CN116283702A - 一类具有抗糖尿病活性的化合物及其制备方法和应用 - Google Patents
一类具有抗糖尿病活性的化合物及其制备方法和应用 Download PDFInfo
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
本发明涉及具有抗糖尿病活性的化合物及其制备方法和应用,所述化合物是diprotin A的类似物,化合物具有较强的抗糖尿病活性,属于DPP–IV抑制剂,可以改善血胰岛素水平,为糖尿病的治疗开辟了新的途径;将所述化合物应用于预防或/和治疗糖尿病的食品、保健品和药物的制备中,具有较高的社会价值和重要意义。
Description
本专利申请是申请号为2021116040348,专利名称为“一类具有抗糖尿病活性的化合物及其应用”(申请日:2021年12月24日)的中国发明专利申请的分案申请,通过参考其全部而将其内容结合于此处。
技术领域
本发明涉及具有抗糖尿病活性化合物的技术领域,具体涉及了一类具有抗糖尿病活性的化合物及其制备方法和应用。
背景技术
II-型糖尿病(T2DM)是一种血糖、胆固醇、蛋白质、水、电解质水平的代谢紊乱,以及细胞功能低下、胰岛素分泌受损和胰岛素抵抗的常见疾病。血糖控制不良的患者易发生各种糖尿病并发症,包括肾衰竭、酮症酸中毒和糖尿病非酮症高渗综合征。血糖调节是一个由多种酶、激素和神经控制的高度复杂的过程。研究发现,在众多酶中,血糖水平与二肽基肽酶IV(DPP–IV)的活性有着密切的关系。
DPP–IV是治疗II-型糖尿病的一个众所周知的药物靶点,因为它在体内以高选择性降解胰高血糖素样肽(GLP-1)和葡萄糖依赖性促胰岛素肽(GIP)。同时,DPP–IV抑制剂可以增强外部GLP-1和GIP的活性,从而改善血胰岛素水平。一些合成的抗糖尿病分子,如西格列汀、利格列汀和吉米列汀,已被批准通过DPP–IV抑制治疗II-型糖尿病。目前,全球每年有很多II-型糖尿病患者的产生,病程较长,需要较强的控制力,给越来越多的患者带来病痛的困扰,因此,寻找更多的具有抗糖尿病活性的化合物对糖尿病的治疗有着重要的意义。
发明内容
本发明的目的在于:针对糖尿病患者受病痛困扰的问题,提供一类具有抗糖尿病活性的化合物及其制备方法和应用。本发明公开的化合物具有较强的抗糖尿病活性,对糖尿病的预防和治疗开辟了新的途径。
为了实现上述目的,本发明采用的技术方案为:
一类具有抗糖尿病活性的化合物,所述化合物是diprotin A的类似物。
本发明公开的diprotin A的类似物具有较强的抗糖尿病活性,属于DPP–IV抑制剂,可以改善血胰岛素水平,为糖尿病的治疗提供了新的选择。
进一步的,所述化合物选自以下结构式中的至少一种;
进一步的,所述化合物选自以下结构式中的至少一种;
进一步的,所述化合物选自以下结构式中的至少一种;
进一步的,所述化合物从白背三七但不仅限于白背三七中分离得到。优选地,所述化合物从白背三七中分离得到的。
本发明的另一目的是为了提供上述化合物的应用。
如上述具有抗糖尿病活性的化合物在食品或保健品中的应用。
如上述具有抗糖尿病活性的化合物在制备药物中的应用,所述药物是预防或/和治疗糖尿病药物。
本发明的另一目的是为了提供一类包含上述化合物的药物。
一类药物,所述药物包含上述具有抗糖尿病活性的化合物。
综上所述,由于采用了上述技术方案,本发明的有益效果是:
1、本发明从药食两用白背三七中发现了抗糖尿病活性成分,对25种diprotin A类似物的化学结构进行了表征,并进行了抗糖尿病活性的验证;本发明所要保护的化合物属于DPP–IV抑制剂,IC50值为0.40mg/mL;分子对接研究还证实了diprotin A类似物和DPP–IV之间的相互作用;此外,细胞实验和动物实验也证明本发明公开的化合物可以改善血胰岛素水平,具有较好的降糖作用,为糖尿病的治疗开辟了新的途径。
2、本发明还公开了具有抗糖尿病活性的化合物的应用,具有较高的社会价值。
附图说明
图1是diprotin A类似物的分子网络。
图2是diprotin A(a)、式(2)(b)和式(3)(c)的二级质谱图和可能的裂解途径。
图3是不同浓度diprotin A类似物的DPP–IV抑制率。
图4是25种diprotin A类似物的分子对接得分图。
图5是DPP–IV与diprotin A、式(2)和式(3)三种化合物的分子对接相互作用示意图。
图6是实施例2中diprotin A的类似物对NCI-H716细胞中GLP-1水平的影响。
具体实施方式
下面结合附图,对本发明作详细的说明。
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合附图及实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅用以解释本发明,并不用于限定本发明。
以下实施例中,LC-MS级乙腈和LC-MS级甲酸购自Fisher Scientific(美国马萨诸塞州)。乙醇购自Titan Scientific(中国上海)。甲醇购自金山化试(中国成都)。无水磷酸氢二钠购自科试(中国成都)。盐酸购自西陇化工(Chengdu,China)。Milli-Q水净化系统(Billerica,MA,USA)用于产生超纯水。白背三七采自泸县(中国四川),并根据其形态特征进行了种属鉴别。
实施例1
天然产物在现代生命科学和新药开发中起着至关重要的作用。从天然产物中发现活性化合物引起了科学家的关注,但由于天然产物是极其复杂的体系,这仍然是一个巨大的挑战。
快速分析白背三七中抗糖尿病成分
步骤1、取白背三七样品,以甲醇-水溶液为溶剂,制备供试品溶液。
将1kg白背三七浸泡在20L含0.1%的盐酸的甲醇–水(50:50,v v-1)中两周。对白背三七的提取物(GD-E)进行过滤、浓缩、冻干,以供进一步处理。
步骤2、将所述步骤1制备的供试品溶解并用超高效液相色谱–质谱法分析,获取粗提取物的质谱信息。
采用超高效液相色谱法对GD-E分析。该过程使用Inertsil C18色谱柱(100×2.1mm,3μm),柱温箱温度设置为40℃,以0.1%甲酸的水溶液(A)和乙腈(B)作为流动相,以0.3mL/min的流速进行梯度洗脱。梯度洗脱程序如下:0–2min为5%B,2–18min为5–70%B,18–20min为50–100%B,20–25min为100%B。
将超高效液相色谱的洗脱液引入质谱仪,使用X500R Q-TOF质谱仪采集化合物一级和二级质谱数据。电喷雾电离(ESI)参数如下:温度:500℃;离子源气体1和2:50psi;气帘气:35psi;CAD气:7psi。IDA具体设置为:碰撞能40V,最大候选离子10;强度阈值;400cps;全扫描质量范围:100~1500Da;离子喷雾电压:5500V。
步骤3、将所述步骤2得到的质谱数据导入GNPS平台,利用GNPS数据库对供试品溶液中的化学成分通过搜库进行表征,再通过与文献中报道的化合物进行确认,确定潜在活性成分。
使用SCIEX OS 1.4软件采集和输出原始数据文件。使用MSconver软件将原始数据文件转换为mzXML格式,并建立分子网络(MN)。MN操作参数如下:前体离子质量偏差±0.02Da;子离子质量偏差±0.02Da;最小配对余弦值:0.7;最小簇大小:2;最小匹配碎片离子:6。
GNPS根据化合物二级质谱数据的相似程度形成可视化的网络图,其中一个节点代表一种化合物,不同节点的颜色代表不同的来源或属性。具有相似结构(类似物)的节点聚集在一个簇中。两个节点之间存在余弦值;余弦(0–1)越高,结构越相似。使用这种方法,diprotin A被成功鉴定。Diprotin A是一种已知的DPP–IV抑制剂,其IC50为1.6~5.8μg/mL,通常用作DPP–IV抑制试验中的阳性对照;它还可以阻止GLP-1的降解,从而发挥降血糖作用。
步骤4、采用强阳离子交换SPE法从白背三七提取物中富集潜在活性成分类似物。
首先,将白背三七提取物溶解在含有0.1%盐酸的乙醇-水(20:80,v v-1)中。使用强阳离子交换固相萃取(SPE)柱进行分离。先用甲醇活化柱子,再用250mmol/L Na2HPO4的甲醇–水(20:80,v v-1)继续活化柱子。上样前使用甲醇-水(20:80,v v-1)清洗色谱柱以去除残留的Na2HPO4。上样后,用甲醇-水(50:50,v-1)洗涤柱子以去除中性化合物。使用含有150mmol/L Na2HPO4的甲醇-水(20:80,v v-1)洗脱。用C18(10μm,Acchrom,中国)为填料脱盐,收集甲醇洗脱液。
步骤5、取甲醇洗脱液,用超高效液相色谱进行分析,然后将洗脱液引入质谱仪中,获得供试品溶液的质谱数据;然后将质谱数据上传入GNPS平台,构建分子网络,对潜在活性成分进行表征。
如图1所示,实心圆圈表示通过库搜索鉴定的化合物,被鉴定为diprotin A,因为余弦值设置为>0.7,表明其他节点是diprotin A的类似物。如图2(a)所示,diprotin A产生离子m/z 229.1566、86.0968、72.0812和70.0815,并进行碎片归属,其中m/z 72.0812和70.0815是含N5元环的特征离子,将这些用于辅助分析类似物。分子碎裂时脱掉异亮氨酸和缬氨酸,分别产生M–113Da和M-99Da离子。此外,diprotin A类似物由于消除了异亮氨酸和甲酸组成,表现为中性丢失159Da。如图2(b)中,式(1)产生的母离子为m/z 328.2238(–2.2ppm,C16H29N3O4),产生与diprotin A碎片相似的子离子,包括m/z 229.1561、86.0968、72.0812和70.0815。m/z 229.1561处的碎片离子对应于[M+H–99]+。此外,式(1)的分子量比diprotin A小13Da。因此,通过比较MS和MS/MS数据,将式(1)鉴定为diprotin C。在正模式下,如图2(c)中,式(2)在m/z 243.1709(2.4ppm,C12H22N2O3)处产生[M+H]+离子,通过裂解产生m/z 144.1028([M+H–99]+)离子和与式(1)相同的碎片离子(m/z 70、72),因此,成功表征了式(2)的结构。基于上述碎裂途径,初步表征了25种diprotin A类似物,如表1所示。
表1 25种diprotin A类似物结构及分子信息
步骤6、将潜在活性成分类似物进行DPP–IV抑制活性测定,得到IC50;并将这些类似物与DPP–IV进行分子对接,得到若干分子对接结合能值,以验证若干种潜在活性成分类似物的抗糖尿病活性。
分子对接技术作为一种基于计算机的方法,可用于预测药物-酶相互作用。采用分子对接方法研究diprotin A的类似物与DPP–IV(PDB晶体结构:1WCY)之间的相互作用。较高的分数(结合能值)表明配体蛋白之间的相互作用更加合理和稳定。所有受体蛋白的制备步骤如下:去除水分子,向蛋白质中加入氢原子,并应用CHARMM力场。所有用于对接的化合物均使用DS3.1中的“准备配体”模块制备。分子对接评分统计数据列于图4。所有diprotin A类似物都不同的程度与DPP–IV相互作用,表明它们是DPP–IV的潜在抑制剂。DPP–IV以二聚体的形式出现,并形成两个开口,提供通往空腔的通道,这是25种类似物的确切结合位点。三种类似物的得分高于diprotin A。如图5所示,表1中的,式(6)(图5b)稳定对接在DPP–IV的腔内并与几个氨基酸残基相互作用,对接值为40.5567kcal/mol。式(6)与氨基酸残基Ser209、Glu 205、Arg 125、Ser 630和Tyr 547形成五个常规氢键,与氨基酸残基Glu 206、Glu205和Tyr 547形成三个碳氢键,以及与氨基酸残基His 126和His 740相互作用的两个疏水作用。类似地,式(3)(图5a)和式(23)(图5c)也与DPP–IV中的氨基酸形成氢键和疏水相互作用。其他化合物也通过氢键和疏水相互作用与DPP–IV相互作用。
使用DPP–IV抑制剂筛选试剂盒(Merck,德国)测定DPP–IV的抑制活性。反应混合物的总体积为100μL。首先,使用DPP–IV试剂盒自带的缓冲液溶解样品。然后,将25μL样品和1μL DPP–IV酶与49μL DPP–IV检测缓冲液加入到96孔黑色板中。混合均匀,37℃孵育10min。随后,每孔加入25μL酶反应混合物(2μL DPP–IV底物加入23μL缓冲液),混合。最后,使用酶标仪(JIYUANBIO-TECH,中国)检测。
DPP–IV的抑制活性计算如下:
其中:
FLU1为T1处的荧光强度;FLU2为T2处的荧光强度;SlopeSM为样品抑制组的斜率;SlopeEC为酶对照组的斜率。不可逆DPP–IV抑制剂的ΔFLU值为0,相对抑制率为100%。
采用已知的DPP–IV酶抑制剂(西格列汀)用作阳性对照,测定diprotin A类似物对DPP–IV的抑制作用,并计算IC50值。如图3所示,diprotin A类似物的IC50为0.40mg/mL,并呈剂量依赖性(n=3)。通过定向合成分子对接得分较高的几个化合物(3,6,10,12和16),并测试了各个化合物抑制DPP–IV的IC50,结果如表2所示。
组别 | 西格列汀 | 3 | 6 | 10 | 12 | 16 | 23 |
IC50 | 0.18±0.07 | 150±5.05 | 120±6.32 | 310±6.12 | 301±7.36 | 450±8.08 | 160±7.07 |
实施例2
将实施例1中,所述步骤5得到的diprotin A的类似物和定向合成的6个单体化合物,进行细胞实验。
NCI-H716细胞以1×106个/mL密度培养在12孔板中,48h后吸取上清液,加入1mL缓冲液和待测药物,阳性药物为阿格列汀(2μg/mL),待测药物浓度分别为100,200,300μg/mL的25种化合物的混合物,37℃孵育2h,吸取上清液,采用ELISA试剂盒检测GLP–1含量,diprotin A类似物测试结果如图6所示。Diprotin A的类似物可浓度依赖性的升高GLP-1浓度,浓度为200μg/mL时GLP-1浓度为7.33±0.44pmol/L,浓度300ug/mL时GLP-1浓度为7.87±0.25pmol/L,皆有显著性差异(P<0.05)。阿格列汀使GLP-1浓度从6.73±0.14pmol/L升高到7.45±0.12pmol/L,且具有显著性(P<0.05)。浓度均为50μg/mL的单体化合物对GLP–1浓度测试结果如表3所示。
表3
组别 | 对照组 | 阳性组 | 3 | 6 |
GLP–1 | 6.8±0.23 | 7.35±0.54 | 7.53±0.36** | 7.51±0.11** |
组别 | 10 | 12 | 16 | 23 |
GLP–1 | 7.02±0.33* | 7.23±0.02* | 6.89±0.36 | 7.56±0.12** |
注:与对照组相比,*P<0.05,**P<0.01
实施例3
将实施例1中,所述步骤5分离得到的diprotin A的类似物,即表1中编号为2-26的25种化合物的混合物和定向合成的6个单体化合物,进行动物实验。
使用体重,年龄相同的雄性大鼠,高脂饲养大鼠4周后,禁食不禁水6h后一次性腹腔注射30mg/kg STZ(0.5mL/100g),继续高脂饮食喂养4周,测定血糖,选出造模成功组进行分组给药,换用普通饲料。选出造模成功(血糖值15–20mmol/L)的糖尿病大鼠72只,随机分为9组:阿格列汀(3mg/kg)组,模型组,药物组。药物组分为Diprotin A类似物组(20mg/kg),6个单体化合物组(5mg/kg)。另取8只同批次正常雄性大鼠为正常组。前7组连续静脉注射给药7天后,正常组给予等体积的生理盐水;禁食5h测定血糖,再分别注射2g/kg葡萄糖,注射后30min、60min、90min、120min于大鼠尾尖取血,采用血糖仪测(强生稳豪型)血糖。结果如表4所示。
表4 Diprotin A类似物及6个单体化合物的耐糖量
注:与模型相比,*P<0.05,**P<0.01
组别 | 正常组 | 阳性组 | 模型组 | Diprotin A类似物 | 3 |
血糖 | 4.61±0.80 | 14.32±1.33 | 17.80±1.25 | 16.19±0.32* | 14.45±1.51** |
组别 | 6 | 10 | 12 | 16 | 23 |
血糖 | 15.02±1.44** | 16.88±0.21* | 15.96±1.33** | 15.39±0.16** | 14.13±2.01** |
注:与模型组相比,*P<0.05,**P<0.01
如所表4所示,模型组大鼠的糖耐量实验时各点血糖值均高于正常组大鼠(P<0.05)。如所表5所示,给药后,Diprotin A类似物及6个单体化合物显著降低血糖水平(P<0.05)。
本发明采用上述方法从白背三七天然产物中发现了具有抗糖尿病活性的化合物,并高效选择性分离了25种diprotin A的类似物,进行了抗糖尿病活性的表征;本发明所要保护的化合物属于DPP–IV抑制剂,IC50值为0.40mg/mL;分子对接研究还证实了diprotin A类似物和DPP–IV之间的相互作用,diprotin A类似物促进NCI-H716细胞释放GLP-1,具有显著的作用,动物实验发现本发明公开的化合物对降血糖有明显作用,可以改善血胰岛素水平,对糖尿病的治疗开辟了新的途径。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明的保护范围之内。
Claims (5)
2.一种如权利要求1所述的具有抗糖尿病活性的化合物的制备方法,其特征在于,包括以下步骤:
步骤1、将白背三七浸泡在含盐酸的甲醇-水溶剂中一周以上,得到白背三七的提取物;
步骤2、对所述步骤1得到的白背三七提取物进行过滤、浓缩;
步骤3、将所述步骤2得到的浓缩液进行色谱分离,再进行分离即可得到化合物。
3.如权利要求1所述的具有抗糖尿病活性的化合物在制备药物中的应用,所述药物是预防或/和治疗糖尿病的药物。
4.如权利要求1所述的具有抗糖尿病活性的化合物在制备辅助降血糖保健品中的应用。
5.一类药物,其特征在于,所述药物包含有效量的如权利要求1所述的具有抗糖尿病活性的化合物。
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