PTP1B抑制剂的制备与构效关系研究
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摘要
蛋白酪氨酸磷酸酶1B(protein tyrosine phosphatase, PTP1B)是蛋白酪氨酸磷酸酶(protein tyrosine phosphatases, PTPs)家族中的一个经典的非受体型酪氨酸磷酸酶,在胰岛素信号通路中起着重要的负调控作用,是目前公认的一个新颖的糖尿病和肥胖症治疗靶点。寻找PTP1B的高活性抑制剂对糖尿病和肥胖症治疗有着重要的应用前景。
双-(2,3-二溴-4,5-二羟基苯基)-甲烷(BDDPM)是从松节藻醇提物中分离鉴定出的溴酚类化合物,体外活性筛选发现,它具有极强的蛋白酪氨酸磷酸酶1B(PTP1B)抑制活性(IC_(50)=2.4μmol/L)。采用高脂饮食-链脲佐菌素诱导的大鼠模型(STZ-DM)对富含BDDPM的松节藻醇提物进行动物实验,发现中、高剂量组同样表现出惊人的活性,降糖效果优于阳性对照临床药物文迪雅,并呈剂量依赖性。于是拟采用STZ-DM大鼠模型对单一组分BDDPM进行药理、药效学等体内降糖活性研究,但体内动物实验需要30g以上BDDPM,所以首先要解决药源的问题。本文尝试从天然海藻提取分离和化学合成两种途径来解决BDDPM制备的问题。
首先本文尝试从松节藻中提取分离BDDPM的制备方法。通过正相硅胶色谱、凝胶Sephadex LH-20色谱和重结晶等纯化手段分离纯化目标化合物BDDPM,并借助IR,MS和NMR等技术确定了其化学结构。最终从常温风干的50kg松节藻干样品中分离得到7.8g BDDPM。由于松节藻藻体构成复杂,给分离纯化BDDPM带来极大困难,致使分离纯化过程耗费大量时间和金钱;并且原材料松节藻的采集也易受季节和原料短缺等自然因素的影响。所以,从天然海藻中分离纯化的方法不适宜用于BDDPM的制备。
本文的重点是对BDDPM(4e)的化学合成途径进行研究。本文通过5步合成法(Friedel-Craftz酰基化反应、苯环逐级溴代、羰基还原、羟基脱保护)成功地合成了BDDPM,合成总产率为23.6%。同时本文采用上述合成路线获得了四个系列共计20个溴酚系列衍生物(4e为目标产物BDDPM,其余19个为溴酚系列衍生物),其中10个为新化合物。合成的20个化合物经1H NMR、13C NMR、MSEI和IR进行了结构鉴定。合成的20个化合物在体外活性筛选中均表现出不同程度的PTP1B抑制活性,其中合成的目标产物4e具有与天然分离纯化获得的BDDPM同等效率的PTP1B抑制作用。
另外,通过比较四个系列化合物PTP1B抑制活性间的差异,对此类溴酚化合物的构效关系作了初步分析,结果表明:1.羰基官能团的存在会明显降低此类化合物的PTP1B抑制率;2.化合物中的羟基官能团被甲氧基保护后,PTP1B抑制活性会得到一定程度的加强;3.化合物苯环上溴原子取代基数目增多时,其PTP1B抑制率也会随之增强。但是,筛选结果中也有少部分化合物的PTP1B抑制作用与上述规则相违背。因此,本文总结的初步构效关系还需要进一步的实验研究加以验证。
最后本文通过化学合成的方法,经过5步反应成功地制备出了30g BDDPM,为后续的药理、药效学研究奠定了基础。
Protein tyrosine phosphatase 1B(PTP1B), as a typical non-receptor type member of the family of PTPs(protein tyrosine phosphatases, PTP), is a key element in the negative regulation of insulin signaling pathway,and also has been a novel drug target for diabetes and obesity.Discovery for highly effective inhibitors of PTP1B has a promising application in diabetes and obesity therapy.
Bis-(2,3-dibromo-4,5-dihydroxy-phenyl)-methane (BDDPM) is a natural bromophenol with significant inhibition against PTP1B (IC_(50)=2.4μmol/L), which was isolated from the ethanol extract of red algae Rhodomela confervoides. In vivo anti-hypoglycemic effects on streptozotocin-diabetes in male Wistar rats (STZ-DM) fed with high fat diet revealed that the STZ-DM treated with medium-dose and high-dose algae ethanol extract showed remarkable reductions in fasting blood glucose as compared with the STZ-DM control. So it is necessary to develop BDDPM pharmacological study in vivo, however, above 30g BDDPM is needed. Thus, in this thesis two medthods extraction from algae and total organic synthesis were evaluated to the prepartion of BDDPM.
Firstly, 7.8g BDDPM was isolated from EtOAc-soluble portion of 50kg red alga R. confervoides by chromatography including normal phase silica gel, Sephadex LH-20 gel and recrystallization. Then its structure was elucidated by spectroscopic methods including IR, MS and NMR. The results revealed that it is too hard to isolate BDDPM from R. confervoides, which contains too much constituent which makes separation and purification process of BDDPM taking a lot of money and time. In additon, the collection of raw material is easily affected by natural, noncontrollable factors, such as shortage of raw materials. So this method is not suitable for the preparation of BDDPM.
Secondly, in this thesis starting from the readily accessible materials, a linear sequence of five steps (Friedel-Crafts acylation, Bromine reaction、Carbonyl reduction, Demethylation) was designed and applied to synthesize the targeting compound BDDPM in 23.6% overall yield. Moreover, the synthesized target compound shown nearly the same PTP1B inhibitory activity as the natural ingredients and all the other synthesized compounds demonstrated moderate to good PTP1B inhibitory activity in colorimetric assay.
In addition by comparing of PTP1B inhibition of four series compound, the preliminary structure-activity relationship of the screened compounds were revealed. First, the existence of carbonyl functional group on such compounds signifcantly lower rate of their PTP1B inhibition. Second, in the majority of those compounds, when the hydroxy functional groups to be protected by methoxy group their PTP1B inhibitory activity strengthening at a certain degree. Third, the presence of one or more bromines on the benzyl ring is benefite to PTP1B inhibitory activity and the increasing of bromine number on benzyl ring could obviously upgrade potency of PTP1B inhibitory activity. However, in this thesis it is not obvious to see a structure–activity pattern of selective compounds; more analogues need to be prepared further.
Finally, 30g BDDPM was successfully synthesized by five steps, which laid foundation for further pharmaceutical research.
双-(2,3-二溴-4,5-二羟基苯基)-甲烷(BDDPM)是从松节藻醇提物中分离鉴定出的溴酚类化合物,体外活性筛选发现,它具有极强的蛋白酪氨酸磷酸酶1B(PTP1B)抑制活性(IC_(50)=2.4μmol/L)。采用高脂饮食-链脲佐菌素诱导的大鼠模型(STZ-DM)对富含BDDPM的松节藻醇提物进行动物实验,发现中、高剂量组同样表现出惊人的活性,降糖效果优于阳性对照临床药物文迪雅,并呈剂量依赖性。于是拟采用STZ-DM大鼠模型对单一组分BDDPM进行药理、药效学等体内降糖活性研究,但体内动物实验需要30g以上BDDPM,所以首先要解决药源的问题。本文尝试从天然海藻提取分离和化学合成两种途径来解决BDDPM制备的问题。
首先本文尝试从松节藻中提取分离BDDPM的制备方法。通过正相硅胶色谱、凝胶Sephadex LH-20色谱和重结晶等纯化手段分离纯化目标化合物BDDPM,并借助IR,MS和NMR等技术确定了其化学结构。最终从常温风干的50kg松节藻干样品中分离得到7.8g BDDPM。由于松节藻藻体构成复杂,给分离纯化BDDPM带来极大困难,致使分离纯化过程耗费大量时间和金钱;并且原材料松节藻的采集也易受季节和原料短缺等自然因素的影响。所以,从天然海藻中分离纯化的方法不适宜用于BDDPM的制备。
本文的重点是对BDDPM(4e)的化学合成途径进行研究。本文通过5步合成法(Friedel-Craftz酰基化反应、苯环逐级溴代、羰基还原、羟基脱保护)成功地合成了BDDPM,合成总产率为23.6%。同时本文采用上述合成路线获得了四个系列共计20个溴酚系列衍生物(4e为目标产物BDDPM,其余19个为溴酚系列衍生物),其中10个为新化合物。合成的20个化合物经1H NMR、13C NMR、MSEI和IR进行了结构鉴定。合成的20个化合物在体外活性筛选中均表现出不同程度的PTP1B抑制活性,其中合成的目标产物4e具有与天然分离纯化获得的BDDPM同等效率的PTP1B抑制作用。
另外,通过比较四个系列化合物PTP1B抑制活性间的差异,对此类溴酚化合物的构效关系作了初步分析,结果表明:1.羰基官能团的存在会明显降低此类化合物的PTP1B抑制率;2.化合物中的羟基官能团被甲氧基保护后,PTP1B抑制活性会得到一定程度的加强;3.化合物苯环上溴原子取代基数目增多时,其PTP1B抑制率也会随之增强。但是,筛选结果中也有少部分化合物的PTP1B抑制作用与上述规则相违背。因此,本文总结的初步构效关系还需要进一步的实验研究加以验证。
最后本文通过化学合成的方法,经过5步反应成功地制备出了30g BDDPM,为后续的药理、药效学研究奠定了基础。
Protein tyrosine phosphatase 1B(PTP1B), as a typical non-receptor type member of the family of PTPs(protein tyrosine phosphatases, PTP), is a key element in the negative regulation of insulin signaling pathway,and also has been a novel drug target for diabetes and obesity.Discovery for highly effective inhibitors of PTP1B has a promising application in diabetes and obesity therapy.
Bis-(2,3-dibromo-4,5-dihydroxy-phenyl)-methane (BDDPM) is a natural bromophenol with significant inhibition against PTP1B (IC_(50)=2.4μmol/L), which was isolated from the ethanol extract of red algae Rhodomela confervoides. In vivo anti-hypoglycemic effects on streptozotocin-diabetes in male Wistar rats (STZ-DM) fed with high fat diet revealed that the STZ-DM treated with medium-dose and high-dose algae ethanol extract showed remarkable reductions in fasting blood glucose as compared with the STZ-DM control. So it is necessary to develop BDDPM pharmacological study in vivo, however, above 30g BDDPM is needed. Thus, in this thesis two medthods extraction from algae and total organic synthesis were evaluated to the prepartion of BDDPM.
Firstly, 7.8g BDDPM was isolated from EtOAc-soluble portion of 50kg red alga R. confervoides by chromatography including normal phase silica gel, Sephadex LH-20 gel and recrystallization. Then its structure was elucidated by spectroscopic methods including IR, MS and NMR. The results revealed that it is too hard to isolate BDDPM from R. confervoides, which contains too much constituent which makes separation and purification process of BDDPM taking a lot of money and time. In additon, the collection of raw material is easily affected by natural, noncontrollable factors, such as shortage of raw materials. So this method is not suitable for the preparation of BDDPM.
Secondly, in this thesis starting from the readily accessible materials, a linear sequence of five steps (Friedel-Crafts acylation, Bromine reaction、Carbonyl reduction, Demethylation) was designed and applied to synthesize the targeting compound BDDPM in 23.6% overall yield. Moreover, the synthesized target compound shown nearly the same PTP1B inhibitory activity as the natural ingredients and all the other synthesized compounds demonstrated moderate to good PTP1B inhibitory activity in colorimetric assay.
In addition by comparing of PTP1B inhibition of four series compound, the preliminary structure-activity relationship of the screened compounds were revealed. First, the existence of carbonyl functional group on such compounds signifcantly lower rate of their PTP1B inhibition. Second, in the majority of those compounds, when the hydroxy functional groups to be protected by methoxy group their PTP1B inhibitory activity strengthening at a certain degree. Third, the presence of one or more bromines on the benzyl ring is benefite to PTP1B inhibitory activity and the increasing of bromine number on benzyl ring could obviously upgrade potency of PTP1B inhibitory activity. However, in this thesis it is not obvious to see a structure–activity pattern of selective compounds; more analogues need to be prepared further.
Finally, 30g BDDPM was successfully synthesized by five steps, which laid foundation for further pharmaceutical research.
引文
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