CN111728969B - 抗衰老抗氧化的化合物在制备药物或者抗衰老化妆品中的用途 - Google Patents
抗衰老抗氧化的化合物在制备药物或者抗衰老化妆品中的用途 Download PDFInfo
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Abstract
本发明涉及抗衰老抗氧化的化合物在制备药物或者抗衰老化妆品中的用途。本发明证实了式（I）化合物具有较好的抗氧化效果，具有防止细胞衰老的功能。通过将所述的化合物制备成为相应的防衰老药物或者防衰老化妆品具有较好的商业价值。
Description
技术领域
本发明属于药物领域，具体的涉及抗衰老抗氧化的化合物在制备药物或者抗衰老化妆品中的用途。
背景技术
抗衰老机制是目前研究较热的课题之一，随着生物化学与分子生物学技术的不断发展，氧自由基、抗氧化剂、干细胞技术、端粒、基因等与细胞衰老有关的研究越来越受到重视，成为抗衰老研究的热点。研究证明随着年龄的增长，细胞内自由基的生成增加，自由基对细胞有破坏作用，而受损的细胞下一代也会受到损坏，细胞损伤死亡增加，因此引起衰老。抗衰老的实验研究中发现，机体内存在过氧化物酶体，其主要作用是生成和清除H202，在体内具有防止活性氧损伤的重要作用。如何减少自由基的生成也是现在研究的热门。
研究表明，在衰老过程中，来自外界的物理损伤、生化毒物以及体内本身的DNA复制错误、自发水解反应、活性氧(reactiveoxygenspecies，ROS)等有害因素不断损伤DNA，导致基因突变、易位、端粒缩短、染色体数目异常等，使基因组的完整性和稳定性遭到破坏。在衰老机体的细胞中可以观察到体细胞突变的累积。为了维持基因组的稳定性，机体进化出复杂的DNA修复机制，如果这种修复机制被破坏，便会加速机体的衰老和相关疾病的发生，许多表现为早衰的疾病如着色性干皮病、Werner综合征、Bloom综合征、Cockayne综合征等均有DNA损伤修复机制缺陷的参与。随着衰老的进展，有丝分裂检验点基因BubR1在组织中的表达水平降低，有研究显示过表达BubR1可保证体内染色体的准确分离，延长小鼠的寿命。除了核基因，线粒体基因(mitochondrialDNA，mtDNA)在机体衰老的过程中也发挥着重要作用。DNA聚合酶γ负责mtDNA的复制，DNA聚合酶γ基因敲除小鼠mtDNA发生突变或缺失，表现为早衰和寿命缩短。与细胞核DNA不同，mtDNA缺乏完整的修复机制，早期突变的mtDNA可克隆扩增，造成线粒体呼吸链损伤，从而促进衰老的发生。核纤层为核膜和染色质提供支架，在维持基因组稳定性方面也发挥着重要作用。
细胞衰老是指细胞周期停滞，永久失去分裂能力。衰老是细胞适应性降低、停止增殖并死亡的过程，肿瘤细胞的特性与之相反，但其实二者都是由损伤逐步累积所致，只是表现不同而已。不同于静止期细胞与终末分化期细胞，衰老细胞主要具有以下特点：高表达p16INK4a和p19ARF，细胞周期停滞于G1期；染色质重塑形成衰老相关异染色质聚集(SAHF)；表达衰老相关的β半乳糖甘酶(SABG)；DNA损伤应答(DNAdamageresponse，DDR)持续存在，P53表达增加。然而增加小鼠体内p16INK4a、p19ARF、P53的表达不仅可以抑制肿瘤还可以延长寿命，减少P53的表达反而加速衰老，这是因为细胞衰老也是机体的一种代偿机制。免疫系统可识别衰老细胞并将其清除，组织内的祖细胞分化形成年轻的细胞代替衰老细胞，防止衰变或潜在的肿瘤细胞等有害细胞的扩散，但随着机体老化，细胞衰老加速，免疫系统对衰老细胞的清除减慢，从而造成体内的衰老细胞增多。衰老细胞通过分泌促炎因子和基质金属蛋白酶作用于周围细胞的现象称为衰老相关分泌表型(SASP)。SASP与NF-κB过度激活、免疫系统功能紊乱、自噬功能降低等因素共同作用于机体造成炎性衰老。许多炎症因子如IL-1、肿瘤坏死因子(TNF)、干扰素等在衰老机体中含量增高。炎性衰老与许多ARD的发生有关，如动脉粥样硬化、2型糖尿病、阿尔茨海默病、肿瘤等。通过药物或基因操作抑制NF-κB可使衰老小鼠趋于年轻化。下丘脑内NF-κB的表达可导致促性腺激素释放激素(GnRH)分泌减少，从而促进机体的衰老。长期服用阿司匹林可延长小鼠寿命，促进人体的健康老化。
目前研究的抗衰老药物很多，许多药物通过作用于衰老相关的信号通路起到抗衰老作用，较有代表性的药物包括雷帕霉素、二甲双胍、白藜芦醇等。雷帕霉素是一种新型免疫抑制剂，通过作用于mTOR抑制mTOR信号通路，使其下游的mTORC1和S6K生成减少，从而发挥抗衰老作用。该药可使小鼠的寿命延长约60%，而雷帕霉素的类似物RAD001可改善老年人的免疫衰老。雷帕霉素引发的副作用包括白内障、造血系统功能障碍、代谢失调(如高血糖、高胰岛素血症、胰岛素抵抗)等，这些副作用有些是因为雷帕霉素抑制了mTORC1的同时也抑制了mTORC2。但无论是雷帕霉素还是其类似物，目前都缺乏充足的临床证据来证明其在人体中的抗衰老作用。二甲双胍是临床用于治疗2型糖尿病的常用药，长期服用该药还可降低心血管疾病和癌症的发病率。二甲双胍可延长线虫、小鼠的寿命，这种抗衰老作用被认为与其可激活AMPK通路有关，其在人体的抗衰老效用有待于进一步临床试验证实。白藜芦醇是一种多酚类化合物，可提高SIRT1的活性，维护线粒体呼吸链的正常功能。白藜芦醇可增加高脂饮食小鼠的寿命，但不能延长正常饮食小鼠的寿命，给肥胖的人服用白藜芦醇可改善其代谢失调状况，而对于糖耐量正常的非肥胖妇女来说，添加白藜芦醇并不会增强机体的代谢功能。亚精胺是一种多聚胺，可延长酵母、果蝇、小鼠的寿命，其具有诱导自噬的作用，可提高年老果蝇的记忆、改善小鼠的心血管健康状况。
CN103936608B中公开了一种具有抗衰老作用的新型查尔酮化合物，可以可以显著抑制H2O2诱导的端粒酶活性降低; 可以用作制备各种剂型的具有延缓衰老或与免疫调节、促进大脑功能相关药物的原料药; 可以用作制备各种剂型的具有延缓衰老或与免疫调节、促进大脑功能相关药物的原料药。
虽然目前抗衰老的药物已经有一些，但是药物的种类和类型还不够丰富，可选择的机会也不多，因此需要持续研发和研究满足社会需求。
发明内容
本发明克服了现有技术的缺陷，提供了一种新的能够延缓衰老的化合物的新用途。
申请人在研究皮肤抗衰老研究时，利用已有的化合物库针对皮肤细胞进行特异性的筛选，获得了能够延缓皮肤细胞衰老的化合物。
所述化合物为式（I）的化合物：
式I化合物通常以包含一种或多种式I化合物和药学上可接受的载体的药物组合物的形式使用。优选这些组合物为单位剂型，例如片剂、丸剂、胶囊、粉剂、颗粒剂、混悬液、计量气雾剂或液体喷雾剂、滴剂、安瓿剂、透皮贴剂；用于涂抹或者涂覆或者其他方式给药。
通常将主要的活性成分混合在药用载体例如常规压片成分例如玉米淀粉、乳糖、蔗糖、山梨醇、滑石粉、硬脂酸、硬脂酸镁和磷酸二钙，或树胶、分散剂、悬浮剂或表面活性剂例如去水山梨糖醇单油酸酯和聚乙二醇，和其它的药用稀释剂例如水中，以形成均匀的含本发明化合物或其药学上可接受的盐的预制剂组合物。
当称这些预制剂组合物为均匀时，是指活性成分均等分散在整个组合物中，以便该组合物可以容易地细分为同等有效的单位剂型例如片剂、丸剂和胶囊。
在进一步的方面，本发明提供药物组合物，其包含药学上可接受的载体、式I化合物。优选地，该药物组合物为适合表皮给药的单位剂型，例如药膏或者喷雾。
进一步的，还提供了式I化合物在制备治疗人表皮角质细胞衰老的药物组合物中的用途。
进一步的，所述人表皮角质细胞是本领域商业化的人表皮角质细胞。
本发明还提供一种防止皮肤衰老的化妆品，所述化妆品中含有式I的化合物。
进一步的，还提供了式I化合物在制备防止皮肤衰老的化妆品中的用途。
有益效果
本发明通过研究发现式（I）化合物具有较好的抗氧化效果，具有防止细胞衰老的功能。通过将所述的化合物制备成为相应的防衰老药物或者防衰老化妆品具有较好的商业价值。
附图说明
图1 化合物对人表皮角质细胞ROS 表达的影响结果图。
图2 不同浓度条件下H2O2 损伤下人表皮角质细胞的结果图。
图3 化合物在H2O2 损伤中的功能结果图。
图4 化合物在H2O2 损伤中的功能验证结果图。
具体实施方式
下面通过实施例对本发明进行具体的描述，有必要在此指出的是以下实施例只用于对本发明进行进一步说明，不能理解为对本发明保护范围的限制，该领域的技术人员可以根据上述本发明内容对本发明做出一些非本质的改进和调整。
实施例1 式（I）化合物的制备
在0℃下将0.73ml的30% H2O2溶液加入至1g 4-溴苯甲硫醚的5ml乙酸溶液。在RT下将混合物搅拌12h和用10% NaOH溶液后处理。水相用乙酸乙酯萃取。有机相用饱和NaCl溶液洗涤，经Na2SO4干燥。除去溶剂，得到0.99g粗产物A。在0℃下将223mg叠氮化钠滴加至900mg产物A的18ml氯仿溶液。在0℃下将混合物搅拌12h和加入冰水。常规后处理得到592.6mg产物B。将253mg 3-羟基-2-氧代-吡咯烷-3-甲酸-3-氯-5-氟-苄基酰胺、359mg碳酸钾、382mgN‘,N‘-二甲基-乙烷-1,2-二胺和330mg碘化铜连续加入来自上述步骤制备的200mg产物B的12ml脱气二噁烷溶液。在140℃下在微波炉中将混合物反应2h。混合物经硅藻土过滤，和真空除去溶剂。制备型HPLC得到53.4mg的式（I）化合物；鉴定结果为：1H NMR 400 MHz ,DMSO-d6:δ[ppm] 8.79 (t，J = 6.40 Hz , 1H) , 7.90-7.96(m，4H) , 7.26-7.29 (m，1H), 7.20 (s，1H) , 7.10 (d，J = 9.60 Hz , 1H) , 6.87 (s ,1H) , 4.35-4.41 (m，1H) ,4.20-4.27 (m，2H) , 3.90-3.93 (m，2H) , 3.04 (d , J =0.80 Hz , 3H) , 2.58-2.62(m，1H) , 2.12-2.19 (m，1H)，分子式如下式（I）所示。重复所述制备步骤，得到足够量的化合物用于后续实验。
实施例2 化合物对人表皮角质细胞ROS 表达的影响
（1）取对数生长期的人表皮角质细胞（货号2110， Sciencell），并调整密度为5×105/mL，加到6 孔板（100μL/孔），37℃、5 % CO2 贴壁培养。
（2）实施例1制备得到的化合物稀释成一系列浓度：1、10、50μg/mL，槲皮素作为阳性对照，浓度为50μg/mL。用无血清培养基作为阴性对照组。
（3）贴壁24 h 后，加入化合物。孵育12 h 后，吸弃原培养基，在每个孔中加入含DCFH-DA（20 mM）的无血清培养基，空白组除外。
（4）使用多功能酶标仪，立即测定荧光值，激发波长（485 nm），发射波长（538nm），37℃下，每5 min 检测一下，检测时长为120 min。
（5）结果计算：根据化合物处理组和空白对照组下的荧光值计算化合物的相对荧光值，取相对荧光值最大的时间点进行计算，及可得到ROS的相对表达量。
所有的样品检测3 次平行试验。结果如下图1所示。检测化合物对人表皮角质细胞内ROS的含量变化结果显示，阴性对照组的ROS 的含量设置为1，槲皮素为阳性对照组ROS的相对表达量在：0.452±0.070。而不同浓度化合物处理的细胞的ROS相对表达量在0.127-0.355之间。具有一定的细胞浓度依赖性，其中50μg/mL化合物对于细胞内ROS的抑制效果最好，其含量只有0.127±0.031。
实施例3 化合物对于MAPK通路的抑制作用
培养人表皮角质细胞，收集细胞，密度为5×105 个/mL。首先将人表皮角质细胞接种到Transwell 细胞小室（2 mL/孔）。加入PBS（2 mL/孔），选择辐照剂量辐照剂量为100μj/cm2 时进行辐照2min。辐照结束后，部分检测p38MAPK 的表达量。部分再加浓度化合物，将Transwell 板中的小室放在铺有HFF 细胞的6 孔板中，继续孵育24 h 后，取细胞测定p38MAPK的表达量。以正常未辐射的表皮角质细胞作为阴性对照，结果如图2所示。从图2可以看出，50μg/mL化合物可明显降低人表皮角质细胞内的MAPK 相关因子p38MAPK。与辐照组相比辐照后加化合物组可将p38MAPK 的表达量下调54.22±1.27%。从结果可以看出，辐照可引起MAPK信号通路关键因子的高表达，加入化合物后可显著抑制MAPK信号通路关键因子的过量表达。说明化合物可通过抑制p38MAPK信号通路保护表皮角质细胞免受辐照损伤。
实施例4 H2O2 损伤下人表皮角质细胞模型的建立
取处于生长状态良好的细胞，弃去原培养基，用PBS 缓冲液洗三次，胰酶消化后，加入培养基终止消化，轻轻吹打混匀细胞悬液，用细胞计数板进行细胞计数，取出96 孔板，每孔细胞数约为1×104 个，培养24 h 后，弃去原培养基。分别向铺有细胞的96 孔板中加入含有不同浓度H2O2的培养基，同时设有空白对照组。培养24 h 后，用CCK-8 法检测各细胞的存活率，探究最佳造模浓度，重复实验3 次，取平均值。如图3所示，用不同浓度的H2O2作用于细胞24 h后，得到的实验结果显示，随着H2O2 浓度的增加，细胞的存活率也随着降低，而在H2O2 浓度为500μmol/l时细胞的存活率显著性降低（P<0.05），表明500μmol/l为细胞的最佳H2O2造模浓度，氧化损伤模型构建成功。
实施例5 化合物在H2O2 损伤中的功能验证
将500umol/l的H2O2造加入到人表皮角质细胞，同时加入含有50μg/mL的化合物的角质上皮细胞培养基，同时设有空白对照组、阳性对照组（加入槲皮素50μg/mL），H2O2 造模的模型组（不加化合物处理）。培养24h后，用CCK-8 法检测各孔细胞的存活率，重复实验3次，取平均值。结果如图4所示，由过氧化氢诱导的人表皮角质细胞的存活率降低，从模型组可以看出。而加入了化合物之后的实验组细胞的存活率得到显著的增加，比阳性对照组的存活率显著的提高，结果表明，化合物能够比能槲皮素具有更好的通过提高细胞的抗氧化能力从而改善过氧化氢诱导引起的细胞损伤，阻止细胞衰老与凋亡。
实施例6 细胞安全性检测
将人红细胞、人胚胎肺成纤维细胞、人表皮角质细胞分别按照常规的培养方法进行细胞培养，收集细胞浓度为1XlO5个。5 XlO3个细胞/孔的密度将细胞分别加到96孔板中同时添加化合物与细胞共同孵育4小时，以不加药物的PBS溶液为对照。检测细胞密度发现，加药组细胞密度与对照组没有较少，这说明，本发明提供的组合物对正常细胞没有显著的杀伤作用，具有较好的应用前景。
实施例7 化合物安全性检测
试验动物：普通级实验动物大白兔。体查动物未见异常。环境条件：室温：22°C-25°C，相对湿度：60% -70% ；试验方法：
依据《化妆品卫生规范》（2007年版）急性皮肤刺激性试验，试验前24小时，将试验动物背部脊柱两侧毛剪掉，去毛范围3厘米*3厘米。取受试的化合物直接涂抹在右侧皮肤上，以洁净纱布覆盖，用无刺激性胶布固定2小时。另外一侧为阴性对照。除去受试物后的1小时、24小时、48小时72小时观察受试动物接触部位皮肤反应并做记录。在本试验条件下，72h后化合物对大白兔急性皮肤刺激试验按皮肤刺激强度分级为无刺激性，具有较好的安全性。
Claims (6)
1.式（I）的化合物在制备抗细胞氧化、抗细胞衰老的药物中的用途；所述化合物结构式为：
2.如权利要求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。
3.如权利要求1或2所述的用途，其特征在于所述药物为片剂、丸剂、胶囊、粉剂、颗粒剂、混悬液、计量气雾剂或液体喷雾剂、滴剂、安瓿剂、透皮贴剂。
4.式I化合物在制备防止皮肤衰老的化妆品中的用途；所述化合物结构式为：
5.如权利要求4所述的用途，其特征在于所述化妆品中还含有美白的组分。
6.如权利要求5所述的用途，其特征在于所述化妆品是乳液形式。
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