),4.10(2H,t,J＝6.0Hz,7'-CH2),3.78(1H,m,6-CH),3.14(1H,d,J＝9.9Hz,13-CH),2.61(2H,m,2'-CH2),2.15(2H,m,3'-CH2),1.99(3H,s,-CH3),1.47(2H,m,-CH2),1.13(6H,s,18,19-CH3)；13C NMR(CDCl3,100M Hz),δ(ppm):215.15,206.07,172.96,171.95,170.92,169.83,162.09,149.44,134.67,128.62(×2),124.32,120.63,115.47(×2),95.92,75.96,75.37,74.16,64.80,63.53,61.62,61.48,59.98,53.78,41.12,39.75,38.14,33.56,32.43,30.24,29.70,29.54,28.83,28.40,25.16,21.61,21.53,18.08；HRMS(ESI)m/z calcd for C38H44O11S3[M-H]-771.1968,found 771.1999。
实施例3
参照实施例1的合成方法制备得化合物8c，橘红色固体,产率29.6％。1H NMR(CDCl3,400MHz),δ(ppm):7.61,6.96(each 2H,d,JA＝JB＝8.9Hz,Ar-H),7.40(1H,s,8”-CH),6.16(1H,s,17-CH2),6.09(1H,d,J＝10.5Hz,6-OH),5.88(1H,s,14-CH),5.52(1H,s,17-CH2),4.62(1H,dd,J＝11.2,5.4Hz,1-CH),4.28,4.19(each 1H,d,JA＝JB＝10.6Hz,20-CH2),4.09(2H,m,5'-CH2),4.02(2H,t,J＝6.3Hz,10'-CH2),3.78(1H,m,6-CH),3.16(1H,d,J＝9.9Hz,13-CH),2.60(2H,m,2'-CH2),1.99(3H,s,-CH3),1.12(6H,s,18,19-CH3)；13C NMR(CDCl3,100MHz),δ(ppm):215.11,206.11,173.13,172.06,171.00,169.84,162.50,149.44,134.57,128.59(×2),124.01,120.58,115.44(×2),95.94,76.03,75.38,74.10,68.23,64.83,63.52,61.60,60.04,53.78,41.10,39.75,38.15,33.57,32.42,30.23,29.70,29.59,28.92,28.89,28.46,25.63,25.17,21.60,21.53,18.06；HRMS(ESI)m/zcalcd for C41H50O11S3[M-H]-813.2437,found 813.2459。
实施例4
参照实施例1的合成方法制备得化合物8d，橘红色固体,产率33.6％。1H NMR(CDCl3,400MHz),δ(ppm):7.63,7.00(each 2H,d,JA＝JB＝8.6Hz,Ar-H),7.40(1H,s,8”-CH),6.16(1H,s,17-CH2),6.05(1H,d,J＝10.5Hz,6-OH),5.84(1H,s,14-CH),5.50(1H,s,17-CH2),4.61(1H,dd,J＝11.1,5.4Hz,1-CH),4.44(2H,t,J＝4.7Hz,6'-CH2),4.27,4.18(each 1H,d,JA＝JB＝10.5Hz,20-CH2),4.23(2H,t,J＝4.8Hz,7'-CH2),4.07(1H,s,-OH),3.77(1H,m,6-CH),3.15(1H,d,J＝9.2Hz,13-CH),2.58-2.32(8H,m,-CH2),2.00(3H,s,-CH3),1.13(3H,s,-CH3),1.12(3H,s,-CH3)；13C NMR(CDCl3,100MHz),δ(ppm):215.22,206.06,172.52,171.34,169.86,161.72,149.42,134.83,128.66(×2),124.69,120.53,115.56(×2),96.03,77.20,76.06,75.37,74.03,66.15,63.55,62.42,61.56,60.07,53.76,41.12,39.77,38.15,33.57,33.45,32.87,32.40,30.24,29.69,25.17,21.53,19.74,18.04；HRMS(ESI)m/z calcd for C38H44O11S3[M-H]-771.1968,found 771.2000。
实施例5
参照实施例1的合成方法制备得化合物8e，橘红色固体,产率41.6％。1H NMR(CDCl3,400MHz),δ(ppm):7.62,6.98(each 2H,d,JA＝JB＝8.6Hz,Ar-H),7.40(1H,s,8”-CH),6.15(1H,s,17-CH2),6.06(1H,d,J＝10.5Hz,6-OH),5.84(1H,s,14-CH),5.51(1H,s,17-CH2),4.63(1H,dd,J＝11.2,5.5Hz,1-CH),4.28(2H,t,J＝6.3Hz,6'-CH2),4.26(1H,m,20-CH2),4.19(1H,d,J＝10.6Hz,20-CH2),4.10(2H,t,J＝6.1Hz,8'-CH2),3.77(1H,dd,J＝10.3,6.6Hz,6-CH),3.15(1H,d,J＝9.2Hz,13-CH),2.35(4H,m,-CH2),2.14,1.91(each 2H,m,2'-CH2,4'-CH2),2.00(3H,s,-CH3),1.12(6H,s,18,19-CH3)；13C NMR(CDCl3,100MHz),δ(ppm):215.17,206.07,172.98,172.59,171.34,169.84,162.10,149.42,134.69,128.63(×2),124.32,120.53,115.47(×2),96.03,76.08,75.36,74.02,64.79,63.56,61.56,61.08,60.07,53.76,41.12,39.77,38.14,33.56,32.99,32.41,30.24,29.69,28.45,25.17,21.58,21.53,19.78,18.04；HRMS(ESI)m/z calcd for C39H46O11S3[M-H]-785.2124,found 785.2172。
实施例6
参照实施例1的合成方法制备得化合物8f，橘红色固体,产率33.4％。1H NMR(CDCl3,400MHz),δ(ppm):7.61,6.96(each 2H,d,JA＝JB＝8.6Hz,Ar-H),7.40(1H,s,8”-CH),6.15(1H,s,17-CH2),6.10(1H,d,J＝10.5Hz,6-OH),5.84(1H,s,14-CH),5.51(1H,s,17-CH2),4.63(1H,dd,J＝11.2,5.5Hz,1-CH),4.28,4.18(each 1H,d,JA＝JB＝10.6Hz,20-CH2),4.07(2H,t,J＝6.7Hz,6'-CH2),4.02(2H,t,J＝6.4Hz,11'-CH2),3.78(1H,dd,J＝10.2,6.6Hz,6-CH),3.16(1H,d,J＝9.9Hz,13-CH),2.39-2.30(4H,m,-CH2),2.00(3H,s,-CH3),1.91(2H,m,2'-CH2),1.83(2H,m,4'-CH2),1.13(6H,s,18,19-CH3)；13C NMR(CDCl3,100M Hz),δ(ppm):215.27,206.13,173.12,172.73,171.43,169.85,162.51,149.43,134.58,128.58(×2),124.01,120.49,115.45(×2),96.03,76.10,75.37,73.97,68.24,64.44,63.54,61.56,60.12,53.75,41.12,39.77,38.15,33.57(×2),33.07,32.39,30.23,29.69(×2),28.92,28.51,25.64(×2),25.17,21.56,19.84,18.03；HRMS(ESI)m/z calcdfor C42H52O11S3[M-H]-827.2594,found 827.2588。
下面是本发明部分化合物的药理实验结果：
实验设备与试剂
仪器 超净工作台(苏净集团安泰公司)
恒温培养箱(Thermo electron Corporation)
酶标仪(BIO-RAD公司)
倒置生物显微镜(重庆光学仪器厂)
试剂 细胞培养基RPMI-1640、DMEM(高糖)(GIBCO公司)
胎牛血清(杭州四季清有限公司)
MTT(Biosharp公司产品)
台盼蓝(Solarbio公司产品)
DMSO(Sigma公司)
细胞株 人肝癌细胞HepG2、人乳腺癌细胞MCF-7、人结肠癌细胞HCT-116、黑色素瘤细胞MV3或B16、人慢性髓系白血病细胞K562、人正常肝细胞L-02、外周血单个核细胞PMBC
实验方法
细胞抑制活性实验方法
细胞在37℃、5％CO2饱和湿度的培养箱中常规培养。培养液为含10％热灭活胎牛血清，青霉素100U/mL和链霉素100U/mL的RPMI1640细胞培养基。48h更换培养液，细胞贴壁后，用0.25％胰蛋白酶消化传代。实验用细胞均处于对数生长期，台盼蓝拒染法表明细胞活力>95％。
取处于对数生长期状态良好的细胞一瓶，加入消化液(0.125％胰蛋白酶+0.01％EDTA)消化，计数2～4×104cell/mL，制成细胞悬液接种于96孔板上，100μL/孔，置恒温CO2培养箱中培养24小时。换液，加入不同浓度受试药物(100μL/孔)，培养72小时。将MTT溶液加入96孔板中，50μL/孔，培养箱中孵育4小时。吸去上清液，加入DMSO(200μL/孔)，置平板摇床上低速震荡10分钟。受试物考察3个浓度(0.25μM，0.5μM，1μM)，用酶联免疫监测仪在波长为490nm处测定每孔的吸光度，分别计算各浓度下的细胞抑制率。
抑制率计算方法：
药敏孔相对OD值＝药敏孔绝对OD值﹣空白对照孔绝对OD值
实验结果
表1实施例对6种人类癌细胞株和2种人类正常细胞抗增殖活性的IC50值(μM)
药理试验证明，本发明的目标衍生物具有更好的抗肿瘤细胞增殖活性，并且对肿瘤细胞和正常细胞具有一定的选择性，可以用于进一步制备抗肿瘤药物。
Claims (8)
1.通式Ⅰ所示的毛栲利素硫化氢供体衍生物及其药学上可接受的盐：
其中，n1、n2为2-6的整数。
2.权利要求1所述的毛栲利素硫化氢供体衍生物及其药学上可接受的盐：
其中，n1为2-6的整数，n2为2-3的整数。
3.毛栲利素硫化氢供体衍生物及其药学上可接受的盐，选自：
4.一种药物组合物，含有治疗有效量的权利要求1-3任何一项所述的衍生物及其药学上可接受的盐和药学上可接受的载体。
5.如权利要求1所述的通式Ⅰ所示的毛栲利素硫化氢供体衍生物及其药学上可接受的盐的制备方法，其特征在于：
（1）二硫杂环化合物5-对羟基苯基-3H-1,2-二硫杂环戊烯-3-硫酮与溴代醇反应，得到ADT-OH衍生物2；
（2）从冬凌草甲素3出发，经过7,14-位丙酮叉保护4，1-位乙酰化5，再脱去丙酮叉保护，得到1-O-乙酰基冬凌草甲素即毛栲利素6；
（3）将毛栲利素6溶于二氯甲烷，依次加入三乙胺、DMAP和二酸酐，室温反应得到相应的化合物7；
（4）化合物7溶于二氯甲烷中，分别与ADT-OH衍生物2a-c经酯化反应得到目标化合物8；
其中，n1、n2如权利要求1所述。
6.权利要求1-3任何一项所述的毛栲利素硫化氢供体衍生物及其药学上可接受的盐在制备治疗肿瘤疾病的药物中的应用。
7.权利要求4所述的药物组合物在制备治疗肿瘤疾病的药物中的应用。
8.如权利要求6或7所述的应用，其特征在于，所述的肿瘤为肝癌、乳腺癌、结肠癌、黑色素瘤或白血病。
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