CN117064900A - 化合物(s)-sto021在制备抗衰老药物上的用途 - Google Patents
化合物(s)-sto021在制备抗衰老药物上的用途 Download PDFInfo
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Abstract
本发明属于医药技术领域,尤其是涉及一种化合物(S)‑STO021在制备抗衰老以及与衰老相关疾病的药物中的用途。本发明证实了(S)‑STO021较好地抑制细胞衰老的效果,具体涉及改善骨髓间充质干细胞(BMSC)衰老后的形态并促进其增殖和集落形成,抑制衰老染色质变化异染色质灶(SAHF)阳性细胞率,并显著抑制衰老相关生物标志物的功能,如β‑半乳糖苷酶(SA‑β‑gal)活性,以及p16和p21相关mRNA和蛋白的表达水平,具备了良好防止细胞衰老的功能且安全可靠。通过将所述的化合物(S)‑STO021制备成为用于治疗衰老以及与衰老相关疾病的药物具有较好的商业价值。
Description
技术领域
本发明属于医药技术领域,尤其是涉及一种化合物(S)-STO021在制备抗衰老药物上的用途。
背景技术
衰老是一种复杂的生物学过程,通常被定义为机体生理完整性随年龄增长而进行性丧失最终导致机体功能退化的不可逆现象。老龄化已成为全球关注的重要公共卫生问题,人口老龄化会导致衰老性疾病的发病率不断增高,如骨质疏松症、阿尔兹海默症、心血管疾病等。抗衰老药物按理化属性可分为:①化学药物,包括抗氧化剂、抗衰老激素、营养素、单胺氧化酶抑制剂、免疫调节剂、生化制剂、大脑功能促进药等;②中药,包括单味中药如抗哀老植物药、抗衰老动物药、抗衰老矿物药以及复方制剂等。虽然市场上存在大量抗衰老药物,其中代表性药物是白藜芦醇、雷帕霉素、二甲双胍,但这些药物有些是老药新用、有些则是近年来为其他医疗目的如抗高血压、降血脂、抗肿瘤而研制出来的新药,专一用作抗衰老的药物目前还很少。因此,研发专一有效的抗衰老及衰老相关疾病药物已经吸引了相关领域科学家的目光,这可以为人类衰老时的健康提供重要保障。
白藜芦醇(resveratrol)是一种广泛存在于葡萄皮、花生、虎杖、藜芦、决明等植物中的多酚类化合物。大量研究表明白藜芦醇具备了广泛的生物多样性,涉及抗衰老、抗肿瘤、抗心血管疾病、抗炎、抗氧化、抗自由基、保肝、神经细胞保护、雌激素样作用及调节骨代谢等多种药理学作用,其中抗衰老活性是目前研究最明确的适应症之一。2003年K.T.Howitz等学者提出白藜芦醇可作为最强的沉默信息调节因子1(silentinformationregulation 2 homolog 1,SIRTl)的激活剂,参与有机生物平均生命期的调控(Nature 2006,444,337)。SIRTl作为一种多功能转录调节因子,能够使多种控制代谢及内分泌信号的转录因子(FOXO、PGCl-α、p53、PPAR-γ及NF-κB)脱乙酰基而调节其活性,进而广泛参与调控哺乳动物细胞寿命的多条信号通路,并与细胞的存活和代谢过程及增殖、衰老和凋亡等生命活动密切相关(Nature 2011,477,482)。白藜芦醇是SIRT 1的强诱导剂,能增加SIRTl在脑、心、肠、肾、肌肉和脂肪等器官组织中的表达,已有证据表明白藜芦醇所引起的生理变化包括延缓衰老和延长寿命,最显著者可延长50%(Trends EndocrinalMetabol,2009,20,325)。此外,白藜芦醇可竞争性抑制cAMP磷酸二酯酶,致cAMP降解受阻而提高其表达水平,从而激活cAMP效应蛋白Epacl,引起Ca2+通道开放,Ca2+内流增加,进一步激活CamKK8-AMPK途径,导致NAD+及SIRT l活性增强,最终改善年龄相关代谢表型(Cell2012,148,421),因此,基于以上白藜芦醇抗衰老的机制研究不仅为抗衰老适应症应用提供了理论依据,而且摄入白藜芦醇能使酵母、线虫、果蝇和低等鱼类等延长寿命的科学数据已得到科学家们的广泛认可(Nature,2004,430,686)。
从中药金雀根中提取的植物雌激素样抗骨质疏松活性作用的白藜芦醇倍半体(±)-Isopaucifloral F,通过成药性结构优化,经引入2个对骨高度靶向性质的双磷酸酯基团后合成得到了光学异构体化合物(S)-STO021。
化合物(S)-STO021的结构如式(I)所示:
化合物(S)-STO021的全称为:(S)-4-(3-((二乙氧基磷酰基)氧基)-2-(3,5-二羟基苯基)-5,7-二羟基-1H-茚-1-基)苯基磷酸二乙酯,分子量:636.15;
式(I)所示化合物(S)-STO021体外研究不仅证明了它具有抑骨吸收和促骨形成的双重作用机制,尤其在抗骨质疏松作用方面表现优异。例如在斑马鱼模型中,口服给药浓度25μg/mL时,明显恢复骨量;在去卵巢大鼠的骨质疏松模型中,在4mg·kg-1的给药剂量下,化合物(S)-STO021给药去卵巢SD大鼠24周,经Micro-CT对腰椎骨和股骨的骨微结构研究发现,能够时间和浓度依赖性地恢复大鼠骨质疏松的症状,优于或相当于临床一线药物阿伦磷酸钠。特别是在大鼠体内具有好的口服生物利用度(46.2%),适宜于口服给药,拓展抗骨质疏松临床药物具有较大的商业应用价值。但是,鉴于化合物(S)-STO021具有白藜芦醇倍半体的优势骨架,其抗衰老活性至今未见文献报道。
发明内容
基于现有技术中未有化合物(S)-STO021与抗衰老活性相关的研究,本发明提供一种化合物(S)-STO021在制备抗衰老药物上的用途。
本发明的目的可以通过以下技术方案来实现:
本发明提供化合物(S)-STO021在制备抗衰老以及与衰老相关疾病的药物中的用途;所述化合物(S)-STO021结构式如式(I)所示:
化合物(S)-STO021的全称为:(S)-4-(3-((二乙氧基磷酰基)氧基)-2-(3,5-二羟基苯基)-5,7-二羟基-1H-茚-1-基)苯基磷酸二乙酯,分子量:636.15;
化合物(S)-STO021来源于天然植物金雀根中具有植物激素样活性的白藜芦醇倍半体(±)-Isopaucifloral F经双磷酸酯化结构优化、并通过合成消旋体后进行手性拆分得到的单一构型化合物。
在本发明的一些实施方式中,所述药物还包含药学上可接受的药用盐。所述药用盐包括无机酸盐与有机酸盐,无机酸盐包括但不限于:盐酸盐、硫酸盐、磷酸盐、二磷酸盐、氢溴酸盐和硫酸盐;有机酸盐包括但不限于:苹果酸盐、马来酸盐、延胡索酸盐、酒石酸盐、琥珀酸盐、柠檬酸盐、醋酸盐、乳酸盐、甲磺酸盐、对甲苯磺酸盐、双羟萘酸盐、水杨酸盐和硬脂酸盐。
在本发明的一些实施方式中,所述药物还包含药学上可接受的载体。
在本发明的一些实施方式中,所述药物的剂型为片剂、丸剂、粉剂、液体剂、混悬剂、乳剂、颗粒剂、胶囊剂、糖浆剂、栓剂、注射液、软膏、贴剂、眼科液体剂或滴鼻剂。本发明药物的剂型没有特别限制,可根据治疗目的或者给药方案来选择。
在本发明的一些实施方式中,所述抗衰老为延缓衰老、或改善与衰老相关的外貌变化;所述衰老相关疾病为动脉粥样硬化、骨骼畸形或II型糖尿病等。
在本发明的一些实施方式中,所述化合物(S)-STO021在制备恢复衰老的BMSC细胞形态,促进BMSC细胞的增殖和集落形成的药物中的用途。
在本发明的一些实施方式中,所述化合物(S)-STO021在制备降低衰老时染色质变化异染色质灶(SAHF)阳性细胞率的药物中的用途。
在本发明的一些实施方式中,所述化合物(S)-STO021在制备降低衰老标志物β-半乳糖苷酶(SA-β-gal)、p16和p21的mRNA及蛋白表达水平的药物中的用途。
考虑到(S)-STO021具有类似植物雌激素样的作用,本发明针对它聚焦人类衰老过程中涉及的相关生物标志物开展了较系统的功能调控作用。例如骨髓间充质干细胞(BoneMarrow Stromal Cell,BMSC)作为长寿命细胞,在应激条件下更容易发生衰老。因此,本发明通过应激刺激因子即电离辐射诱导BMSC细胞衰老,给予药物(S)-STO021干预,在白藜芦醇(Res)作为阳性对照的情况下,观察对衰老BMSC细胞的作用以及退行性分化潜能的影响,其中包括鉴别衰老相关染色质变化的特殊标志异染色质病灶(SAHF,在DAPI染色的衰老细胞中形成点状DNA病灶)的阳性细胞率以及衰老细胞的生物学标志物β-半乳糖苷酶的表达和p16INK4A和p21Cip1(p16和p21,可反映细胞衰老和生物老化)的表达,进而考察(S)-STO021防止细胞衰老的效果。
本发明在细胞水平研究发现(S)-STO021对BMSC细胞的活力具有剂量依赖地恢复;能够改善BMSC细胞衰老后的形态、显著提高其增殖能力,增加其集落形成率,并且异染色质灶(SAHF)阳性染色结果发现(S)-STO021显著降低染色质变化异染色质灶(SAHF)阳性细胞率;衰老标志物β-半乳糖苷酶(SA-β-gal)染色结果发现(S)-STO021降低SA-β-gal的表达水平;RT-qRCR和Western Blot结果显示(S)-STO021可剂量依赖性地降低衰老标志物p16和p21的mRNA和蛋白表达水平。
本发明研究发现,所述化合物(S)-STO021在人类衰老过程中针对相关生物标志物的功能可发挥关键性的调控作用,证明它在抗衰老方面具有较为显著的作用,进而达到较好地防止细胞衰老的效果。
本发明研究发现,化合物(S)-STO021在小鼠体内最大耐受剂量考察实验中的血清肝、肾功能指标评价表明(S)-STO021未表现出明显的肝、肾功能异常或损伤;脏器HE染色结果同样未见明显的器官炎症或损伤,其LD50>300mg/kg,治疗指数TI>75,表明(S)-STO021具有较宽的治疗窗和优秀的安全性。在hERG心脏毒性评价实验中,(S)-STO021对hERG钾离子通道的IC50>30μM,心脏毒性低。
因此,本发明中,所述化合物(S)-STO021在制备具备抗衰老作用的同时显示了较好的体内安全性。
本发明药物的给药时间没有特别的限制,可根据目标疾病进行适当的选择。
与现有技术相比,本发明具有以下优点及有益效果:
1)化合物(S)-STO021具有较好的改善BMSC细胞衰老形态和提高其增殖和集落形成能力,其同等剂量在体内优于或相当于阳性对照药白藜芦醇。
2)化合物(S)-STO021具有显著的降低衰老的染色质变化、降低异染色质灶(SAHF)阳性细胞率的能力,其同等剂量在体内优于阳性对照药白藜芦醇。
3)化合物(S)-STO021具有显著的降低衰老标志物β-半乳糖苷酶(SA-β-gal)的活性及p16和p21的基因及蛋白表达的能力,其同等剂量在体内均优于阳性对照药白藜芦醇。
4)化合物(S)-STO021能够降低衰老的染色质变化和衰老生物标志物的表达,可被用于制备抗衰老及衰老相关疾病的药物应用。
5)化合物(S)-STO021具有优秀的体内安全性和较低的心脏毒性,具有开发抗衰老药物的潜力。
附图说明
图1:化合物(S)-STO021对BMSC细胞活力的影响。
图2:化合物(S)-STO021对衰老BMSC细胞形态变化产生的影响。
图3:化合物(S)-STO021对衰老BMSC细胞集落形成情况的影响。
图4:化合物(S)-STO021对衰老相关异染色质灶(SAHF)阳性细胞率的影响。
图5:化合物(S)-STO021对衰老生物标志物β-半乳糖苷酶(SA-β-gal)的表达水平的影响。
图6:化合物(S)-STO021对衰老相关基因p16和p21的mRNA的表达水平的影响。
图7:化合物(S)-STO021对衰老相关蛋白p16和p21的蛋白表达水平的影响。
图8:化合物(S)-STO021的小鼠体内最大耐受剂量考察和hERG心脏毒性评价结果。图8包括图8-1和图8-2。
具体实施方式
下面结合附图和具体实施例对本发明进行详细说明。
下面结合实施例对本发明作进一步阐述,由于篇幅原因,实验过程的描述无法做到非常详细,凡是实验中未详细描述的部分均为本领域技术人员熟知的常规操作,但实施例绝不是对本发明的任何限制。
下列实施例中所用方法如无特别说明,均为常规方法,以下实施中所需的试剂,如无特殊说明均为市场购得。
实例中的数据分析均采用Graphpad Prism 8.0统计分析软件进行One-Way ANOVA多组比较。
实施例1(S)-4-(3-((二乙氧基磷酰基)氧基)-2-(3,5-二羟基苯基)-5,7-二羟基-1H-茚-1-基)苯基磷酸二乙酯[(S)-STO021]的制备
(S)-STO021的制备路线如下所示:
反应条件:(I)N,O-二甲基羟胺盐酸盐,三乙胺,二氯甲烷,0℃;(II)3,5-二甲氧基溴苯,正丁基锂,无水四氢呋喃,氮气保护,-78℃;(III)溴三苯基(4-((三异丙基甲硅烷基)氧基)苄基)-λ5-膦,双(三甲基硅烷基)氨基钾,甲苯,60℃;(Ⅳ)四丁基氟化铵,四氢呋喃;(Ⅴ)三氟化硼乙醚,二氯甲烷;(Ⅵ)氯磷酸二乙酯,氢化钠,无水四氢呋喃;(Ⅶ)三溴化硼,二氯甲烷,0℃;(VIII)手性柱拆分条件:高效液相色谱仪:岛津LC-20AT,CP-HPLC-07;流动相:7:1:2=正己烷/二氯甲烷/乙醇;流速:1.0mL/min;温度:35℃;紫外检测波长:254nm;运行时间:10min;进样量:5μL。
1)化合物2(N1,N2-二甲氧基-N1,N2-二甲基酰胺)的合成:化合物1(草酰氯)(10.0mL,110mmol)和二甲羟胺盐酸盐(23.70g,237mmol)溶解在230mL无水二氯甲烷中,冰浴条件下搅拌加入三乙胺(66.6mL,480mmol),0℃反应30min,升温至室温搅拌30min,加水淬灭反应,二氯甲烷萃取,合并有机层,旋干,得化合物2粗品。重结晶,干燥后得化合物2。结构表征:白色晶体;1H NMR(CDCl3,400MHz)δ3.16(s,6H),3.66(s,6H)ppm.ESI-MS:m/z 176.1[M+H]+。
2)化合物3(3,3′,5,5′-四甲氧基二苯基乙二酮)的合成:称取1-溴-3,5-二甲氧基苯(10.36g,47mmol)于250mL三口瓶中,加入50mL无水四氢呋喃搅拌使其充分溶解,N2保护;-78℃的条件下加入18mL正丁基锂(29.00g,450mmol);化合物2(2.00g,11mmol)以8mL无水四氢呋喃充分溶解,用注射器将溶解好的化合物2注入三口瓶中,-78℃搅拌5min。将体系移至室温,加入适量无水乙醇后加水淬灭反应。低温放置,化合物3以黄色晶体形式析出,过滤得化合物3。结构表征:黄色晶体;1H NMR(CDCl3,400MHz)δ6.93(d,J=1.7Hz,4H),6.73(s,2H),3.97(s,12H)ppm.ESI-MS:m/z 330.1[M+H]+。
3)化合物4(1,2-双(3,5-二甲氧苯基)-3-三苯基硅烷乙二酮)的合成:化合物3(5.00g,15mmol)与Wittig试剂(15.00g,25mmol)于250mL圆底烧瓶中,加入50mL无水甲苯,升温至60℃搅拌使混合均匀;60℃搅拌条件下加入25mL双(三甲基硅烷基)氨基钾(21.93g,110mmol),滴加完后搅拌20min,取样点板,待化合物3完全反应后结束反应。冷却至室温,加水淬灭反应,乙酸乙酯萃取,合并有机层,旋干,硅胶色谱柱[V(石油醚):V(乙酸乙酯)=5:1]纯化,得到化合物4。结构表征:黄绿色油状物;1H NMR(CDCl3,400MHz)δ7.67(m,1H),7.48(d,J=7.6Hz,1H),7.34(d,J=8.6Hz,4H),7.08(d,J=8.6Hz,2H),6.90(s,1H),6.85(d,J=8.5Hz,2H),6.72(d,J=11.2Hz,1H),3.78(d,J=4.1Hz,1H),1.06(m,33H)ppm.ESI-MS:m/z576.3[M+H]+。
4)化合物5(1,2-双(3,5-二甲氧苯基)-3-羟苯基乙二酮)的合成:化合物4(15.00g,26mmol)于500mL圆底烧瓶中,加入30mL无水四氢呋喃,常温下搅拌10min;加入7.2mL四丁基氟化铵(6.80g,25mmol),常温反应1h。取样点板,待化合物4充分反应后结束反应;加水淬灭反应,乙酸乙酯萃取,合并有机层,旋干,硅胶色谱柱[V(石油醚):V(乙酸乙酯)=3:1]纯化,得到化合物5。结构表征:黄色油状物;1H NMR(CDCl3,400MHz)δ7.26(s,1H),7.16(d,J=9.1Hz,1H),7.04(m,2H),6.96(s,1H),6.66-6.56(dd,J=18.8,11.7Hz,3H),6.43(m,2H),5.10(d,1H),3.77(dd,J=17.6,11.3Hz,12H)ppm.ESI-MS:m/z 420.1[M+H]+。
5)化合物6(2-(3,5-二甲氧基苯基)-3-(4-羟苯基)-4,6-二甲氧基茚酮)的合成:化合物5(9.50g,23mmol)于500mL圆底烧瓶中,加入45mL无水二氯甲烷,常温搅拌10min;加入2.86mL三氟化硼乙醚(3.21g,23mmol);常温搅拌30min;有白色固体析出,结束反应。所得白色固体即为化合物6。结构表征:白色固体;1H NMR(400MHz,CDCl3)δ6.98(s,1H),6.72(s,1H),6.45(s,4H),6.19(s,1H),5.92(d,J=2.30Hz,2H),4.90(d,J=2.75Hz,1H),4.27(d,J=2.75Hz,1H),3.90(s,3H),3.72(s,3H),3.68(s,6H)ppm;ESI-MS:m/z 420.1[M+H]+.HRMScalcd for C28H28O6[M+H]+421.1648,found 421.1651。
6)化合物7(2-(3,5-二甲氧基苯基)-3-(4-羟苯基)-4,6-二甲氧基茚酮磷酸酯衍生物)的合成:化合物6(1.20g,2.9mmol)于100mL双口瓶中,加入15mL无水四氢呋喃使其充分溶解;称取氢化钠(0.47g,19mmol)加入双口瓶中,氮气保护;常温搅拌条件下滴加0.9mL氯磷酸二乙酯(1.0g,5.8mmol),常温反应4h。取样点板,待化合物6完全反应后结束反应,化合物7具有特征性紫蓝色荧光。加水淬灭反应,乙酸乙酯萃取,合并有机层,旋干,硅胶色谱柱[V(石油醚):V(乙酸乙酯)=1:2]纯化,得到化合物7。结构表征:粉红色油状物;1H NMR(400MHz,CDCl3)δ6.94(s,1H),6.85(d,J=8.0Hz,2H),6.75(d,J=2.0Hz,2H),6.67(s,1H),6.46(s,2H),6.06(s,1H),4.66(s,1H),3.76-3.96(m,8H),3.61(s,3H),3.47(d,6H),3.32(d,3H),0.93-1.12(m,12H)ppm.ESI-MS:m/z 692.2[M+H]+。
7)(±)-STO021(2-(3,5-二羟苯基)-3-(4-羟苯基)-4,6-二羟基茚酮磷酸酯衍生物)的合成:化合物7(0.69g,1mmol)于100mL圆底烧瓶中,加入20mL无水二氯甲烷,氮气保护,0℃搅拌10min,用注射器向其中小心注入7mL三溴化硼溶液,移至室温,常温搅拌3h。取样点板,待化合物5充分反应后结束反应。乙醇与水淬灭反应,乙酸乙酯萃取三次,合并有机层,旋干,硅胶色谱柱[V(二氯甲烷):V(甲醇)=10:1]纯化,得到产物(±)-STO021。结构表征:粉紫色固体;1H NMR(400MHz,DMSO-d6)δ9.30(s,1H),9.12(d,3H),7.04(d,J=8.0Hz,2H),6.96(d,J=8.0Hz,2H),6.62(d,J=2.0Hz,1H),6.38(d,J=2.0Hz,2H),6.10(d,J=2.0Hz,1H),6.07(t,J=2.0Hz,1H),4.87(s,1H),4.11-3.96(m,8H),1.36-1.06(m,12H)ppm.ESI-MS m/z:637.1[M+H]+。
8)(S)-STO021的制备:(S)-STO021经合成的(±)-STO021通过手性柱拆分得到,手性拆分的系统条件如下:高效液相色谱仪:岛津LC-20AT,CP-HPLC-07;流动相:7:1:2=正己烷/二氯甲烷/乙醇;流速:1.0mL/min;温度:35℃;紫外检测波长:254nm;运行时间:10min;进样量:5μL。
结构表征:粉色固体;IR(film):νmax=3422.22,1603.61,1502.88,1245.20,1162.06,1030.22,843.07cm-1;1H NMR(600MHz,DMSO-d6)δ9.28(s,1H),9.11(s,2H),9.09(s,1H),7.04(d,J=8.3Hz,2H),6.95(d,J=8.3Hz,2H),6.51(s,1H),6.38(s,2H),6.08(d,J=18.6Hz,2H),4.86(d,J=4.1Hz,1H),4.18–3.94(m,9H),1.25(t,J=7.0Hz,3H),1.20(t,J=7.0Hz,6H),1.15(t,J=7.0Hz,3H)ppm;13C NMR(151MHz,DMSO-d6)δ158.05,157.74,152.80,148.30,148.25,144.11,144.05,140.40,135.98,133.86,133.13,133.09,129.16,121.03,119.12,106.64,101.68,101.35,98.17,64.27,64.23,64.11,64.05,64.01,55.91,49.33,39.95,18.45,15.69ppm.HRMS calcd forC29H34O12P4[M+H]+637.1616,found 637.1612。
实施例2化合物(S)-STO021对BMSC细胞活力具有剂量依赖地恢复
BMSC细胞按各组照射计划照射24h后更换相应组别的培养液,培养1-7天,分别于照射后3、5、7天时间点使用CCK8试剂盒检测细胞活力。弃去培养液,各孔加入含有10%CCK8试剂的培养液,避光孵育,酶标仪450nm处测得吸光度值,表示细胞活力。结果如图1所示,结果显示(S)-STO021(0.1~10μM)处理可恢复照射处理过的BMSC细胞活力(***p<0.001)。
实施例3化合物(S)-STO021在一定程度上恢复BMSC细胞形态的损伤
照射计划如下,137Csγ射线,剂量为2Gy。取生长状态良好的P2~P3代小鼠BMSC细胞,接种培养24h后,采用137Csγ射线照射,剂量为2Gy。将对照组细胞(0Gy)置于辐照器中相同时间,但不接受辐射,后续培养条件与照射组细胞相同。
化合物(S)-STO021(0.1~10μM)处理用137Csγ射线照射24h后的BMSC细胞24h,使用四甲基罗丹明(TRITC)标记的鬼笔环肽对F-肌动蛋白(F-actin)染色,用DAPI对细胞核染色,观察各组BMSCs的细胞形态变化。方法简要描述如下:收集生长状态良好的P2~P3代BMSC细胞,以每孔5×103个细胞接种于48孔板,培养24h后,按各组照射计划照射,照射24h后将上述浓度的(S)-STO021加入小鼠BMSC培养24h,2.5%戊二醛室温下固定细胞10min,PBS清洗固定液。每孔加入200μL TRITC标记的鬼笔环肽工作液覆盖细胞,室温下避光孵育。PBS清洗后,每孔加入200μL DAPI溶液,室温下避光孵育。PBS清洗后,使用徕卡荧光显微镜观察并拍摄图像,观察各组BMSC细胞的形态变化。结果如图2所示,图2显示的是400X的放大照片,结果显示:对照组(0Gy)细胞具有星状或成纤维细胞样形态,边界清晰,而2Gy剂量可引起BMSC细胞形态的改变,视野内细胞稀少,边界模糊不清,胞体变大;使用抗衰老阳性药物白藜芦醇和测试药物(S)-STO021后,形态的损伤及视野内细胞较少的情况有一定程度的恢复。
实施例4化合物(S)-STO021可增强BMSC细胞的集落形成情况
(A)用结晶紫法进行集落染色,方法简要描述为,用137Csγ射线照射BMSC细胞24h后,用含相应组别化合物培养基培养细胞2~3周,待其成集落样生长,培养皿中出现肉眼可见的克隆时,终止培养,进行染色观察,并于显微镜下观察各组BMSC集落形成情况。
(B)对集落进行定量分析,测定BMSC集落形成率。结果如图3所示,结果显示:(S)-STO021(0.1~10μM,**p<0.01)能够提高BMSC细胞的集落形成率。
实施例5化合物(S)-STO021可显著降低衰老相关异染色质灶(SAHF)阳性细胞率
BMSC细胞接种于细胞培养专用爬片,按各组照射计划照射,照射24小时后更换相应组别的培养液。培养1天后,使用DAPI荧光染色法显示各组BMSCs细胞核中衰老相关异染色质灶点。染色方法简述为,2.5%戊二醛室温下固定细胞10min,PBS清洗固定液,每孔加入200μL DAPI溶液,室温下避光孵育。PBS清洗后,使用激光共聚焦显微镜进行观察拍照,观察各组BMSC细胞核中衰老相关异染色质灶点。参考图4,点状DNA焦点的衰老相关异染色质灶(SAHF)形成(200X)(A)和SAHF阳性细胞比例分析结果(B)显示(S)-STO021(0.1~10μM,***p<0.001)可显著降低点状DNA焦点的衰老相关异染色质灶(SAHF)形成,显著降低衰老相关异染色质灶(SAHF)阳性细胞率。
实施例6化合物(S)-STO021可显著降低衰老相关β-半乳糖苷酶(SA-β-gal)的表达水平
BMSC细胞按各组照射计划照射24h后更换相应组别的培养液。当细胞汇合至80%左右时进行衰老相关β-半乳糖苷酶(SA-β-gal)表达的检测,使用衰老相关β-半乳糖苷酶显色试剂盒进行操作。染色方法简述为,专用固定液室温固定15min,PBS清洗后,每孔加入现配制的工作液,密封培养板,37℃(无CO2)条件下孵育染色过夜。去除染液,PBS清洗后光学显微镜下观察各组SA-β-gal的表达。
结果参考图5,SA-β-gal染色结果(A)和SA-β-gal阳性细胞比例分析(B)显示(S)-STO021(1μM)和白藜芦醇(Res,1μM)均能降低SA-β-gal的表达。与照射组相比,(S)-STO021(0.1~10μM,***p<0.001)可显著降低SA-β-gal的表达,1μM(S)-STO021降低SA-β-gal的表达水平与阳性对照白藜芦醇处于相当水平。
实施例7化合物(S)-STO021可显著降低衰老相关基因p16和p21的mRNA的表达水平
BMSC细胞按各组照射计划照射24h后更换相应组别的培养液,培养4天后采用RT-qPCR检测衰老相关基因p21、p16表达的改变。检测方法简述为,提取所收集各组细胞总RNA。以提取的细胞总RNA为模板RNA,进行RNA逆转录以获得cDNA。使用实时定量荧光PCR系统进行全程反应。程序结束后保存反应Ct值,使用2-ΔΔCq方法对指定基因的相对mRNA表达水平进行定量。GAPDH被用作对照进行标准化。结果参考图6,结果显示(S)-STO021(0.1~10μM,***p<0.001)可剂量依赖性地显著降低p16和p21的mRNA表达水平。
实施例8化合物(S)-STO021可显著降低衰老相关蛋白p16和p21的蛋白表达水平
采用Western blot检测p21、p16衰老相关蛋白表达的改变,实验内容为细胞总蛋白提取、BCA法测定蛋白浓度、蛋白变性、PAGE凝胶制备、电泳、转膜、封闭和抗体孵育。化学发光后得到显影条带,使用Image J进行蛋白条带灰度值分析。结果参考图7,结果显示(S)-STO021(0.1~10μM,***p<0.001)可显著降低p16蛋白的表达水平,同时,(S)-STO021(0.1~10μM,***p<0.001)还可剂量依赖性地降低p21蛋白的表达水平。
实施例9化合物(S)-STO021具有优秀的体内安全性和低心脏毒性
针对化合物(S)-STO021开展了小鼠体内最大耐受剂量考察。将体重为20±2g健康成年雌性Balb/c小鼠分为5组,每组8只,即分别为溶媒空白组、25mg/kg组、75mg/kg组、150mg/kg组、300mg/kg组,每天通过灌胃给药,给药容积为0.2mL/10g。对小鼠的行为状态及死亡状况连续观察并记录14天,记录其生活状态包括体重变化情况、食物摄入量变化情况以初步评价其安全性,待实验结束后,对小鼠进行眼球取血后分离血清进行肝、肾功能指标测定;取小鼠脏器称重后计算器官体重比值,再进行固定、包埋、切片和HE染色,检查其组织病理学变化。
实验结果参考图8,其中图8包括图8-1和图8-2,图8-1为A、B两幅图,图8-2为C、D两幅图,表明,(S)-STO021的LD50>300mg/kg;血清肝、肾功能指标评价表明(S)-STO021未表现出明显的肝、肾功能异常或损伤;脏器HE染色结果同样未见明显的器官炎症或损伤。
(A)中a表示5个组别(每组8只雌性小鼠)的小鼠体重在14天中随时间变化曲线,结果显示:(S)-STO021与空白组(平均增重1.63g)体重变化趋势相同,略有增加,表明口服连续给药14天后未对各组小鼠的生存状态产生明显影响;b表示5个组别(每组8只雌性小鼠)的食物摄入量在14天中随时间变化的曲线,结果显示:(S)-STO021连续给药14天未对各组小鼠的生存状态产生明显影响;c表示5个组别(每组8只雌性小鼠)的脏器与体重比值的比较,结果显示:与空白溶媒组相比,(S)-STO021组各器官体重比例无明显变化,说明(S)-STO021对小鼠安全性高。
(B)中a、b、c表示小鼠血清的肝功能指标分析结果,比较5组小鼠血清中的谷丙转氨酶(ALT,a)、谷草转氨酶(AST,b)、碱性磷酸酶(ALP,c)水平,给药组与空白溶媒组无显著性差异,证明(S)-STO021未对小鼠造成明显的肝损伤。d、e、f表示小鼠血清的肾功能指标分析结果,比较5组小鼠血清中的肌酐(CREA,d)、尿素(UREA,e)水平,发现给药组与对照组无显著差异;比较尿酸(UA,f)水平(从左至右分别为80.0、48.94、80.89、36.19、36.73μmol·L-1),发现300mg/kg的给药组相比空白组在300mg/kg时存在显著差异,*P<0.05,说明连续给药300mg/kg(S)-STO021 14天使小鼠尿酸降低,但这对肾功能的影响并不明显。
(C)表示最大耐受剂量考察结束后小鼠的脏器HE染色结果,心脏(Heart)各组HE染色结果未见明显器官毒性;肝脏(Liver)各组的肝小叶和肝细胞形态完整,内部的细胞核染色为蓝色,细胞核居中且圆而大,可以清晰看到核仁结构,无明显异常变化;脾脏(Spleen)各组脾小体形态正常,滤泡无明显增多,也未发现转化的淋巴母细胞,无明显异常变化。肺(Lung)各组组织均呈网状结构,管腔扩张正常,无明显异常变化;肾脏(Kidney)各组的肾小管扩张正常,肾小球结构清晰,细胞间质无明显充血,无明显异常变化。HE染色结果证实了(S)-STO021具有较好的体内安全性。
hERG心脏毒性评价实验通过传统膜片钳技术评估(S)-STO021的hERG抑制活性,以hERG抑制剂奎尼丁(Quinidine)作为阳性对照,空白对照为Control组。
(D)表示hERG心脏毒性评价结果。给予(S)-STO021和阳性对照药的典型电流图结果(a)显示,阴性对照钾电流最高,表明未对hERG离子通道产生阻断,而阳性对照药奎尼丁几乎将钾电流完全抑制,(S)-STO021则无抑制活性;不同浓度的(S)-STO021对Control组的电流抑制率(b)显示,可看到随着浓度变化,(S)-STO021对电流的抑制率接近于零且没有变化。化合物(S)-STO021对于hERG钾离子通道抑制活性的IC50>30μM,这一结果说明(S)-STO021在测试浓度范围内几乎无阻滞作用,心脏毒性低。
上述的对实施例的描述是为便于该技术领域的普通技术人员能理解和使用发明。熟悉本领域技术的人员显然可以容易地对这些实施例做出各种修改,并把在此说明的一般原理应用到其他实施例中而不必经过创造性的劳动。因此,本发明不限于上述实施例,本领域技术人员根据本发明的揭示,不脱离本发明范畴所做出的改进和修改都应该在本发明的保护范围之内。
Claims (10)
1.一种化合物(S)-STO021在制备抗衰老以及与衰老相关疾病的药物中的用途,其特征在于,所述化合物(S)-STO021结构式如式(I)所示:
2.根据权利要求1所述的用途,其特征在于,所述药物还包含药学上可接受的药用盐。
3.根据权利要求2所述的用途,其特征在于,所述药用盐包括无机酸盐与有机酸盐,无机酸盐选自盐酸盐、硫酸盐、磷酸盐、二磷酸盐、氢溴酸盐和硫酸盐中的一种;有机酸盐选自苹果酸盐、马来酸盐、延胡索酸盐、酒石酸盐、琥珀酸盐、柠檬酸盐、醋酸盐、乳酸盐、甲磺酸盐、对甲苯磺酸盐、双羟萘酸盐、水杨酸盐和硬脂酸盐中的一种。
4.根据权利要求1所述的用途,其特征在于,所述药物还包含药学上可接受的载体。
5.根据权利要求1所述的用途,其特征在于,所述药物的剂型为片剂、丸剂、粉剂、液体剂、混悬剂、乳剂、颗粒剂、胶囊剂、糖浆剂、栓剂、注射液、软膏、贴剂、眼科液体剂或滴鼻剂。
6.根据权利要求1所述的用途,其特征在于,所述抗衰老为延缓衰老、或改善与衰老相关的外貌变化。
7.根据权利要求1所述的用途,其特征在于,所述衰老相关疾病为动脉粥样硬化、骨骼畸形或II型糖尿病。
8.根据权利要求1所述的用途,其特征在于,所述化合物(S)-STO021在制备恢复衰老的BMSC细胞形态,促进BMSC细胞的增殖和集落形成的药物中的用途。
9.根据权利要求1所述的用途,其特征在于,所述化合物(S)-STO021在制备降低衰老时染色质变化异染色质灶阳性细胞率的药物中的用途。
10.根据权利要求1所述的用途,其特征在于,所述化合物(S)-STO021在制备降低衰老标志物β-半乳糖苷酶、p16和p21的mRNA及蛋白表达水平的药物中的用途。
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