CN101467991B - 烯丙基半胱氨酸及其类似物在制备治疗心肌损伤药物中的用途 - Google Patents
烯丙基半胱氨酸及其类似物在制备治疗心肌损伤药物中的用途 Download PDFInfo
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Abstract
本发明属制药领域,涉及烯丙基半胱氨酸及其类似物在制备心肌损伤药物中的用途,尤其是在制备治疗缺血缺氧心肌损伤药物中的用途。本发明通过体内、外心肌细胞和动物模型实验,结果证明烯丙基半胱氨酸及其类似物能提高细胞存活率,生成内源性H2S;降低缺氧缺糖损伤心肌细胞的LDH的漏出率;可提高SOD,Catalase的活性,提高组织抑制羟自由基产生的能力;抑制脂质过氧化以及具有抑制心肌细胞凋亡的作用,所述的烯丙基半胱氨酸及其类似物可作为治疗药物应用于治疗心肌损伤尤其是缺血缺氧心肌损伤心脏病。
Description
技术领域
本发明属制药领域,涉及烯丙基半胱氨酸及其类似物在制备心肌损伤药物中的用途,尤其是在制备治疗缺血缺氧心肌损伤药物中的用途。
背景技术
烯丙基半胱氨酸(SAC)是大蒜中的天然有机硫化合物,是陈年大蒜提取物(Aged garlic extract)中的主要有效成分。文献报道SAC具有抗氧化、神经保护作用及抑制过量氧自由基诱导的脂质过氧化等活性。
据文献报道SAC的烯丙基结构与其神经保护作用有一定的构效关系,SAC类似物-乙基半胱氨酸(SEC)、丙基半胱氨酸(SPC)、烯丙基巯基半胱氨酸(SAMC)也是大蒜中的天然有机硫化合物,具文献报道也具有一定的抗氧化性,丁基半胱氨酸(SBC)及戊基半胱氨酸(SPEC)较前两者结构分别延长一个和两个碳,推测具有类似抗氧化活性;化合物炔丙基半胱氨酸(SPRC)与炔丙基甘氨酸的结构有相似性,推测其对CSE酶有较好选择性。但至今未见有关SAC对缺氧缺糖损伤心肌细胞以及心肌损伤的作用的报道。
发明内容
本发明的目的是提供烯丙基半胱氨酸及其类似物在制备药物组合物中的新用途,具体涉及烯丙基半胱氨酸及其类似物在制备治疗心肌损伤药物中的用途。
本发明所述的烯丙基半胱氨酸及其类似物具有如下的分子式和结构:
SPEC C8H17O2NS
所述的烯丙基半胱氨酸类似物其中的炔丙基半胱氨酸(SPRC)通过下述合成路线合成:
L-半胱氨酸盐酸盐溶解在预冷的NH4OH(2M,240ml)溶液中,加入3-溴丙炔(14.5g,0.124mol)充分搅拌,混合溶液在0℃下搅拌2h后过滤,滤液减压蒸馏(<40℃)浓缩到较少容量后再过滤。析出固体用乙醇反复洗涤后,真空蒸干,经2∶3体积比的水/乙醇重结晶得到白色针状晶体,经核磁共振检测氢谱结构确定。
本发明通过缺氧缺糖心肌细胞实验,检测了经SAC及其类似物处理的缺氧缺糖心肌细胞的上清液,结果显示H2S的浓度明显提高,表明SAC及其类似物在体内生成内源性H2S。
本发明通过体外心肌细胞培养实验,结果证明SAC及其类似物可以提高细胞存活率,能生成内源性H2S;可降低缺氧缺糖损伤心肌细胞的LDH的漏出率;可提高SOD,Catalase的活性,提高组织抑制羟自由基产生的能力;可以抑制脂质过氧化以及具有抑制心肌细胞凋亡的作用,表明所述的烯丙基半胱氨酸及其类似物可作为治疗药物应用于治疗心肌损伤尤其是缺血缺氧心肌损伤心脏病。
附图说明
图.1是SAC及其类似物对缺氧缺糖6h/复氧复糖3h损伤的心肌细胞的存活率的影响,
其中,Control:正常对照组;Vehicle:模型组;a:模型组与正常对照组相比,p<0.05;*:SAC及其类似物各处理组与模型组相比,p<0.05。
图2是SAC及其类似物对缺氧缺糖6h/复氧复糖3h损伤的心肌细胞的H2S释放量的影响,
其中,Control:正常对照组;Vehicle:模型组,a:模型组与正常对照组相比,p<0.05;*:SAC及其类似物各处理组与模型组相比,p<0.05。
图3是SAC及其类似物对缺氧缺糖6h/复氧复糖3h损伤的心肌细胞LDH漏出率的影响,
其中,Control:正常对照组;Vehicle:模型组;a:模型组与正常对照组相比,p<0.05;*:SAC及其类似物各处理组与模型组相比,p<0.05;#:各SAC及类似物组与经PAG干预组比较,p<0.05。
图4是SAC及其类似物对缺氧缺糖6h/复氧复糖3h损伤的心肌细胞总SOD活力的影响,
其中,Control:正常对照组;Vehicle:模型组;a:模型组与正常对照组相比,p<0.05;*:SAC及其类似物各处理组与模型组相比,p<0.05;#:各SAC及类似物组与经PAG干预组比较,p<0.05。
图5是SAC及其类似物对缺氧缺糖6h/复氧复糖3h损伤的心肌细胞Cu-Zn SOD活力的影响,
其中,Control:正常对照组;Vehicle:模型组;a:模型组与正常对照组相比,p<0.05;*:SAC及其类似物各处理组与模型组相比,p<0.05;#:各SAC及类似物组与经PAG干预组比较,p<0.05。
图6是SAC及其类似物对缺氧缺糖6h/复氧复糖3h损伤的心肌细胞Mn SOD活力的影响,
其中,Control:正常对照组;Vehicle:模型组:a:模型组与正常对照组相比,p<0.05;*:SAC及其类似物各处理组与模型组相比,p<0.05;#:各SAC及类似物组与经PAG干预组比较,p<0.05。
图7是SAC及其类似物对缺氧缺糖6h/复氧复糖3h损伤的心肌细胞过氧化氢酶活力的影响,
其中,Control:正常对照组;Vehicle:模型组;a:模型组与正常对照组相比,p<0.05;*:SAC及其类似物各处理组与模型组相比,p<0.05。
图8是SAC及其类似物对缺氧缺糖6h/复氧复糖3h损伤的心肌细胞羟自由基抑制率的影响,
其中,Control:正常对照组;Vehicle:模型组;a:模型组与正常对照组相比,p<0.05;*:SAC及其类似物各处理组与模型组相比,p<0.05;#:各SAC及类似物组与经PAG干预组比较,p<0.05。
图9是SAC及其类似物对缺氧缺糖6h/复氧复糖3h损伤的心肌细胞MDA的影响,
其中,Control:正常对照组;Vehicle:模型组;a:模型组与正常对照组相比,p<0.05;*:SAC及其类似物各处理组与模型组相比,p<0.05;#:各SAC及类似物组与经PAG干预组比较,p<0.05。
图10是SAC及其类似物对缺氧缺糖损伤心肌细胞凋亡的影响,其中,箭头所指处为调亡固缩深染的细胞核。
图.11SPRC合成路线图及氢谱鉴定结果。
图.12SPRC及SAC对心肌梗死大鼠梗死面积的影响,
其中,Vehicle:MI模型组。*:与MI模型组相比,p<0.01。
图.13SPRC及SAC对心肌梗死大鼠心电图的影响,
其中,Sham:假手术组,Sham+SPRC:假手术+SPRC 50mg/kg组,Sham+SAC:假手术+SAC 50mg/kg组,MI:心肌梗死模型组,MI+SPRC:模型+SPRC 50mg/kg组,MI+SAC:模型+SAC 50mg/kg。
图.14SPRC及SAC对心肌梗死大鼠血浆中LDH,CK,MDA与SOD的影响,
其中,Sham:假手术组,Sham+SPRC:假手术+SPRC 50mg/kg组,Sham+SAC:假手术+SAC 50mg/kg组,MI:心肌梗死模型组,MI+SPRC:模型+SPRC 50mg/kg组,MI+SAC:模型+SAC 50mg/kg。*:与MI组相比,p<0.01;#:MI组与Sham组相比,p<0.01。
图.15SPRC及SAC对心肌梗死大鼠血清中H2S浓度及心肌组织中CSE活性的影响,
其中,Sham:假手术组,Sham+SPRC:假手术+SPRC 50mg/kg组,Sham+SAC:假手术+SAC 50mg/kg组,MI:心肌梗死模型组,MI+SPRC:模型+SPRC 50mg/kg组,MI+SAC:模型+SAC 50mg/kg。*:SPRC及SAC各处理组与模型组相比,p<0.01;#:MI组与Sham组相比,p<0.01。
图.16SPRC及SAC对心肌梗死大鼠左心室中Bc1-2、Bax和CSE蛋白表达的影响,
其中,Sham:假手术组,Sham+SPRC:假手术+SPRC 50mg/kg组,Sham+SAC:假手术+SAC 50mg/kg组,MI:心肌梗死模型组,MI+SPRC:模型+SPRC 50mg/kg组,MI+SAC:模型+SAC 50mg/kg。
图.17SPRC及SAC对心肌梗死大鼠左心室中Bc1-2、Bax和CSE基因表达的影响,
其中,Sham:假手术组,Sham+SPRC:假手术+SPRC 50mg/kg组,Sham+SAC:假手术+SAC 50mg/kg组,MI:心肌梗死模型组,MI+SPRC:模型+SPRC 50mg/kg组,MI+SAC:模型+SAC 50mg/kg。
图.18SPRC各剂量组对H2O2损伤的H9c2心肌细胞存活率和损伤程度的影响,
其中,Control:正常对照组,Model:模型组,PAG:PAG 10-4mol/L,mol/L,SPRC 1E-7:SPRC 10-7mol/L,SPRC 1E-6:SPRC 10-6mol/L,SPRC 1E-5:SPRC 10-5mol/L,SPRC+PAG:SPRC 10-5mol/L+PAG 10-4mol/L。#:模型组与正常对照组相比,p<0.01;*:SPRC各剂量组与模型组相比,p<0.05;&:SPRC+PAG组与SPRC高剂量组相比较。
图.19SPRC各剂量组对H2O2损伤的H9c2心肌Mn-SOD活力和MDA含量的影响,
其中,Control:正常对照组,Model:模型组,PAG:PAG 10-4mol/L,mol/L,SPRC 1E-7:SPRC 10-7mol/L,SPRC 1E-6:SPRC 10-6mol/L,SPRC 1E-5:SPRC 10-5mol/L,SPRC+PAG:SPRC 10-5mol/L+PAG 10-4mol/L。#:模型组与正常对照组相比,p<0.01;*:SPRC各剂量组与模型组相比,p<0.05;&:SPRC+PAG组与SPRC高剂量组相比较。
图.20SPRC对H2O2损伤H9c2心肌细胞凋亡的影响,
其中,Control:正常对照组;Model:模型组。PAG:PAG 10-4mol/L,mol/LSPRC:SPRC 10-5mol/L,SPRC+PAG:SPRC 10-5mol/L+PAG 10-4mol/L
具体实施方式
实施例1SAC及其类似物提高细胞存活率,能生成内源性H2S实验
原代培养3日龄SD乳鼠,按常规方法无菌条件下取心脏样本于PBS中清洗、处理,移入含有0.08%胰酶的三角烧瓶中37℃消化10分钟,持续磁力搅拌下共消化8次。每次消化后收集上清液,血清中止消化,2000转离心5分钟,收集细胞沉淀调细胞密度为10-6,培养在含10%小牛血清的DMEM中,第三天用于实验。分为正常对照组:不给于药物干预,不缺氧缺糖;模型组:不给于药物干预,缺氧缺糖6h/复氧复糖;SAC及其类似物组:分别给予药物10-5mol/L,缺氧缺糖/复氧复糖。MTT法检测细胞存活率,结果显示(图1),模型组存活率54.35%明显低于正常对照组,SAC及其类似物均能明显提高细胞存活率,单因素方差分析p<0.05。
取细胞上清液500μl,加入醋酸锌250μl,与N,N二甲基对苯二胺盐酸盐20mM 133μl和三氯高铁30mM 133μl充分震荡后室温反应10min,10%三氯乙酸沉淀蛋白,10000g离心10min,670nm测量吸光度值。结果显示(图2),模型组较正常对照组相比H2S浓度明显下降,单因素方差分析p<0.05,而SAC及其类似物均能明显提高上清液中H2S浓度明显升高(p<0.05)。
实施例2.SAC及其类似物降低缺氧缺糖损伤心肌细胞的LDH的漏出实验
每组(n=4)每个样本取106个细胞,充分裂解,丙酮酸法检测细胞内LDH的含量,正常对照组细胞内LDH为100%,各用药组与模型组细胞内LDH与正常对照组的差值为LDH漏出率,在反应体系中产生1μmol丙酮酸为1单位,计算每单位/mg蛋白。各用药组平行给予H2S生成阻断剂PAG阻断,结果显示(图.3),各用药组的LDH漏出率较模型组均明显降低,而PAG可以显著阻断SAC及其类似物的保护作用,说明SAC及其类似物的心血管保护作用部分与内源性生成H2S有关。
实施例3.SAC及其类似物提高SOD,Catalase的活性,提高组织抑制羟自由基产生的能力实验
羟胺法检测SOD,每毫克组织蛋白在1ml反应液中SOD抑制率达50%时所对应的SOD量为一个SOD活力单位(U)。结果显示(图4),SAC及其类似物均能够明显提高总SOD的活力,较模型组显著升高(p<0.05),分型检测发现饱和碳链SPC、SBC、SPEC主要提高胞浆中Cu-Zn SOD的活力(图5),且可被PAG阻断;而新化合物SPRC和SEC主要提高线粒体中Mn SOD的活力(图6),同样可被PAG阻断,说明SAC及其类似物可明显提高SOD的活力,其作用部分与H2S产生有关。
过氧化氢酶催化剩余的过氧化氢在过氧化物酶的催化下可以氧化生色底物,产生红色的产物(N-(4-antipyryl)-3-chloro-5-sulfonate-p-benzpquinonemonoimine),最大吸收波长520nm。1个酶活力单位(U)在25℃,pH7.0条件下,在1分钟内可以催化分解1微摩尔过氧化氢。结果显示(图7),模型组较正常对照组过氧化氢酶的活力显著下降(p<0.05),SAC及其类似物较模型组均能提高过氧化氢酶的活力(p<0.05)。
检测Fenton反应中OH-量,H2O2的量和Fenton反应产生的OH-量成正比,给予电子受体后,用gress试剂显色,形成红色物质,550nm波长检测。结果显示(图8),SAC及其类似物用药组的羟自由基抑制率明显升高(p<0.05),证实经SAC及其类似物可以显著抑制OH-的产生。PAG不能阻断SAC及其类似物的抑制羟自由基的能力。
实施例4.SAC及其类似物抑制脂质过氧化实验
氧自由基攻击生物膜中的多不饱和脂肪酸,引发脂质过氧化作用,并因此产生脂质过氧化物丙二醛(MDA)。MDA可与硫代巴比妥酸(TBA)缩合,形成红色产物,在532nm处有最大吸收峰。结果显示(图9),模型组MDA含量与正常对照组相比显著增高(p<0.05)。SEC、SPC、SPRC处理组较模型组均明显降低,证实SEC、SPC、SPRC能抑制抑制活性氧诱导的脂质过氧化,且PAG可阻断其作用。其中的化合物SPRC的抗脂质过氧化作用更显著。
实施例5.SAC及其类似物抑制心肌细胞凋亡实验
Hoechst染色初步证实了SAC及其类似物对凋亡的抑制作用(图10),心肌细胞的凋亡对于心脏的结构和功能具有很大的损害作用,是发生心功能衰竭的诸多原因之一,实验结果表明SAC及其类似物具有抑制心肌细胞凋亡的作用,SAC及其类似物抗凋亡作用在心脏病的治疗中具有重要应用价值。
实施例6.SPRC合成路线
L-半胱氨酸盐酸盐溶解在预冷的NH4OH(2M,240ml)溶液中,加入3-溴丙炔(14.5g,0.124mol)充分搅拌。混合溶液在0℃下搅拌2h后过滤,滤液减压蒸馏(<40℃)浓缩到较少容量后再过滤。析出固体用乙醇反复洗涤后,真空蒸干,经2∶3体积比的水/乙醇重结晶得到白色针状晶体。核磁共振检测氢谱结构(图11)。
实施例7.SPRC对心肌梗死面积的影响实验
SPRC用生理盐水溶解。体重200-250g雄性SD大鼠,随机分为假手术组(Sham,生理盐水,ip.n=4),假手术+SPRC组(Sham+SPRC,50mg/kg/day,n=4),假手术+SAC组(Sham+SAC,50mg/kg/day,n=4),模型组(MI,生理盐水,ip.n=8),模型+SPRC组(MI+SPRC,50mg/kg/day,n=8),模型+SAC组(MI+SAC,50mg/kg/day,n=8),预给药7天(ip.)。第八天,7%水合氯醛5ml/kg腹腔内注射麻醉后仰卧固定,胸部备皮。于左侧胸腔第三肋间开胸,用6-0号丝线弯针在左心耳和肺动脉圆锥之间,距主动脉根部约2-3mm处永久性结扎左冠状动脉前降支,观察到供血区域心肌变白、并以标准肢体导联II导心电图ST段抬高为模型成功标准。迅速关闭胸腔,缝合皮肤,保温待大鼠清醒后给予水和标准饲料分笼饲养。假手术组除不结扎冠状动脉外,其余操作相同。继续给药2天,术后48小时检测心电图变化,腹主动脉取血,处死后取迅速心脏,置入pH7.4的0.1%TTC液中,于37℃孵育15min染色观察梗死面积。
与模型组相比,SPRC和SAC能明显的减小心肌梗死面积p<0.01(图.12),48小时后ST段抬高有所恢复(图.13)。SAC与SPRC作用相似,p>0.05。表1是SPRC对心肌梗死面积的影响。
表1
实施例8.SPRC对LDH漏出率,血浆中CK浓度及MDA和SOD的影响实验
上述实验中还观察到,模型组的血浆中LDH、CK活性,MDA的含量明显升高,SOD活性降低。心肌梗死损伤时,氧自由基大量产生,LDH反应心肌细胞膜完整性破坏,LDH、CK外漏;MDA反映心肌细胞膜脂质过氧化,过氧化产物进入血液;对SOD的监测可间接反映机体清除氧自由基的能力。结果表明,SPRC和SAC均能明显减少心肌梗死后LDH和CK漏出,抑制MDA的升高,并有效保护SOD活力,显示其抗缺血引起的脂质过氧化反应和较强的氧自由基清除能力(图.14)。能降低LDH漏出率,减少血浆中CK浓度及MDA的产生,提高血浆中SOD的水平。
表2是SPRC对血浆中LDH、CK活性,MDA的含量及SOD活性影响。
表2
实施例9.SPRC对血浆中H2S及心肌组织中CSE酶的影响实验
SPRC组H2S浓度较模型组显著升高(图15A),提示有内源性H2S生成。心肌组织中CSE的活性与血浆中H2S浓度变化的趋势相同,SPRC组CSE活性较模型组CSE活性显著提高(p<0.01),且较SAC组CSE活性高,有显著差异(p<0.05)。(图.15B)
根据文献报道,H2S具有清除活性氧的作用,因此推测SPRC、SAC对心肌梗死后的心肌保护作用是通过内源性生成H2S介导的。
表3是SPRC对血浆中H2S及心肌组织中CSE酶的影响。
表3
实施例10.SPRC可提高Bc1-2和CSE,降低Bax蛋白水平的表达。
Sham组Bax蛋白表达水平较低,Sham+SPRC组和Sham+SAC组对Bax和Bc1-2与Sham组没有显著差异;结扎左冠状动脉使左心室Bax蛋白表达增加,Bc1-2表达降低,有显著差异性(p<0.05);与MI组比较,SPRC组和SAC组的Bc1-2蛋白表达显著增加,Bax蛋白表达明显降低(p<0.05)。与MI组相比,SPRC组和SAC组的CSE蛋白表达显著增加,且SPRC对CSE的作用明显(p<0.01,p<0.05),SPRC在蛋白水平降低了凋亡相关因子Bax,提高抗凋亡因和子Bc1-2和CSE蛋白水平的表达。(图.16)
实施例11.SPRC可降低Bax,提高CSE基因水平的表达,对Bc1-2基因表达没有明显的影响。
SPRC和SAC与Sham组和MI组比较Bc1-2的基因表达均无显著性差异(p<0.01);MI组Bax的基因表达与Sham组比较显著增加(p<0.01);SPRC组和SAC组与MI组比较Bax基因表达显著降低(p<0.05);与MI组相比,SPRC组CSE基因表达显著增加(p<0.01),SAC组的CSE基因表达也有明显增加,但不如SPRC对CSE的作用明显(p<0.05),提示SPRC在分子水平降低了凋亡相关基因Bax,提高CSE基因水平的表达(图.17)。
实施例12.SPRC可以提高H2O2损伤心肌细胞系H9c2的存活率,可降低H2O2损伤H9c2心肌细胞的LDH的漏出率
H9c2培养于含有10%小牛血清的DMEM中,置37℃,5%CO2孵箱中培养,待细胞生长至90%单层传代。调细胞密度为5×10-4/孔,接种于96孔板。分为正常对照组(Control):不给于药物干预,不缺氧缺糖);模型组(Model):不给于药物干预,200μmol/L H2O2作用2小时)PAG组(PAG):PAG 10-4mol/L;SPRC各剂量组:SPRC 1E-7、SPRC 1E-6、SPRC 1E-5,分别给予SPRC 10-7、10-6、10-5mol/L。SPRC+PAG组(SPRC+PAG):SPRC 10-5mol/L+PAG 10-4mol/L。MTT法检测细胞存活率,结果显示(图18A),模型组存活率明显低于正常对照组,SPRC中剂量组和高剂量组均能明显提高细胞存活率(p<0.05)。PAG可阻断SPRC对细胞的保护作用。
每组(n=4)每个样本取106个细胞,充分裂解,丙酮酸法检测细胞内LDH的含量,结果如图.18B所示,SPRC各剂量组的LDH漏出率较模型组均明显降低,而PAG可以显著阻断SPRC的保护作用,说明SPRC的心血管保护作用至少部分与内源性生成H2S有关。
表4是SPRC提高H2O2损伤心肌细胞系H9c2的存活率,降低H2O2损伤H9c2心肌细胞的LDH的漏出率结果。
表4
实施例13.SPRC可提高SOD的活性,抑制脂质过氧化产物MDA的产生。
结果显示(图.19A),SPRC中高剂量组均能明显提Mn-SOD的活力,较模型组显著升高(p<0.05),此作用可被PAG阻断,说明SPRC显著提高Mn-SOD的活力,其作用至少部分与H2S产生有关。
模型组与正常对照组相比MDA含量显著增高(图.19B)(p<0.05)。SPRC低、中、高剂量组较模型组均明显降低,证实SPRC可抑制活性氧诱导的脂质过氧化,且PAG可阻断其作用。
表5是SPRC提高SOD的活性,抑制脂质过氧化产物MDA的结果。
表5
实施例14.SPRC具有抑制心肌细胞凋亡的作用
Hoechst及PI双染证实了所述SPRC对凋亡的抑制作用(图.20),心肌细胞的凋亡对于心脏的结构和功能具有很大的损害作用,是发生心功能衰竭的诸多原因之一,本实验在整体动物模型中从基因和蛋白水平证实了SPRC的抗凋亡作用,并在细胞水平,通过Hoechst和PI双染法验证SPRC在不受其他因素干扰下对H2O2诱导H9c2心肌细胞凋亡的作用。证实了SPRC在心脏病的治疗中具有重要应用价值。
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