CN117986205A - 一种异甜菊醇衍生物及其制备方法和应用 - Google Patents
一种异甜菊醇衍生物及其制备方法和应用 Download PDFInfo
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- CN117986205A CN117986205A CN202410244464.0A CN202410244464A CN117986205A CN 117986205 A CN117986205 A CN 117986205A CN 202410244464 A CN202410244464 A CN 202410244464A CN 117986205 A CN117986205 A CN 117986205A
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- dichloromethane
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Abstract
本发明公开了一种异甜菊醇衍生物及其制备方法和应用;旨在提供一种具有心脏保护活性的异甜菊醇衍生物;其对异甜菊醇的C‑19位进行改造,利用哌嗪环将19位羧基酰胺化后,进一步连接脂肪酸、芳香酸以及苯环片段得到全新的异甜菊醇衍生物,具有良好的心脏保护活性,可用于制备心脏保护药物;本发明涉及医药技术、药物化学及细胞生物学技术领域。
Description
技术领域
本发明涉及医药技术,药物化学及细胞生物学技术领域,具体涉及一种异甜菊醇衍生物,本发明还涉及该异甜菊醇衍生物的制备方法和应用。
背景技术
针对急性心肌梗死的药物研发和治疗靶点的探索具有极其重要的研究价值,积极开展心脏保护药物的研发工作为重中之重。
天然产物是药物研发过程中的宝贵资源,其结构及结构类似物在研发和疾病治疗中做出极大贡献。异甜菊醇(isosteviol)由甜菊糖苷(steviolside)酸性条件下水解,经过Wagner-Meerwein重排而来的,属于对映贝壳杉烷型四环二萜类化合物。异甜菊醇具有广泛的生物活性,如抗肿瘤、抗病毒、抗菌、抗血栓、降血糖、心血管保护等。目前对于异甜菊醇的心脏保护活性的结构修饰并不多,因此针对心脏保护活性的新型异甜菊醇衍生物的开发具有重要科学意义和研究价值。
中国专利CN113105348A公开了一种异甜菊醇衍生物,其通过在isosteviol C-15位进行修饰得到的心机保护药物分子,药物使用浓度较高,结果不够理想。
发明内容
本发明的目的之一在于提供一种具有心脏保护活性的异甜菊醇衍生物。
本发明的目的之二在于提供异甜菊醇衍生物的制备方法。
本发明的目的之三在于提供异甜菊醇衍生物在制备心脏保护药物方面的应用。
为此,本发明提供的第一个技术方案为一种异甜菊醇衍生物,具有式1结构通式:
其中:R1为3-丙烯酸基、3-丁酸基、3-(3-甲基丁酸)基、2-(6-甲基苯甲酸)基、2-(5-甲基苯甲酸)基、2-(5-甲氧基苯甲酸)基、3-(2-萘甲酸)基、2-(环己-1-稀-1-羧酸)基、2-(环己-1-羧酸)基、2-(3-甲基环己-1-羧酸)基、2-(4-甲基环己-1-羧酸)基、2’-(2-苯基乙酸)基、苯基、4-(1-甲氧基苯)基、3-(1,2-二甲氧基苯)基、4-(1,2,3-三甲氧基苯)基、5-(1,2,3-三甲氧基苯)基、2-苯甲酸钠基的其中之一。
本发明提供的第二个技术方案是当式1中:当R1为3-丙烯酸基、3-丁酸基、3-(3-甲基丁酸)基、2-(6-甲基苯甲酸)基、2-(5-甲基苯甲酸)基、2-(5-甲氧基苯甲酸)基、3-(2-萘甲酸)基、2-(环己-1-稀-1-羧酸)基、2-(环己-1-羧酸)基、2-(3-甲基环己-1-羧酸)基、2-(4-甲基环己-1-羧酸)基、2’-(2-苯基乙酸)基、苯基、4-(1-甲氧基苯)基、3-(1,2-二甲氧基苯)基、4-(1,2,3-三甲氧基苯)基、5-(1,2,3-三甲氧基苯)基的其中之一时,异甜菊醇衍生物的制备方法,其具体包括下述步骤:
(1)化合物2的合成
将3.14mmol化合物1、62.8mmol草酰氯溶解在5ml二氯甲烷中,混合物在室温搅拌反应3h,旋蒸除去反应液,随后加入3.8mmol 1-Boc-哌嗪、15.7mmol三乙胺和5ml二氯甲烷,室温搅拌4h,TLC板检测进程至反应结束,加入乙酸乙酯和饱和食盐水的混合溶液进行萃取,收集有机层,在无水硫酸钠上干燥后浓缩,柱层析分离提纯,得到化合物2;
(2)化合物3的合成
将0.42mmol化合物1、0.84mmol三氟乙酸溶解在10ml二氯甲烷中,混合物在室温搅拌反应2h,TLC板检测进程至反应结束,加入二氯甲烷和饱和食盐水的混合溶液进行萃取,收集有机层,在无水硫酸钠上干燥后浓缩,柱层析分离提纯,得到化合物3;
(3)化合物4a-4l的合成
将0.43mmol化合物3、0.86mmol 4-二甲氨基吡啶、0.48mmol酸酐类化合物,溶解于2ml吡啶中,室温搅拌1h,TLC板检测进程至反应结束,用1N盐酸稀溶液中和,加入乙酸乙酯和饱和食盐水的混合溶液进行萃取,收集有机层,在无水硫酸钠上干燥后浓缩,柱层析分离提纯,得到化合物4a-4l;
(4)化合物4m-4q的合成
将0.43mmol化合物3、0.65mmol 1-乙基-3-(3-二甲基铵丙基)碳铵、0.52mmol 1-羟基苯并三唑、0.86mmol苯羧酸类化合物,溶解于5ml二氯甲烷中,室温搅拌4h,TLC板检测进程至反应结束,加入二氯甲烷和饱和食盐水的混合溶液进行萃取,收集有机层,在无水硫酸钠上干燥后浓缩,柱层析分离提纯,得到化合物4m-4q;
其合成路线如下:
进一步的,上述的酸酐类化合物为马来酸酐、甲基丁二酸酐、1,2-二甲基琥珀酸酐、3-甲基邻苯二甲酸酐、4-甲基邻苯二甲酸酐、4-甲氧基邻苯二甲酸酐、2,3-萘二甲酸酐、四氢邻苯二甲酸酐、六氢苯酐,3-甲基六氢苯二甲酯酐、4-甲基六氢苯二甲酯酐、高邻苯二甲酸酐的其中之一。
本发明提供的另一个方案是:当式1中R为2-苯甲酸钠基时,异甜菊醇衍生物的制备方法,包括下述步骤:
(1)化合物2的合成
将3.14mmol化合物1、62.8mmol草酰氯溶解在5ml二氯甲烷中,混合物在室温搅拌反应3h,旋蒸除去反应液,随后加入3.8mmol 1-Boc-哌嗪、15.7mmol三乙胺和5ml二氯甲烷,室温搅拌4h,TLC板检测进程至反应结束,加入适量乙酸乙酯和饱和食盐水的混合溶液进行萃取,收集有机层,在无水硫酸钠上干燥后浓缩,柱层析分离提纯,得到化合物2;
(2)化合物3的合成
将0.42mmol化合物1、0.84mmol三氟乙酸溶解在10ml二氯甲烷中,混合物在室温搅拌反应2h,TLC板检测进程至反应结束,加入适量二氯甲烷和饱和食盐水的混合溶液进行萃取,收集有机层,在无水硫酸钠上干燥后浓缩,柱层析分离提纯,得到化合物3;
(3)化合物5的合成
将0.43mmol化合物3、0.86mmol 4-二甲氨基吡啶、0.48mmol酸酐类化合物,溶解于2ml吡啶中,室温搅拌1h,TLC板检测进程至反应结束,用1N盐酸稀溶液中和,加入适量乙酸乙酯和饱和食盐水的混合溶液进行萃取,收集有机层,在无水硫酸钠上干燥后浓缩,柱层析分离提纯,得到化合物5;
(4)化合物6的合成
将0.19mmol化合物5、溶解在2.8ml丙酮中,混合物在80℃下回流搅拌15min,将76.1mg氢氧化钠溶解于1ml超纯水当中配成氢氧化钠水溶液,取0.1ml氢氧化钠水溶液缓慢滴加进入反应体系中,继续在80℃回流搅拌反应直到观察到大量沉淀析出,停止反应,冷却至室温,离心获得沉淀,用丙酮跟超纯水洗涤后烘干,得到化合物5;
其合成路线如下:
本发明提供的最后一个技术方案是上述的异甜菊醇衍生物在制备心脏保护活性药物中的应用。
本发明还提供一种心脏保护活性药物,包括第一个技术方案所述的异甜菊醇衍生物。
更优选的,所述药物还包括药学上可接受的辅料;所述药学上可接受的辅料为粘合剂、崩解剂、润滑剂、填充剂、表面活性剂、抗氧剂或pH调节剂中的至少一种。
所述药物的剂型为注射液、片剂、口服液、颗粒剂或胶囊。
与现有技术相比,本发明对异甜菊醇针对C-19位点进行修饰,包括利用哌嗪环将19位羧基酰胺化后,进一步连接脂肪酸、芳香酸以及苯环片段得到全新的异甜菊醇衍生物,可显著增加化合物的心脏保护活性;通过阿霉素诱导的斑马鱼心肌损伤模型体内评价化合物的心脏保护活性,发现该系列异甜菊醇衍生物可以用于治疗心肌损伤,显著改善阿霉素引起的斑马鱼形态学畸变和心功能损伤,通过降低细胞内活性氧含量,降低MDA、GSH水平,提高SOD活力,提高抗氧化损伤能力,阻止心肌细胞的损伤和死亡。
附图说明
图1为异甜菊醇衍生物对阿霉素诱导的斑马鱼胚胎存活率的影响。
图2为不同浓度的异甜菊醇衍生物对阿霉素诱导的斑马鱼胚胎存活率的影响和斑马鱼胚胎毒性试验。
图3为心脏保护活性优异的异甜菊醇衍生物对阿霉素诱导的斑马鱼胚胎心脏功能评价。
图4为心脏保护活性优异的异甜菊醇衍生物对阿霉素诱导的斑马鱼胚胎心肌病变生物标志物ANP、BNP和cTnT的相对mRNA水平的影响。
图5为化合物4r和化合物5对斑马鱼胚胎存活率、毒性、心脏功能评价、mRNA水平变化的影响
图6为化合物5对阿霉素诱导的H9C2细胞损伤、ANP、BNP和cTnT的相对mRNA水平变化的影响。
图7为化合物5对阿霉素诱导的H9C2细胞中ROS、MDA、GSH、SOD相对水平变化的影响。
具体实施方式
以下结合实施和附图进一步解释本发明,但实施并不对本发明做任何形式的限定。除非特别说明,本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。除非特别说明,本发明所用试剂和材料均为市购。
实施例1化合物4a-4r的合成
如合成路线1所示,以异甜菊醇为起始原料,在酰氯化后,在N,N-二乙基乙胺和二氯甲烷溶剂中与1-叔丁氧羰基哌嗪反应生成化合物2,然后在含三氟乙酸的二氯甲烷溶液中反应脱去Boc可得到化合物3,化合物3在4-二甲氨基吡啶和无水吡啶溶剂中与相对应的酸酐类化合物反应得到化合物4a-4l和4r,化合物3则在二氯甲烷溶剂中,1-乙基-3-(3-二甲基铵丙基)碳铵和1-羟基苯并三唑的催化作用下,与相对应的苯羧酸类化合物反应得到化合物4m-4q。
合成路线1中反应条件与试剂:(a)草酰氯,二氯甲烷,1-叔丁氧羰基哌嗪、三乙胺;(b)三氟乙酸,二氯甲烷;(c)4-二甲氨基吡啶,无水吡啶;(d)1-乙基-3-(3-二甲基铵丙基)碳铵,1-羟基苯并三唑,无水二氯甲烷。
具体步骤如下:
(1)化合物2的合成
将异甜菊醇(1045mg,3.14mmol)、草酰氯(5.3mL,62.8mmol)和无水二氯甲烷(5mL)分别加入50mL圆底烧瓶中室温搅拌活化3h。旋蒸除去反应液,反复加入二氯甲烷旋蒸以完全去除草酰氯。随后,加入1-Boc-哌嗪(701.8mg,3.8mmol)、三乙胺(2.18mL,15.7mmol)和无水二氯甲烷(5mL),室温搅拌4h,TLC板检测进程至反应结束,加入适量乙酸乙酯,再用饱和食盐水洗涤以去除无机物,用无水硫酸钠干燥后浓缩。利用硅胶柱对混合物进行分纯(正己烷:乙酸乙酯=9:1),得到白色固体化合物6(642mg,60%)。化合物2的结构、外观、核磁共振谱图数据以及高分辨质谱数据如下所示:
化合物2结构式如下:
化合物2:白色固体;mp 141.6-142.5℃;[α]25 D-9.5(c 0.7,CH3OH);1H NMR(CDCl3,400MHz)δ3.44-3.52(8H,m,19-CON(CH2CH2)2-N-),2.73(1H,dd,J=3.7,18.6Hz,H-15),2.31(1H,d,J=14Hz,H-3),1.46(9H,s,Boc),1.30(3H,s,H-18),0.97(3H,s,H-17),0.84(3H,s,H-20),2.12-0.84(18H,m,CH,CH2 in ent-beyerane skeleton);13C NMR(CDCl3,100MHz)δ222.7,176.6,154.7,80.1,61.9,56.1,54.4,48.7,48.7,48.5,48.5,46.2,45.8,43.7,42.5,40.8,39.7,39.6,38.6,37.3,28.4,28.4,28.4,28.0,22.5,20.4,19.9,19.8,16.1;HRMS(ESI,m/z)calcd for C29H46N2O4Na,509.3355[M+Na+];found,509.3305。
(2)化合物3的合成
将化合物2(203mg,0.42mmol)、三氟乙酸(11.3mL,0.84mmol)和无水二氯甲烷(10mL)加入反应瓶中,室温搅拌2h。TLC板检测进程至反应结束,旋蒸除去三氟乙酸,反复加入二氯甲烷旋蒸以完全去除三氟乙酸。加入适量二氯甲烷,再用饱和食盐水洗涤以去除无机物,用无水硫酸钠干燥后浓缩,使用硅胶板对混合物进行分纯(二氯甲烷:甲醇=9:1),得到白色固体化合物3(63mg,63%)。化合物3的结构、外观、比旋光度、核磁共振谱图数据以及高分辨质谱数据如下所示:
化合物3结构式如下:
化合物3:白色固体;mp 126.0-127.3℃;[α]25 D-32.9(c 1.2,CH3OH);1H NMR(CDCl3,400MHz)δ4.41(2H,s,19-CON(CH2CH2)2-N-),3.56(4H,d,J=14.7Hz,19-CON(CH2CH2)2-N-),2.84(3H,overlap,19-CON(CH2CH2)2-N-,H-15),2.66(1H,d,J=18.7Hz,H-3),1.23(3H,s,H-18),0.90(3H,s,H-17),0.77(3H,s,H-20),2.24-0.81(18H,m,CH,CH2inent-beyerane skeleton);13C NMR(CDCl3,100MHz)δ222.8,177.0,61.9,56.0,54.4,54.4,48.7,48.5,48.5,46.1,46.1,45.9,42.4,40.8,39.7,39.5,38.6,37.4,27.9,22.5,20.4,19.9,19.8,16.0;C24H38N2O2。
(3)化合物4a-4l、4r的合成
将化合物3(153,0.43mmol)、4-二甲氨基吡啶(105.1mg,0.86mmol)、相对应的酸酐化合物(0.50mmol)加入无水吡啶(2mL)中,室温搅拌1h。TLC板检测进程至反应结束,加入适量乙酸乙酯,用1N盐酸稀溶液中和,再加入饱和食盐水洗涤以去除无机物,用无水硫酸钠干燥后浓缩。利用硅胶柱对混合物进行分纯,分别得到纯产物4a-4l和4r中的其中一种;
其中:合成4a使用马来酸酐,4b使用甲基丁二酸酐,4c使用1,2-二甲基琥珀酸酐,4d使用3-甲基邻苯二甲酸酐,4e使用4-甲基邻苯二甲酸酐,4f使用4-甲氧基邻苯二甲酸酐,4g使用2,3-萘二甲酸酐,4h使用四氢邻苯二甲酸酐,4i使用六氢苯酐,4j使用3-甲基六氢苯二甲酯酐,4k使用4-甲基六氢苯二甲酯酐,4l使用高邻苯二甲酸酐,4r使用邻苯二甲酸酐。
化合物4a-4l、4r的结构、比旋光度、核磁共振谱图数据如下所示:
化合物4a结构式如下:
化合物4a:浅黄色油状;[α]25 D-13.9(c 1.3,CH3OH);1H NMR(CDCl3,400MHz)δ6.41(1H,d,J=11.9Hz,CO-CH),6.15(1H,d,J=12.2Hz,CH-COOH),3.55(8H,m,19-CON(CH2CH2)2-N-),2.64(1H,dd,J=3.6,18.7Hz,H-15),2.23(1H,d,J=14.0Hz,H-3),1.24(3H,s,H-18),0.90(3H,s,H-17),0.75(3H,s,H-20),1.48-0.75(18H,m,CH,CH2 in ent-beyeraneskeleton);13C NMR(CDCl3,100MHz)δ222.8,177.0,176.9,171.2,131.6,131.0,61.8,56.0,54.4,48.7,48.5,46.5,46.2,45.6,45.4,42.4,42.0,40.7,39.7,39.6,38.6,37.3,28.0,22.5,20.4,19.9,19.8,16.0;HRMS(ESI,m/z)calcd for C28H40N2O5K,523.2574[M+K+];found,523.2584。
化合物4b结构式如下:
化合物4b:浅黄色油状;[α]25 D-79.1(c 1.0,CH3OH);1H NMR(CDCl3,400MHz)δ3.58(8H,m,19-CON(CH2CH2)2-N-),3.09(1H,m,CON-CH(CH3)),2.78(2H,overlap,CH2-COOH,H15),2.44(2H,overlap,CH2-COOH,H-3),1.26(3H,s,H-18),0.97(3H,s,H-17),0.83(3H,s,H-20),2.12–0.90(21H,m,CH,CH2 in ent-beyerane skeleton or carbon chain);13C NMR(CDCl3,100MHz)δ222.9,176.9,174.8,170.5,61.8,56.0,54.4,48.7,48.5,46.3,46.2,42.4,42.2,41.9,40.7,39.7,39.6,38.6,37.4,36.5,35.7,32.0,28.0,22.5,20.4,19.9,19.8,17.3,16.0;HRMS(ESI,m/z)calcd for C29H44N2O5Na,523.3148[M+Na+];found,523.3100。
化合物4c结构式如下:
化合物4c:白色固体;mp 193.8-195.3℃;[α]25 D-25.9(c 2.1,CH3OH);1H NMR(CDCl3,400MHz)δ3.50(8H,m,19-CON(CH2CH2)2-N-),2.65(1H,dd,J=3.6,18.7Hz,H-15),2.54(2H,s,CH2-COOH),2.24(1H,dd,J=3.6,14.0Hz,H-3),1.23(3H,s,H-18),1.22(6H,s,2×CH3),0.90(3H,s,H-17),0.76(3H,s,H-20),1.52-0.76(18H,m,CH,CH2 in ent-beyeraneskeleton);13C NMR(CDCl3,100MHz)δ222.8,181.5,176.9,169.9,61.8,56.0,54.4,48.7,48.5,46.3,46.2,45.4,45.2,42.8,42.4,41.7,40.7,40.5,39.7,39.5,38.6,37.4,28.0,25.9,25.8,22.5,20.4,19.9,19.8,16.0;C30H46N2O5。
化合物4d结构式如下:
化合物4d:浅黄色固体;mp 124.4-124.7℃;[α]25 D-72.1(c 0.3,CH3OH);1HNMR(CDCl3,400MHz)δ7.76(1H,s,6-Ph),7.19(2H,s,4,5-Ph),3.17(8H,m,19-CON(CH2CH2)2-N-),2.70(1H,d,J=18.6Hz,H-15),2.18(3H,s,CH3-Ph),2.06(1H,m,H-3),1.27(3H,s,H-18),0.97(3H,s,H-17),0.77(3H,s,H-20),1.53(18H,m,CH,CH2 in ent-beyeraneskeleton);13C NMR(CDCl3,100MHz)δ222.9,176.7,176.7,172.0,160.3,136.1,133.5,132.9,128.4,127.7,61.8,61.8,56.0,54.4,48.7,48.6,46.0,42.4,40.8,39.7,39.4,38.6,37.4,29.7,28.0,27.9,22.5,20.4,19.9,19.9,18.8,16.2,16.1;HRMS(ESI,m/z)calcd for C33H45N2O5,549.3328[M+H+];found,549.3310。
化合物4e结构式如下:
化合物4e:白色固体;mp 124.1-125.0℃;[α]25 D-23.0(c 0.7,CH3OH);1H NMR(CDCl3,400MHz)δ7.66-7.13(3H,overlap,3,4,6-Ph),3.53(8H,m,19-CON(CH2CH2)2-N-),2.71(1H,dd,J=3.5,18.7Hz,H-15),2.36(4H,overlap,CH3-Ph,H-3),1.25(3H,s,H-17),0.97(3H,s,H-18),0.81(3H,s,H-20),1.51-0.81(18H,m,CH,CH2 in ent-beyeraneskeleton);13C NMR(CDCl3,100MHz)δ222.9,176.8,171.3,169.2,137.8,131.3,131.3,129.7,129.7,127.0,61.8,60.4,56.0,54.4,48.7,48.6,46.1,45.5,42.4,40.8,39.7,39.5,38.6,37.4,28.0,22.5,21.5,21.1,20.4,19.9,19.8,16.1,14.2;HRMS(ESI,m/z)calcd for C33H44N2O5Na,571.3148[M+Na+];found,571.3168。
化合物4f结构式如下:
化合物4f:白色固体;mp 157.1-157.9℃;[α]25 D-9.1(c 0.4,CH3OH);1H NMR(CDCl3,400MHz)δ7.84(1H,m,6-Ph),6.90(2H,overlap,3,5-Ph),3.84(3H,d,J=2.7Hz,Ph-OCH3),3.48(8H,m,19-CON(CH2CH2)2-N-),2.71(1H,dd,J=3.5,18.8Hz,H-15),2.22(1H,dd,J=3.6,14.0Hz,H-3),1.25(3H,s,H-18),0.97(3H,s,H-17),0.80(3H,s,H-20),1.58-0.79(18H,m,CH,CH2 in ent-beyerane skeleton);13C NMR(CDCl3,100MHz)δ222.8,176.8,171.5,167.0,162.4,144.5,139.5,133.3,113.9,111.7,61.8,61.6,56.0,55.6,54.4,48.7,48.6,46.1,46.1,43.6,43.3,42.4,40.7,39.7,39.6,38.6,37.3,28.0,22.5,20.4,19.9,16.1,15.9;HRMS(ESI,m/z)calcd for C33H45N2O6,565.3278[M+H+];found,565.3266。
化合物4g结构式如下:
化合物4g:白色固体;mp 173.5-173.8℃;[α]25 D-23.0(c 0.7,CH3OH);1H NMR(CDCl3,400MHz)δ8.53(1H,s,3-naphthalene),7.63(5H,overlap,4,5,6,7,8-naphthalene),3.45(8H,m,19-CON(CH2CH2)2-N-),2.67(1H,d,J=18.5Hz,H-15),2.17(1H,d,J=13.2Hz,H-3),1.17(3H,s,H-18),0.95(3H,s,H-17),0.75(3H,s,H-20),1.52-0.81(18H,m,CH,CH2 in ent-beyerane skeleton);13C NMR(CDCl3,100MHz)δ222.9,179.1,176.7,171.9,138.5,134.2,133.6,132.5,132.4,129.2,128.7,127.7,127.4,125.8,61.8,56.0,54.4,48.7,48.5,47.3,46.1,45.5,42.4,42.1,40.7,39.6,39.5,38.5,37.3,27.9,22.5,20.7,20.4,19.9,19.8,16.0;HRMS(ESI,m/z)calcd for C36H45N2O5,585.3328[M+H+];found,585.3310。
化合物4h结构式如下:
化合物4h:白色固体;mp 171.5-173.4℃;[α]25 D-18.0(c 0.4,CH3OH);1H NMR(CDCl3,400MHz)δ3.40(12H,overlap,19-CON(CH2CH2)2-N-,C=C-(CH2)2),2.63(1H,d,J=18.7Hz,H-15),2.18(1H,d,J=14.5Hz,H-3),1.24(3H,s,H-18),0.90(3H,s,H-17),0.73(3H,s,H-20),1.63-0.73(22H,m,CH,CH2 in ent-beyerane skeleton or carbon chain);13C NMR(CDCl3,100MHz)δ223.9,179.4,177.1,168.9,104.4,101.4,61.5,60.6,55.7,54.2,48.7,48.7,46.1,43.6,43.2,42.1,40.4,39.6,39.4,38.4,37.2,31.3,29.6,29.2,27.8,27.7.22.3,20.3,19.7,19.6,15.7,13.9;HRMS(ESI,m/z)calcd for C32H46N2O5Na,561.3304[M+Na+];found,561.3313。
化合物4i结构式如下:
化合物4i:白色固体;mp 130.3-130.7℃;[α]25 D-11.5(c 1.3,CH3OH);1H NMR(CDCl3,400MHz)δ3.80(4H,m,19-CON(CH2CH2)2-N-),3.11(4H,m,19-CON(CH2CH2)2-N-),2.72(3H,m,NCO-CH,CH-COOH,H-15),2.25(1H,d,J=13.9Hz,H-3),1.30(3H,s,H-17),0.97(3H,s,H-18),0.81(3H,s,H-20),1.64-0.81(26H,m,CH,CH2 in ent-beyerane skeleton orcarbon chain);13C NMR(CDCl3,100MHz)δ222.7,180.8,176.8,175.5,61.7,56.0,54.4,51.5,51.5,48.7,48.7,48.5,46.1,44.6,43.7,43.5,42.8,42.4,40.6,39.7,39.6,38.6,37.3,27.9,27.4,26.5,24.2,22.4,20.4,19.9,19.8,16.0;HRMS(ESI,m/z)calcd forC32H49N2O5,541.3641[M+H+];found,541.3646。
化合物4j结构式如下:
化合物4j:白色固体;mp 141.6-142.4℃;[α]25 D-20.2(c 0.7,CH3OH);1H NMR(CDCl3,400MHz)δ3.64(8H,m,19-CON(CH2CH2)2-N-),3.08(2H,overlap,NCO-CH,CH-COOH),2.72(1H,d,J=18.8Hz,H-15),2.31(1H,d,J=15.6Hz,H-3),1.30(3H,s,H-18),0.97(3H,s,H-17),0.82(3H,s,H-20),1.59-0.82(28H,m,CH,CH2 in ent-beyerane skeleton orcarbon chain);13C NMR(CDCl3,100MHz)δ222.8,179.2,176.8,173.9,61.8,61.7,58.9,65.0,51.4,48.7,48.6,46.2,46.1,44.1,44.0,42.4,40.8,40.7,39.7,39.6,38.6,38.6,37.3,32.2,29.7,28.1,28.0,22.5,22.5,22.4,20.4,19.9,16.0;HRMS(ESI,m/z)calcd forC33H51N2O5,555.3798[M+H+];found,555.3782。
化合物4k结构式如下:
化合物4k:白色固体;mp 166.4-168.4℃;[α]25 D-5.4(c 0.6,CH3OH);1H NMR(CDCl3,400MHz)δ3.34(10H,overlap,19-CON(CH2CH2)2-N-,CO-CH,CH-COOH),2.65(1H,d,J=18.7Hz,H-15),1.23(3H,s,H-18),0.90(3H,s,H-17),0.82(3H,s,CH3),0.74(3H,s,H-20),1.72-0.74(26H,m,CH,CH2 in ent-beyerane skeleton or carbon chain);13C NMR(CDCl3,100MHz)δ222.7,181.6,179.7,176.9,61.7,56.0,54.4,54.4,48.7,48.7,48.5,46.1,43.7,43.4,42.6,42.4,40.6,39.7,39.6,38.6,37.3,37.0,32.4,31.0,28.7,28.4,27.9,22.6,22.4,22.1,20.4,19.9,16.0;HRMS(ESI,m/z)calcd for C33H50N2O5Na,577.3617[M+Na+];found,577.3664。
化合物4l结构式如下:
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化合物4l:白色固体;mp 127.6-128.1℃;[α]25 D-34.7(c 0.3,CH3OH);1H NMR(CDCl3,400MHz)δ7.15(4H,overlap,3,4,5,6-Ph),3.72(2H,s,CH2-Ph),3.51(10H,overlap,CH2-COOH,19-CON(CH2CH2)2-N-),2.71(1H,dd,J=3.5,18.5Hz,H-15),2.27(1H,d,J=13.8Hz,H-3),1.28(3H,s,H-18),0.97(3H,s,H-17),0.81(3H,s,H-20),1.62-0.81(16H,m,CH,CH2in ent-beyerane skeleton);13C NMR(CDCl3,100MHz)δ222.8,179.9,176.9,170.5,133.5,131.1,129.6,129.6,127.6,127.5,61.8,56.0,54.4,48.7,48.6,46.2,46.0,45.9,45.4,42.4,42.1,40.7,39.7,39.5,38.6,37.9,37.4,28.0,22.5,20.4,19.9,19.8,16.1;C33H44N2O5。
化合物4r结构式如下:
化合物4r:白色固体;mp 189.4-191.2℃;[α]25 D-15.8(c 3.0,CH3OH);1H NMR(CD3OD,400MHz)δ7.97(1H,d,J=8.0Hz,3-Ph),7.57(2H,m,5,6-Ph),7.30(1H,d,J=7.0Hz,4-Ph),3.62(6H,m,19-CON(CH2CH2)2-N-),3.10(2H,m,19-CON(CH2CH2)2-N-),2.56(1H,d,J=18.6Hz,H-15),2.28(1H,d,J=14.0Hz,H-3),1.21(3H,s,H-17),0.84(3H,s,H-18),0.74(3H,s,H-20),1.98-0.90(18H,m,CH,CH2 in ent-beyerane skeleton);13C NMR(CD3OD,100MHz)δ223.8,177.3,173.1,172.1,136.5,136.4,129.7,129.4,128.4,125.9,61.4,55.6,53.8,48.5,48.1,46.9,46.0,45.6,45.0,41.9,41.7,40.6,39.5,39.4,38.3,37.1,26.8,22.3,20.2,19.6,18.8,15.1;C32H42N2O5。
(4)化合物4m-4q的合成
将化合物3(243mg,0.69mmol)、1-乙基-3-(3-二甲基铵丙基)碳铵(113.9mg,0.6mmol)、4-二甲氨基吡啶(67.4mg,0.6mmol)、1-羟基苯并三唑(81mg,0.6mmol)和相对应的苯羧酸类化合物(0.83mmol),加入无水二氯甲烷(4mL)中,室温搅拌2h。TLC板检测进程至反应结束,加入适量乙酸乙酯,再用饱和食盐水洗涤以去除无机物,用无水硫酸钠干燥后浓缩。利用硅胶柱对混合物进行分纯,分别得到纯产物4m-4q中的其中一种;
其中:合成4m使用苯甲酸,合成4n使用4-甲氧基苯甲酸,合成4o使用2,3-二甲氧基苯甲酸,合成4p使用2,3,4-三甲氧基苯甲酸,合成4q使用3,4,5-三甲氧基苯甲酸。
化合物4m-4q的结构、比旋光度、核磁共振谱图数据如下所示:
化合物4m结构式如下:
化合物4m:白色固体;mp 136.7-137.1℃;[α]25 D-31.4(c 0.7,CH3OH);1H NMR(CDCl3,400MHz)δ7.41(2H,overlap,2,6-pH),6.82(3H,overlap,3,4,5-pH),3.68(4H,m,19-CON(CH2CH2)2-N-),3.04(4H,m,19-CON(CH2CH2)2-N-),2.63(1H,d,J=17.8Hz,H-15),2.12(1H,d,J=13.9Hz,H-3),1.18(3H,s,H-18),0.90(3H,s,H-17),0.71(3H,s,H-20),1.99–0.83(18H,m,CH,CH2 in ent-beyerane skeleton);13C NMR(CDCl3,100MHz)δ222.7,176.8,176.8,143.0,127.6,125.1,124.7,118.2,110.9,61.7,56.0,54.4,54.4,48.7,48.7,48.5,46.1,43.9,43.9,42.3,40.6,39.7,39.5,38.6,37.3,27.9,22.4,20.4,19.9,19.8,16.0。C31H42N2O3。
化合物4n结构式如下:
化合物4n:白色固体;mp 189.7-190.2℃;[α]25 D-29.1(c 0.6,CH3OH);1H NMR(CDCl3,400MHz)δ7.38(2H,overlap,2,6-Ph),6.92(2H,overlap,3,5-Ph),3.84(3H,s,Ph-OCH3),3.60(8H,m,19-CON(CH2CH2)2-N-),2.72(1H,d,J=18.7Hz,H-15),2.31(1H,d,J=14.1Hz,H-3),1.31(3H,s,H-18),0.97(3H,s,H-17),0.83(3H,s,H-20),2.12-0.90(18H,m,CH,CH2 in ent-beyerane skeleton);13C NMR(CDCl3,100MHz)δ222.8,176.8,170.7,161.1,129.3,129.3,127.2,113.9,113.9,61.8,56.1,55.4,54.4,54.4,48.7,48.7,48.5,46.2,46.1,42.4,42.4,40.8,39.7,39.6,38.6,37.4,28.1,22.5,20.4,19.9,19.8,16.0;HRMS(ESI,m/z)calcd for C32H45N2O4,521.3379[M+H+];found,521.3376。
化合物4o结构式如下:
化合物4o:白色固体;mp 166.6-167.0℃;[α]25 D-18.5(c 0.6,CH3OH);1H NMR(CDCl3,400MHz)δ7.03(3H,overlap,4,5,6-Ph),3.81(3H,s,Ph-OCH3),3.80(3H,s,Ph-OCH3),3.64(4H,m,19-CON(CH2CH2)2-N-),2.90(4H,m,19-CON(CH2CH2)2-N-),2.73(1H,d,J=18.7Hz,H-15),2.25(1H,d,J=12.3Hz,H-3),1.26(3H,s,H-18),0.97(3H,s,H-17),0.82(3H,s,H-20),2.11-0.82(18H,m,CH,CH2 in ent-beyerane skeleton);13C NMR(CDCl3,100MHz)δ222.8,176.4,152.5,144.9,124.4,124.4,122.6,114.9,92.8,61.9,56.1,56.0,54.5,54.5,48.7,48.7,48.6,46.1,45.6,44.9,44.9,42.5,40.8,39.7,39.6,38.6,37.4,28.0,22.5,20.4,19.9,19.8,16.1;HRMS(ESI,m/z)calcd for C33H46N2O5K,589.3044[M+K+];found,589.3000。
化合物4p结构式如下:
化合物4p:浅黄色油状;[α]25 D-15.7(c 0.2,CH3OH);1H NMR(CDCl3,400MHz)δ6.95(1H,d,J=8.5Hz,6-Ph),6.70(1H,d,J=8.5Hz,5-Ph),3.95(9H,overlap,3×OCH3),3.41(8H,m,19-CON(CH2CH2)2-N-),2.73(1H,dd,J=3.7,18.7Hz,H-15),2.30(1H,d,J=14.2Hz,H-3),1.26(3H,s,H-18),0.97(3H,s,H-17),0.83(3H,s,H-20),2.12–0.83(18H,m,CH,CH2in ent-beyerane skeleton);13C NMR(CDCl3,100MHz)δ222.7,176.8,176.8,142.5,128.1,125.6,125.0,118.0,110.9,61.6,56.0,54.4,54.4,48.7,48.7,48.5,46.1,43.7,43.4,42.1,40.6,39.6,39.5,38.5,37.3,29.7,29.3,27.9,22.4,20.4,19.9,19.8,15.9,14.5;HRMS(ESI,m/z)calcd for C34H48N2O6Na,603.3410[M+Na+];found,603.3429。
化合物4q结构式如下:
化合物4q:白色固体;mp 159.7-160.1℃;[α]25 D-5.6(c 0.5,CH3OH);1H NMR(CDCl3,400MHz)δ7.32(2H,overlap,2,6-Ph),3.78(4H,m,19-CON(CH2CH2)2-N-),3.34(9H,s,3×OCH3),3.14(4H,m,19-CON(CH2CH2)2-N-),2.67(1H,dd,J=3.7,18.7Hz,H-15),2.20(1H,d,J=14.5Hz,H-3),1.26(3H,s,H-18),0.94(3H,s,H-17),0.77(3H,s,H-20),1.54-0.77(18H,m,CH,CH2 in ent-beyerane skeleton);13C NMR(CDCl3,100MHz)δ223.6,177.1,176.4,142.3,127.8,125.6,125.1,117.8,110.9,61.6,55.8,54.2,54.2,52.1,49.2,48.5,48.5,46.1,43.6,43.5,42.2,40.5,39.6,39.5,39.5,38.5,37.5,37.3,27.8,22.3,20.3,19.7,15.8,14.1;C34H48N2O6。
实施例2化合物5的合成
如合成路线2所示,以化合物4r为起始原料,溶解在丙酮溶剂当中,混合物在80℃下回流搅拌15min,将氢氧化钠溶解于1ml超纯水当中,配成氢氧化钠水溶液,取相对应当量的氢氧化钠水溶液缓慢滴加进入反应体系中,继续在80℃回流搅拌反应直到观察到大量沉淀析出,停止反应,冷却至室温,离心获得沉淀,用丙酮跟超纯水洗涤后烘干,得到化合物5。
合成路线2中反应条件与试剂:(d)氢氧化钠,丙酮,,水。
具体步骤如下:
(1)化合物5的合成
将化合物4r(100mg,0.19mmol)、溶解在丙酮(2.8ml)中,混合物在80℃下回流搅拌15min,取0.1ml已配好的氢氧化钠水溶液(76.1mg氢氧化钠:1ml超纯水)缓慢滴加进入反应体系中,继续在80℃回流搅拌反应直到观察到大量沉淀析出,停止反应,冷却至室温,离心获得沉淀,用丙酮跟超纯水洗涤后烘干,得到化合物5;
化合物5结构式如下:
化合物5:白色固体;mp 120.7-121.3℃;[α]25 D-11.7(c 0.6,CH3OH);1H NMR(CD3OD,400MHz)δ7.90-7.16(4H,m,3,4,5,6-Ph),3.69–3.20(8H,m,19-CON(CH2CH2)2-N-),2.61(1H,d,J=1.0Hz,H-1),2.35(1H,d,J=9.7Hz,H-3),1.28(3H,s,H-18),0.91(3H,s,H-17),0.81(3H,s,H-20),2.05–1.10(18H,m,CH,CH2 in ent-beyerane skeleton);13C NMR(CD3OD,100MHz)δ228.2,181.1,177.3,176.2,140.2,139.2,134.3,134.0,132.9,129.6,65.6,59.7,58.1,52.8,51.1,50.1,49.6,49.3,49.0,48.6,46.2,45.8,44.6,43.6,43.4,42.4,41.2,31.7,26.4,24.3,23.6,19.8;HRMS(ESI,m/z)calcd for C32H41N2O5,533.3015[M-Na+];found,533.3024。
为了证明本申请提供的技术方案的优点,下面给出本申请提供的技术方案实施例。
试验例1异甜菊醇衍生物进行斑马鱼心脏保护活性筛选实验及心脏功能超声评价实验
(1)斑马鱼养殖与胚胎收集:从国家斑马鱼资源中心购买斑马鱼(3-12月龄),在光周期为14:10h(光照:暗照),温度为28.5±1℃的流动饲养箱中进行养殖,每天两次活饱和食盐水虾喂食;斑马鱼(雌:雄=1:1)交配,收集胚胎,用Holt Buffer缓冲液冲洗,在培养箱(28.5±1℃)中培养24h,通过显微镜检查进行筛选。
(2)阿霉素诱导斑马鱼胚胎心肌损伤模型进行药物筛选:将24hpf(受精后24小时)野生型斑马鱼胚胎分配到24孔板中(20个胚胎/孔),每孔加入不同组溶液(其中阿霉素终浓度为90μM,受试化合物终浓度为5,15,40μM)1mL,每组四个孔做技术重复,培养箱培养72h,在倒置荧光显微镜(蔡司,德国)下观察胚胎存活率及异常情况,心房和心室失去收缩力,被视为死亡,以存活率作为化合物活性的评价标准。如图1和图2所示,化合物4e,4h,4r能有效提高斑马鱼阿霉素模型的存活率,具备显著的心脏保护活性,继而对其进行药物的最佳作用浓度摸索,最终发现1,4e,4h,4r和LSD分别在10,1,5,5,60μM表现出最显著的心脏保护活性。
(3)斑马鱼胚胎对药物毒性评价实验:将24hpf野生型斑马鱼胚胎分配到96孔板中(1个胚胎/孔),加入200mL所需浓度试验化合物,每组20个孔,培养箱培养72h,在倒置荧光显微镜(蔡司,德国)下观察胚胎存活率,为了测试化合物(1,4e,4g,4r,LSD)是否会引起任何毒性,用不同浓度的试验化合物单独处理胚胎。如图2所示,即使给药浓度远高于有效剂量,所有试验化合物也不会导致斑马鱼死亡,并且斑马鱼形体发育正常。
(4)斑马鱼心脏功能评价:将24hpf(受精后24小时)心脏荧光标记转基因型斑马鱼胚胎分配到24孔板中(20个胚胎/孔),每孔加入不同组溶液(其中阿霉素终浓度为90μM,受试化合物终浓度为其最佳作用浓度)1mL,每组四个孔做技术重复,培养箱培养48h。随后将斑马鱼幼虫用Holt buffer清洗干净后固定在4%甲基纤维素固定液上,通过调整使其侧卧且两侧眼睛重合,身躯处于同一水平且保持原有形态。在50x正置荧光显微镜(蔡司,德国)下,拍摄斑马鱼的形体,后改用EGFP荧光通道,在100x下找到心脏位置后进行心脏拍摄及录像40sec。利用AdobePremiere视频软件,通过逐帧播放,截取一个周期内心室最舒张与最收缩时的照片,通过Photoshop软件测量其长轴(a)和短轴(b),收缩分数(%)的计算公式为:(舒张短轴-收缩短轴)/(舒张短轴)×100%。再利用v=4/3πab2分别计算出其心室容积。每搏输出量是舒张末期心室容积和收缩末期心室容积的差值。而搏出量是每搏输出量和心率的乘积。最终处理得到的心率、收缩分数、搏出量和每搏出量,如图3所示,单独给药阿霉素处理的每个数值均显著降低,表明心室收缩异常和功能障碍,而阿霉素与受试化合物4e,4h,4r以最佳给药剂量联合处理后,可显著减轻斑马鱼胚胎心包水肿,恢复心脏的正常形态,有效改善心肌损伤。
(5)斑马鱼胚胎的定量聚合酶链式反应:将24hpf(受精后24小时)野生型斑马鱼胚胎分配到24孔板中(20个胚胎/孔),每孔加入不同组溶液(其中阿霉素终浓度为90μM,受试化合物终浓度为所需浓度)1mL,培养箱培养48h。随后将斑马鱼幼虫用Holt buffer清洗干净,根据标准TRIzol方案(诺维赞,南京)对20只斑马鱼幼虫提取总RNA,提取步骤按试剂盒说明书。随后,利用Nanodrop 2000S分光光度计(赛默飞,德国)检测所提取RNA的纯度及浓度。利用实时定量PCR试剂盒(诺维赞,南京)通过PCR扩增测定特定基因的mRNA水平。qPCR引物如下:ANP-F,5’-ATG GCC GGG GGA CTAATT CT-3’;ANP-R,5’-AGAGTT GCAACC GAG GGTGC-3’;BNP-F,5’-AAGAGCAGC CCG ATACTTACC T-3’;BNP-R,5’-TCC CAAAGACGACAT TGAACC-3’;cTnT-F,5’-GTC TGC ACT TCG GCG GTT ACA-3’;cTnT-R,5’-AGG TAAAAT CTA TAT TGTTCA GTG AAATCTAAC CG-3’;β-actin-F 5’-CCTACTAATACA CAG CCATGGATGA-3’;β-actin-R,5’-TC CCATGC CAACCATCAC-3’。如图4所示,阿霉素处理后心肌损伤标记物ANP、BNP和cTnT的mRNA水平显著增加,化合物4e,4h,4r能显著降低ANP、BNP和cTnT水平,且呈剂量依赖性,这些结果为其心脏保护效力提供了强有力的分子证据。
试验例2化合物4r和化合物5体内斑马鱼抗心肌损伤试验
(1)斑马鱼试验:按照试验例1中所描述的全部实验步骤及方法,将化合物4r和5进行所描述的实验,得到实验结果如图5所示,化合物4r的成钠盐得到的化合物5在斑马鱼上具备同样显著的心脏保护活性,其活性与化合物4r不相上下。
试验例3以化合物5为例的该类化合物的心脏保护作用机制探索试验
(1)药物的细胞活性:将细胞铺至96孔板中,每孔细胞6000-8000个,在培养箱中培养24h。将细胞划分为正常组、模型组和药物处理组,正常组细胞用完全培养基进行培养,模型组用2.5μM阿霉素处理,药物组分别用0.1、1、10、100μM化合物5联合阿霉素处理24h。实验结束后,吸取废液待用,用排枪吸取100μLPBS洗涤三次细胞,吸干洗涤液后,用排枪加入100μL CCK-8工作液(CCK-8原液:完全培养基=1:9),在培养箱中孵育30min,用酶标仪测定溶液在450nm的吸光度,记录数据后计算得出细胞的存活率。收集的废液,按照LDH试剂盒说明书操作步骤进行实验,在450nm测定吸光度,记录数据后计算得到LDH含量。如图6所示,化合物5在0.1,1,10μM给药处理后细胞存活率得到明显提高,以及在1,10μM给药处理后LDH含量得到明显降低,这也说明了该化合物的心脏保护效果。
(2)细胞的定量聚合酶链式反应:将细胞铺至6孔板中,在培养箱中培养24h。将细胞划分为正常组、模型组和药物处理组,正常组细胞用完全培养基进行培养,模型组用2.5μM阿霉素处理,药物组分别用1、10μM化合物5联合阿霉素处理24h。实验结束后,吸弃废液,用PBS清洗细胞2-3次,加入500μL胰酶消化并收集细胞,800rpm离心3min。缓慢吸弃废液,再用PBS重悬以清洗残留的胰酶,800rpm离心3min,吸弃废液后根据实时定量PCR试剂盒(诺维赞,南京)说明书测定基因的mRNA水平。qPCR引物如下:ANP-F,5’-GCT TCCAGG CCATATTGGAG-3’;ANP-R,5’-GGG GGCATGACC TCATCT T-3’;BNP-F,5’-TTAGGT CTCAAGACAGCG CC-3’;BNP-R,5’-CGC CGATCC GGT CTATCT TC-3’;cTnT-F,5’-CAGAGGAGG CCAACG TAGAAG-3’;cTnT-R,5’-CTC CAT CGG GGATCT TGG GT-3’。结果如图6所示,阿霉素给药的模型中心肌损伤标记物ANP、BNP、cTnT的mRNA分子水平显著上调,化合物5可显著下调了ANP、BNP、cTnT的mRNA分子水平,逆转了阿霉素对其造成的损伤,并呈现出剂量依赖性变化,在给药10μM时得到最优的作用效果。
(3)细胞活性氧(ROS)含量测定:将细胞铺至12孔板中,在培养箱中培养24h。将细胞划分为正常组、模型组和药物处理组,正常组细胞用完全培养基进行培养,模型组用2.5μM阿霉素处理,药物组分别用1、10μM化合物5联合阿霉素处理24h。实验结束后,吸弃废液,用PBS清洗细胞2-3次,每孔加入200μLDCFH-DA工作液(DCFH-DA染液:无血清培养基=1:1000),在培养箱中孵育30min,用无血清培养基清洗2-3次,最后加200μLPBS,用倒置荧光显微镜拍摄结果并用Image J分析处理。结果如图7所示,对比正常组,阿霉素单独处理组荧光强度更高,表明阿霉素处理后活性氧水平会上升,而联合给药化合物5后,荧光强度恢复到跟正常组一样,表明化合物5能降低阿霉素诱导升高的活性氧水平。
(4)细胞丙二醛水平(Malondialdehyde,MDA)、谷胱甘肽水平(glutathione,GSH)及超氧化物歧化酶(Superoxide Dismutase,SOD)活力测定:将细胞铺至6孔板中,在培养箱中培养24h。将细胞划分为正常组、模型组和药物处理组,正常组细胞用完全培养基进行培养,模型组用2.5μM阿霉素处理,药物组分别用1、10μM化合物5联合阿霉素处理24h。实验结束后,吸弃废液,用PBS清洗细胞2-3次,加入500μL胰酶消化并收集细胞,800rpm离心3min。缓慢吸弃废液,再用PBS重悬以清洗残留的胰酶,800rpm离心3min,吸弃废液后根据试剂盒说明书分别测定MDA、GSH和SOD。结果如图7所示,阿霉素处理后MDA含量上调,GSH含量下调,SOD活力降低,而在给药化合物5后MDA恢复到正常水平,GSH水平和SOD活力也得到了明显的恢复,并出现了剂量依赖性,在给药10μM时得到最优的作用效果。
上述实验结果表明本发明所述化合物具有显著的心脏保护作用,通过抑制ROS的过度积累,恢复MDA、GSH水平和SOD活力,从而阻止心肌细胞的损伤和死亡,可作为一个潜在的心脏保护临床试验候选药物进行开发。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (9)
1.一种异甜菊醇衍生物,其特征在于,具有式1结构通式:
其中:R1为3-丙烯酸基、3-丁酸基、3-(3-甲基丁酸)基、2-(6-甲基苯甲酸)基、2-(5-甲基苯甲酸)基、2-(5-甲氧基苯甲酸)基、3-(2-萘甲酸)基、2-(环己-1-稀-1-羧酸)基、2-(环己-1-羧酸)基、2-(3-甲基环己-1-羧酸)基、2-(4-甲基环己-1-羧酸)基、2’-(2-苯基乙酸)基、苯基、4-(1-甲氧基苯)基、3-(1,2-二甲氧基苯)基、4-(1,2,3-三甲氧基苯)基、5-(1,2,3-三甲氧基苯)基、2-苯甲酸钠基的其中之一。
2.权利要求1所述的异甜菊醇衍生物的制备方法,其特征在于,依次包括下述步骤:
(1)化合物2的合成
将3.14mmol化合物1、62.8mmol草酰氯溶解在5ml二氯甲烷中,混合物在室温搅拌反应3h,旋蒸除去反应液,随后加入3.8mmol 1-Boc-哌嗪、15.7mmol三乙胺和5ml二氯甲烷,室温搅拌4h,TLC板检测进程至反应结束,加入乙酸乙酯和饱和食盐水的混合溶液进行萃取,收集有机层,在无水硫酸钠上干燥后浓缩,柱层析分离提纯,得到化合物2;
(2)化合物3的合成
将0.42mmol化合物1、0.84mmol三氟乙酸溶解在10ml二氯甲烷中,混合物在室温搅拌反应2h,TLC板检测进程至反应结束,加入二氯甲烷和饱和食盐水的混合溶液进行萃取,收集有机层,在无水硫酸钠上干燥后浓缩,柱层析分离提纯,得到化合物3;
(3)化合物4a-4l的合成
将0.43mmol化合物3、0.86mmol 4-二甲氨基吡啶、0.48mmol酸酐类化合物,溶解于2ml吡啶中,室温搅拌1h,TLC板检测进程至反应结束,用1N盐酸稀溶液中和,加入乙酸乙酯和饱和食盐水的混合溶液进行萃取,收集有机层,在无水硫酸钠上干燥后浓缩,柱层析分离提纯,得到化合物4a-4l;
(4)化合物4m-4q的合成
将0.43mmol化合物3、0.65mmol 1-乙基-3-(3-二甲基铵丙基)碳铵、0.52mmol 1-羟基苯并三唑、0.86mmol苯羧酸类化合物,溶解于5ml二氯甲烷中,室温搅拌4h,TLC板检测进程至反应结束,加入二氯甲烷和饱和食盐水的混合溶液进行萃取,收集有机层,在无水硫酸钠上干燥后浓缩,柱层析分离提纯,得到化合物4m-4q;
其合成路线如下:
3.根据权利要求2所述的异甜菊醇衍生物的制备方法,其特征在于,所述的酸酐类化合物为马来酸酐、甲基丁二酸酐、1,2-二甲基琥珀酸酐、3-甲基邻苯二甲酸酐、4-甲基邻苯二甲酸酐、4-甲氧基邻苯二甲酸酐、2,3-萘二甲酸酐、四氢邻苯二甲酸酐、六氢苯酐,3-甲基六氢苯二甲酯酐、4-甲基六氢苯二甲酯酐、高邻苯二甲酸酐的其中之一。
4.权利要求1所述的异甜菊醇衍生物的制备方法,其特征在于,依次包括下述步骤:
(1)化合物2的合成
将3.14mmol化合物1、62.8mmol草酰氯溶解在5ml二氯甲烷中,混合物在室温搅拌反应3h,旋蒸除去反应液,随后加入3.8mmol 1-Boc-哌嗪、15.7mmol三乙胺和5ml二氯甲烷,室温搅拌4h,TLC板检测进程至反应结束,加入乙酸乙酯和饱和食盐水的混合溶液进行萃取,收集有机层,在无水硫酸钠上干燥后浓缩,柱层析分离提纯,得到化合物2;
(2)化合物3的合成
将0.42mmol化合物1、0.84mmol三氟乙酸溶解在10ml二氯甲烷中,混合物在室温搅拌反应2h,TLC板检测进程至反应结束,加入二氯甲烷和饱和食盐水的混合溶液进行萃取,收集有机层,在无水硫酸钠上干燥后浓缩,柱层析分离提纯,得到化合物3;
(3)化合物5的合成
将0.43mmol化合物3、0.86mmol 4-二甲氨基吡啶、0.48mmol邻苯二甲酸酐,溶解于2ml吡啶中,室温搅拌1h,TLC板检测进程至反应结束,用1N盐酸稀溶液中和,加入乙酸乙酯和饱和食盐水的混合溶液进行萃取,收集有机层,在无水硫酸钠上干燥后浓缩,柱层析分离提纯,得到化合物5;
(4)化合物6的合成
将0.19mmol化合物5、溶解在2.8ml丙酮中,混合物在80℃下回流搅拌15min,将76.1mg氢氧化钠溶解于1ml超纯水当中配成氢氧化钠水溶液,取0.1ml氢氧化钠水溶液缓慢滴加进入反应体系中,继续在80℃回流搅拌反应直到观察到大量沉淀析出,停止反应,冷却至室温,离心获得沉淀,用丙酮跟超纯水洗涤后烘干,得到化合物5;
其合成路线如下:
5.权利要求1所述的异甜菊醇衍生物在制备心脏保护活性药物中的应用。
6.一种心脏保护活性药物,其特征在于,包括权利要求1所述的异甜菊醇衍生物。
7.根据权利要求6所述的一种心脏保护活性药物,其特征在于,还包括药学上可接受的辅料。
8.根据权利要求7所述的一种心脏保护活性药物,其特征在于,所述的辅料为粘合剂、崩解剂、润滑剂、填充剂、表面活性剂、抗氧剂或pH调节剂中的至少一种。
9.根据权利要求6所述的一种心脏保护活性药物,其特征在于,所述的药物的剂型为注射液或片剂或口服液、颗粒剂或胶囊。
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