CN115322086A - 一种β-紫罗兰酮衍生物及其在制备抗氧化和抗衰老药物中的应用 - Google Patents
一种β-紫罗兰酮衍生物及其在制备抗氧化和抗衰老药物中的应用 Download PDFInfo
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Abstract
本发明公开了一种β‑紫罗兰酮衍生物,结构如式(I)所示,式(I)中,R取代基选自氢、烷氧基、卤素、CF3、二甲氨基、烷基、羟基、环丙基、NO2或者NH2中的一个。研究结果表明,该β‑紫罗兰酮衍生物具有较好地抗氧化和抗衰老活性,而且其抗抗氧化和抗衰老活性要远远高于β‑紫罗兰酮。
Description
技术领域
本发明属于药物化学领域,具体涉及一种β-紫罗兰酮衍生物及其在制备抗氧化和抗衰老药物中的应用。
背景技术
衰老是一种复杂的、必然的生命现象,受许多生化途径、遗传特征、环境因素和生活方式的影响。人体的各种组织,器官功能都会随着衰老现象的发生而发生退行性变化。目前,人口老龄化问题愈发严峻,抗衰老药物的研发已成为国内外学者积极探索的课题。根据Denham Harman的理论,活性氧(Reactive Oxygen Species,ROS)等自由基对细胞大分子的长期损伤是衰老的主要驱动因素,也是机体生存和长寿的决定因素。
β-紫罗兰酮是一种单环单萜类化合物,广泛存在于天然食物中,主要源自水果、蔬菜和谷物等食品中,特别是博洛尼亚矮牵牛花和香堇中。一系列研究表明β-紫罗兰酮是一种在体外和体内均具有优异的抗氧化活性天然产物。与传统化学药物相比,β-紫罗兰酮具有简单、安全、环保、成本低、快速且毒性低的优点,曾被认为是理想的抗氧化药物。但β-紫罗兰酮的水溶性差、生物利用度低等特点大大限制了β-紫罗兰酮作为抗氧化药物的开发。同时,进一步的研究还发现,β-紫罗兰酮的抗氧化和抗衰老活性还不够高,尤其是体内活性偏低。因此,对β-紫罗兰酮进行结构优化,提高其活性及成药性具有重要的意义。
发明内容
本发明提供了一种β-紫罗兰酮衍生物及其在制备抗氧化和抗衰老药物中的应用,该β-紫罗兰酮衍生物能够有效地清除自由基,而且其抗氧化和抗衰老活性远远超过β-紫罗兰酮。
一种β-紫罗兰酮衍生物,结构如式(I)所示:
式(I)中,R选自氢、烷氧基、卤素、CF3、二甲氨基、烷基、羟基、环丙基、NO2或者NH2中的一个。
本发明以β-紫罗兰酮骨架为基础,通过构象限制药物设计方法设计了新型β-紫罗兰酮衍生物。体外及体内抗氧化和抗衰老活性测试结果表明,相较于母核β-紫罗兰酮,本发明的苯酚取代β-紫罗兰酮衍生物大部分具有更好的抗氧化和抗衰老活性。
作为优选,所述的β-紫罗兰酮衍生物为化合物4a-4e的一种,其结构及合成反应式如下:
本发明还提供了一种所述的β-紫罗兰酮衍生物的应用,所述的β-紫罗兰酮衍生物用于制备抗氧化和/或抗衰老药物。
作为优选,所述的β-紫罗兰酮衍生物通过清除自由基、抑制体内丙二醛(MDA)的积累,提高过氧化氢酶(CAT)和超氧化物歧化酶(SOD)的活性获得抗氧化和抗衰老的治疗效果。
作为最优选,所述的β-紫罗兰酮衍生物为化合物4d;
本发明还提供了一种药物制剂,包括有效成分和药用辅料,所述的有效成分包括所述的β-紫罗兰酮衍生物。
作为优选,所述的药物制剂为注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、软膏剂、控释剂、缓释剂或纳米制剂的任一种。
同现有技术相比,本发明的有益效果体现在:本发明通过向β-紫罗兰酮的母体结构上引入带修饰的苯酚片段,大大提高了该β-紫罗兰酮衍生物的抗氧化和抗衰老活性。细胞试验表明这类化合物能有效清楚自由基;同时,动物试验表明,这些化合物能够明显增强雄性和雌性果蝇的攀爬能力,减少其活动性,增加睡眠,能提高其存活率和寿命。
附图说明
图1为本申请的化合物对自由基的清除能力。
图2化合物4d的体外抗氧化能力。
图3化合物4d提高衰老果蝇的攀爬能力。
图4化合物4d延长果蝇的寿命。
具体实施方式
下面结合具体实施例对本发明做进一步的描述。
仪器和试剂:熔点采用X-4显微熔点仪测定(温度未经校正);核磁共振氢谱采用BrukerAVANCE III 500核磁共振仪测定(CDCl3为溶剂,TMS为内标);质谱采用Agilent1100四级杆液相色谱质谱联用仪测定。薄层色谱用硅胶GF254购于阿拉丁试剂公司(aladdin,上海晶纯生化科技股份有限公司);柱色谱用硅胶FCP(200~300目)购于国药集团化学试剂有限公司;其他所用试剂和溶剂均为国产分析纯,根据需要经无水干燥处理后使用。
本发明所要保护的化合物的合成路线如下:
羟醛缩合反应最经典的催化条件是碱性催化(KOH/NaOH),但由于本发明所用的苯甲醛含有酚羟基(2a-e),在强碱性条下易发生羟基氢的解离,形成的O-会增强对苯环的给电子共轭作用,从而降低醛羰基的反应活性而影响反应的进行,因此这类醛不适合直接在强碱性条件下催化。通过查阅文献,结合实验室本身条件,先采用3,4-二氢-2H-吡喃进行酚羟基的保护,再用经典的KOH/EtOH-H2O体系催化反应。
目标化合物4a-4e的合成方法:取一洁净干燥的50mL圆底烧瓶,加入大小适宜的磁力搅拌子。向其中加入通过商业或预先制备的方式获得带有不同取代基的酚羟基苯甲醛1.04mmol,将3.12mmol 3,4-二氢-2H-吡喃,用10mL超干二氯甲烷作溶剂,置于磁力搅拌器上搅拌待到两底物完全溶解后,再加入13mg对甲苯磺酸吡啶盐作为催化剂。于室温中搅拌反应,用TLC监测反应进程判断反应终点。反应时间一般为24小时。反应完全后,用饱和碳酸氢钠溶液进行淬灭并用二氯甲烷(3ⅹ25mL)萃取。合并有机层用饱和食盐水(100mL)洗涤,无水MgSO4干燥,抽滤,减压浓缩,将浓缩所得固体与抽滤所得固体合并为粗产物,粗产物经过硅胶色谱纯化,得到中间体3a-3e。
取一洁净干燥的25mL圆底烧瓶,加入大小适宜的磁力搅拌子。向其中加入0.52mmol新制备的中间体3a-3e,0.52mmolβ-紫罗兰酮用6mL无水乙醇溶解。置于磁力搅拌器上搅拌,当两底物完全溶解后滴加1.42mmol新配制的10%NaOH溶液。于室温中搅拌反应,用TLC监测反应进程判断反应终点。反应时间一般为2小时。反应完全后用饱和NH4Cl水溶液(4mL)淬灭并用乙酸乙酯(3ⅹ10mL)萃取。合并的有机层用饱和食盐水(15mL)洗涤,无水MgSO4干燥,抽滤,减压浓缩,将浓缩所得固体与抽滤所得固体合并为粗产物,粗产物经硅胶色谱纯化,得到带有THP保护的化合物。接着另取一洁净干燥的25mL圆底烧瓶,加入大小适宜的磁力搅拌子。向其中加入带有THP保护的化合物,用10mL甲醇溶解。滴加1.42mmol新配制的10%HCl溶液。于室温中搅拌反应,用TLC监测反应进程判断反应终点。反应迅速一般为5-10分钟。用饱和碳酸氢钠溶液进行淬灭并用乙酸乙酯(3ⅹ10mL)萃取。合并有机层用饱和食盐水(100mL)洗涤,无水MgSO4干燥,抽滤,减压浓缩,将浓缩所得固体与抽滤所得固体合并为粗产物,粗产物经过重结晶纯化,得到目标化合物4a-4e。
化合物:4a
(1E,4E)-1-(4-羟基苯基)-5-(2,6,6-三甲基环己-1-烯-1-基)五-1,4-二烯-3-酮(1E,4E)-1-(4-hydroxyphenyl)-5-(2,6,6-trimethylcyclohex-1-en-1-yl)penta-1,4-dien-3-one(4a).Orange powder,26%yield.1H NMR(400MHz,DMSO-d6)δ10.06(s,1H),7.67–7.55(m,3H),7.37(d,J=16.1Hz,1H),7.07(d,J=15.9Hz,1H),6.81(d,J=8.2Hz,2H),6.53(d,J=16.1Hz,1H),2.08(t,J=6.3Hz,2H),1.78(s,3H),1.64–1.55(m,2H),1.50–1.43(m,2H),1.08(s,6H).13CNMR(101MHz,DMSO-d6)δ187.98,159.97,142.75,140.82,136.03,130.68(3),129.79,125.78,122.73,115.84(2),33.80,33.17,28.69(2),21.60,18.48.HRMS(ESI):Calculated for C20H25O2[M+H]+:297.1849,Found 297.1852.
化合物:4b
(1E,4E)-1-(3-溴-4-羟基苯基)-5-(2,6,6-三甲基环己-1-烯-1-基)五-1,4-二烯-3-酮(1E,4E)-1-(3-bromo-4-hydroxyphenyl)-5-(2,6,6-trimethylcyclohex-1-en-1-yl)penta-1,4-dien-3-one(4b).Yellow solid,10%yield.1H NMR(400MHz,DMSO-d6)δ10.87(s,1H),7.99(d,J=1.6Hz,1H),7.64–7.59(m,1H),7.55(d,J=15.9Hz,1H),7.40(d,J=16.1Hz,1H),7.16(d,J=15.9Hz,1H),6.98(d,J=8.4Hz,1H),6.53(d,J=16.1Hz,1H),2.08(t,J=5.7Hz,2H),1.79(s,3H),1.66–1.54(m,2H),1.50–1.42(m,2H),1.08(s,6H).13CNMR(101MHz,DMSO-d6)δ187.94,156.17,141.15,141.09,136.42,136.01,133.18,129.62(2),127.57,124.04,116.49,110.00,33.77,33.19,28.66(2),21.56,18.44.HRMS(ESI):Calculated for C20H24BrO2[M+H]+:375.0954,Found 375.0945.
化合物:4c
(1E,4E)-1-(4-羟基-2-甲氧基苯基)-5-(2,6,6-三甲基环己-1-烯-1-基)五-1,4-二烯-3-酮(1E,4E)-1-(4-hydroxy-2-methoxyphenyl)-5-(2,6,6-trimethylcyclohex-1-en-1-yl)penta-1,4-dien-3-one(4c).Yellow solid,15%yield.1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),7.81(d,J=15.9Hz,1H),7.63(d,J=8.5Hz,1H),7.34(d,J=16.1Hz,1H),7.08(d,J=15.9Hz,1H),6.49–6.39(m,3H),3.82(s,3H),2.07(t,J=6.3Hz,2H),1.77(s,3H),1.64–1.53(m,2H),1.49–1.41(m,2H),1.07(s,6H).13C NMR(101MHz,DMSO-d6)δ188.14,161.75,160.09,140.53,137.47,136.03,135.95,130.39,130.12,122.25,114.33,108.28,99.11,55.56,33.81,33.17,28.70(2),21.58,18.50.HRMS(ESI):Calculated forC21H27O3[M+H]+:327.1955,Found 327.1963.
化合物:4d
(1E,4E)-1-(3-乙氧基-4-羟基苯基)-5-(2,6,6-三甲基环己-1-烯-1-基)五-1,4-二烯-3-酮(1E,4E)-1-(3-ethoxy-4-hydroxyphenyl)-5-(2,6,6-trimethylcyclohex-1-en-1-yl)penta-1,4-dien-3-one(4d).Light green solid,12%yield.1H NMR(400MHz,CDCl3)δ7.59(d,J=15.9Hz,1H),7.48(d,J=16.0Hz,1H),7.14(dd,J=8.2,1.9Hz,1H),7.07(d,J=1.5Hz,1H),6.93(d,J=8.2Hz,1H),6.82(d,J=15.9Hz,1H),6.48(d,J=16.0Hz,1H),6.01(s,1H),4.16(q,J=6.9Hz,2H),2.09(t,J=6.4Hz,2H),1.82(s,3H),1.67–1.60(m,2H),1.52–1.45(m,5H),1.11(s,6H).13C NMR(101MHz,CDCl3)δ189.22,148.36,146.23,143.20,142.83,136.73,136.46,129.55,127.56,123.85,123.25,114.89,110.75,64.75,39.96,34.32,33.82,29.02(2),22.03,19.07,14.95.HRMS(ESI):Calculated for C22H29O3[M+H]+:341.2111,Found 341.2108.
化合物:4e
(1E,4E)-1-(3-羟基-4-甲氧基苯基)-5-(2,6,6-三甲基环己-1-烯-1-基)五-1,4-二烯-3-酮(1E,4E)-1-(3-hydroxy-4-methoxyphenyl)-5-(2,6,6-trimethylcyclohex-1-en-1-yl)penta-1,4-dien-3-one(4e).Yellow powder,15%yield.1H NMR(400MHz,DMSO-d6)δ9.19(s,1H),7.54(d,J=15.9Hz,1H),7.38(d,J=16.0Hz,1H),7.19(d,J=7.3Hz,2H),7.07–6.95(m,2H),6.56(d,J=16.0Hz,1H),3.82(s,3H),2.08(t,J=6.4Hz,2H),1.78(s,3H),1.64–1.54(m,2H),1.51–1.42(m,2H),1.08(s,6H).13C NMR(101MHz,DMSO-d6)δ187.99,150.17,146.69,142.77,140.95,136.18,136.04,129.70,127.63,123.65,121.84,114.41,111.95,55.67,33.80,33.19,28.69(2),21.61,18.49.HRMS(ESI):Calculated forC21H27O3[M+H]+:327.1955,Found 327.1960.
测试例1化合物对自由基的清除能力
在本实施例中,我们测定了所合成的β-紫罗兰酮衍生物在1mmol浓度下对2,2-二苯基-1-苦基肼(DPPH)自由基和羟基自由基的清除作用,并用维生素C(Vc)作为阳性对照。DPPH是一种稳定的自由基,溶于甲醇后显紫色,在515nm处具有最大吸收峰。其被Vc还原后颜色会变浅。因此,根据吸光度的变化可以检测我们所合成的β-紫罗兰酮衍生物清除DPPH自由基的能力,进而对其抗氧化活性进行评价。羟基自由基(·OH)是人体内活性最强的自由基,能与活细胞中核酸、蛋白质等发生反应,从而导致机体衰老和多种疾病产生。邻二氮菲能与多种金属离子(如Fe3+)形成配合物,可用作氧化还原指示剂。H2O2与Fe2+可发生芬顿反应产生·OH自由基,加入邻二氮菲后,将与铁离子(Fe3+)、·OH反应,生成血红色络合物[Fe(pHen)3]2+,该络合物在510nm处有较强吸收。再加入β-紫罗兰酮衍生物等自由基清除剂时,将会清除部分·OH自由基,导致[Fe(pHen)3]2+络合物生成量减少。通过紫外分光光度法在510nm测定吸光度值,计算相应的清除率,可得知清除羟基自由基效果。清除率越高,抗氧化活性越强。具体实验结果如图1所示。我们的实验结果表明,相对于先导化合物β-紫罗兰酮,我们所合成的β-紫罗兰酮衍生物均具有更好的对DPPH和羟基自由基的清除效果;同时在这个衍生物中,化合物4d表现出最好的自由基清除活性。
实施例2化合物4d的体外抗氧化能力:
为进一步评价目标化合物4d的抗氧化活性。我们以维生素C(Vc)为阳性对照,测定了目标化合物4d对DPPH自由基、羟基自由基(·OH)、ABTS(2,2'-azinobis(3-ethylbenzothiazolin-6-sulfonic acid ammonium salt)的清除能力、以及总还原能力和总抗氧化能力,实验结果如图2A所示,结果表明4d对DPPH清除率呈浓度依赖性增加,5mmol时清除率最大为72.31%,4d和Vc的半数最大抑制浓度(IC50)分别为1.61和2.52mmol。同样的,4d显示出对羟基自由基(·OH)和ABTS的剂量依赖性清除活性(图2B和2C)。如图2D所示,4d的总抗氧化能力2也呈浓度依赖性增加且其抗氧化能力强于Vc。总体而言化合物4d表现出良好的抗氧化活性。
实施例3化合物4d提高衰老果蝇的攀爬能力:
运动能力是衡量果蝇健康水平的一个重要指标,垂直爬行能力可以直观的显示果蝇的肌肉质量,从而反映果蝇的运动能力。为了评估化合物4d对果蝇健康和运动能力的影响,我们测试了化合物4d是否能改变果蝇逆重力爬行的生理特性。在本实施例中,我们通过测量果蝇在有限时间内的攀爬能力即攀爬距离,通过与对照组果蝇在有限时间内的攀爬距离对比,可以得出相关化合物对果蝇健康寿命的影响。本实验收集12h内羽化未交配的果蝇720只,采用CO2轻微麻醉后鉴别雌雄,雌雄各半,随机分为四组分别为:空白对照组,目标化合物低、中、高剂量组,每组6支培养管,其中雌雄果蝇每组3管,每管30只果蝇。每5天更换一次培养基。低、中、高剂量组的果蝇喂食含有不同浓度的目标化合物,对照组喂食基础培养基。在果蝇饲养的第10天和第30天,对其攀爬能力进行测试。将实验果蝇置于垂直放置的空试管中,使其适应试管5分钟。然后将果蝇轻晃到试管底部,使其本能地沿管内壁向上爬。记录能够在10秒(A)内爬升8厘米的果蝇数量。每组果蝇至少测试5次,每次至少1分钟,每次测试施加相同的振动力。攀爬指数计算为成功攀爬8cm的果蝇总数除以总数(Cl=A/总数)。实验结果如图3所示,无论雌雄果蝇在自然老化过程中,攀爬指数逐渐下降显示其攀爬能力随着衰老而下降。在第10天,我们测试了雄性和雌性果蝇的攀爬能力,发现其与对照组相比没有显著性差异。在第30天,我们再一次测试了雌雄果蝇的攀爬能力,结果显示雄性果蝇4d给药组(高、中、低)三组的攀爬指数都明显高于对照组(P<0.01)。雌性果蝇给药组(高、中、低)三组的攀爬指数也都高于对照组,且除低剂量组外结果都存在显著性差异(P<0.01)。综上所述,我们认为化合物4d可以提高衰老果蝇的攀爬能力,即化合物4d有利于老年果蝇运动能力的恢复。
实施例4化合物4d延长果蝇的寿命:
由于果蝇生存时间短,所以其可以快速完整地模拟衰老的进程,自然衰老模型一般被用于研究自然状态下寿命变化。本实验收集12h内羽化未交配的果蝇480只,采用CO2轻微麻醉后鉴别雌雄,雌雄各半,随机分为四组分别为:空白对照组,目标化合物低、中、高剂量组。每组6管,每管20至25只果蝇。实验开始后每5天更换一次培养基。每天观察记录果蝇的存活率和存活时间,直至其全部死亡。绘制每组果蝇的寿命曲线,计算每组果蝇的平均寿命、中位数和最大寿命。最长寿命计算为存活时间最长的10%果蝇的平均寿命。为进一步评估化合物4d对果蝇寿命的影响,我们用含不同浓度化合物的培养基进行果蝇饲养,获得果蝇存活曲线。实验结果如图4所示,与对照组相比,给药组可以显著延长雌性果蝇的整体寿命和中位寿命。且在给药44天后,药物组死亡率开始低于对照组,存活曲线右移。这些结果表明化合物4d对果蝇衰老具有延缓作用。
Claims (10)
2.根据权利要求1所述的β-紫罗兰酮衍生物,其特征在于,所述的R选自氢、C1~C5烷氧基、卤素、CF3、二甲氨基、C1~C5烷基、羟基、环丙基、硝基或者NH2中的一个。
3.根据权利要求2所述的β-紫罗兰酮衍生物,其特征在于,所述的R选自H、F、Cl、Br、CF3、NO2、二甲氨基、甲氧基、乙氧基、甲基、羟基、环丙基中的一个。
4.一种如权利要求1~3任一项所述的β-紫罗兰酮衍生物的应用,其特征在于,所述的β-紫罗兰酮衍生物用于制备抗氧化药物和/或抗衰老药物。
5.根据权利要求4所述的β-紫罗兰酮衍生物的应用,其特征在于,所述的β-紫罗兰酮衍生物是通过清除自由基来获得抗氧化的功效。
6.根据权利要求4所述的β-紫罗兰酮衍生物的应用,其特征在于,所述的β-紫罗兰酮衍生物的抗衰老作用是通过抑制体内丙二醛的积累,并提高过氧化氢酶和超氧化物歧化酶活性来实现的。
7.根据权利要求4~6任一项所述的β-紫罗兰酮衍生物的应用,其特征在于,所述的β-紫罗兰酮衍生物中,R为氢、Br、甲氧基或乙氧基。
9.一种如权利要求1~3任一项所述的β-紫罗兰酮衍生物的制备方法,其特征在于,包括以下步骤:
苯酚醛类经PPTS保护后,与β-紫罗兰酮在碱性条件下进行缩合反应,反应结束后经过后处理得到所述的β-紫罗兰酮衍生物;
缩合反应所用的溶剂为乙醇和水的混合物,体积为1~2:1;
所述的碱性条件所用的碱为氢氧化钠。
10.一种药物制剂,包括有效成分和药用辅料,其特征在于,所述的有效成分包括权利要求1~3任一项所述的β-紫罗兰酮衍生物;
所述的药物制剂为注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、软膏剂、控释剂、缓释剂或纳米制剂的任一种。
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