两类FXR拮抗剂的设计、合成与构效关系研究及芳炔参与的反应研究
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摘要
本论文包括两部分,第一部分为药物化学部分,研究两类FXR拮抗剂的设计、合成及其在治疗代谢类疾病中的潜在应用。第二部分为方法学部分,研究了芳炔作为分子切块与含氮亲核试剂发生串联、多组分反应,及其在合成多种杂环衍生物中的应用。
FXR(法尼酯衍生物X受体)是一种重要的配体激活转录因子,是核受体超家族的成员。FXR参与了体内胆固醇代谢、脂代谢和糖代谢等多种生理过程,与糖尿病、肥胖和血脂紊乱等代谢类疾病有密切的联系。现有研究表明FXR拮抗剂在治疗代谢类疾病方面可能具有潜在的应用。目前文献报道的FXR拮抗剂普遍存在活性较低、获取困难等缺点。为了得到高活性的FXR拮抗剂,我们利用高通量筛选得到的两个FXR拮抗剂AA7和DCW229作为先导化合物,对其开展结构优化并取得一些成果。
AA7的构效关系研究：设计、合成了33个AA7类似物,系统研究了AA7结构中各部分对其拮抗FXR活性的影响；获得了比AA7活性提高近30倍、比阳性对照化合物GS提高80倍的新衍生物AA7-2。遗憾的是AA7-2只能在分子水平上拮抗FXR,在细胞水平上对CDCA激活的FXR无显著影响。
DCW229的构效关系研究：经过多轮的结构优化,设计、合成了100多个衍生物；衍生物FXR-21在分子水平具有中等FXR抑制活性,在细胞水平上对FXR及其下游基因具有一定的抑制活性,对FXR有较高的选择性,动物药效学实验揭示其可以有效的降低总胆固醇的水平；在此基础上又进行了深入的结构优化进而发现了衍生物FXR-99,其分子水平拮抗FXR的IC5o为0.3μM,超过了目前文献报道的所有FXR拮抗剂,FXR-99在细胞水平对FXR及其下游基因也具有很强的拮抗活性,对FXR具有较高的选择性,但动物水平的实验却显示对高脂喂养小鼠的胆固醇水平影响不大,分析可能是水溶性太低所致。
随后药理研究小组成功培育出FXR-99与FXR的共晶复合物,并解析了其结构,该晶体复合物是首个拮抗剂与FXR的晶体复合物。通过分析该晶体结构中FXR-99与结合口袋中氨基酸残基的相互作用,设计并合成了一批提高化合物水溶性的衍生物,遗憾的是这些化合物与FXR-99相比FXR抑制活性有较大幅度的下降。进一步的研究还有待开展。
在DCW229衍生物合成过程中,我们发现芳香醛在氮杂卡宾的催化下与苄烯丙二腈或苄烯腈乙酸乙酯发生Stetter反应时可以发生环合得到2-氨基呋喃类衍生物。底物适应性研究发现,芳香醛取代基对该反应影响较大,吸电子的取代基通常具有较高的收率而给电子取代基只能得到中等收率。
芳炔是一类极活泼的化合物,早在1953年就有文献报道。随后也有一些利用芳炔构建复杂分子片段、合成天然产物的研究报道,但由于其制备条件苛刻、反应活性过高,芳炔在有机合成中的应用一直不广。直到上世纪末,众多温和条件制备芳炔的方法被报道和应用,其中Kobayashi报道的邻三甲基硅基三氟甲磺酸酚酯类芳炔前体,因其制备容易、性质稳定且转化成芳炔条件温和而应用最广。
本论文第二部分第二章研究Kobayashi芳炔前体与含氮杂环及醛或酮在氟化铯存在下直接制备苯并噁嗪类化合物,该反应收率较高、底物适用较广。特别值得注意的是,在我们的反应条件下,含α氢的酮也可以得到苯并噁嗪类化合物,而并非郑建鸿所报道的1,2-二取代吡啶或喹啉衍生物。在条件优化过程中,我们意外发现二氯甲烷可以替代醛或酮有效的参与该反应。二氯甲烷中极弱的酸性氢可以被苯基负离子捕获,失去氢的二氯甲烷负离子进而进攻含氮杂环中的亚胺结构,得到1,2-二取代的吡啶、喹啉及异喹啉衍生物。
第二部分第三章研究氮杂Morita-Baylis-Hillman产物与芳炔发生串联反应得到3-亚甲基-2,3-二氢喹啉酮类衍生物。由于羟基对苯炔亲核性较低,初始利用MBH产物与苯炔反应并没有得到目标化合物。将其替换为含氨基的衍生物178a,可以得到目标化合物,但收率较低。分析原因可能是反应中间体优势构型中苯基负离子与羰基相距较远,苯基负离子更倾向于捕获质子得到N-苯基副产物。通过增加氨基邻位取代基的大小,在邻位引入苯基的衍生物180a可以得到收率中等的目标产物。
This dissertation mainly focuses on two parts. The first is the medicinal chemistry research, two HTS (high-throughput screening) hits of FXR antagonists were selected for SAR studies and nearly150derivatives were designed, synthesized and evaluated with biological activity. The second part is the methodological research, several heterocyclic backbones were constructed via multicomponent reaction or cascade reaction involving arynes and nitrogen containing nucleophilic compounds.
FXR (Farnesoid X receptor) is a ligand-acitivated transcriptional factor which is a number of the nuclear receptor superfamilay. FXR is involved in the regulation of bile acid and cholesterol homeostasis, lipoprotein and glucose metabolism as a bile acid sensor. FXR has been thought to be involved in the formation of metabolic syndrome which including obesity, dyslipidemia, diabetes and so on. FXR antagonists lower the contents of triglyceride and cholesterol and increase the high-density lipoprotein (HDL) in HepG2cells and in high-fat diet C57BL/6mice. Despite the promising perspective of FXR antagonists in the regulation of numerous biological processes and related diseases development, the FXR antagonists reported in the literature are limited in low potency and difficulty in obtaining. Two moderate FXR antagonists AA7and DCW229obtained via HTS were selected for further modification and the results are shown as follows.
To exploring the structure-activity relationship of AA7,33analogs were designed, synthesized and evaluated with FXR antagonist activities. The most potent derivative AA7-2was almost30-fold more potent than the hit AA7and more than80-fold stronger than the positive control FXR antagonist GS. To our great disappointment, further evaluation of AA7-2in hepatic cell shown no positive effect on inhibition of FXR.
As for another FXR antagonist DCW229, more than100analogs were designed, synthesized and test with its FXR antagonist activities. The analog FXR-21was found to inhibit the CDCA induced coactivator recruitment of FXR and its downstream target genes in hepatic cells with moderate potency. Besides that, FXR-21also exhibited a high selectivity over other nuclear receptors. Further evaluation in high-fat diet mice found it could efficiently reduced the total level of cholesterol, which implied its promising prospective in the treatment of metabolism disorders. To further improve its potency, several rounds of design, synthesis and evaluation were carried out and more potent FXR antagonist FXR-99was discovered with IC_(50)=0.3μM. FXR-99also showed potent inhibition of FXR and its downstream target genes and high selectivity over other nuclear receptors in hepatic cells. However, FXR-99showed no positive effect on the regulation of total cholesterol in high-fat diet mice. Considering the high Log P value and low water solubility of FXR-99, we supposed the failure in the high-fat diet mice might be attributed to its low solubility and poor physicochemical property.
After the discovery of the potent FXR antagonist FXR-99, our cooperators successfully cultivated the cocrystal complex of FXR-99with FXR and elucidated its structure, which is the first cocrystal complex of FXR with FXR antagonist. Based on the binding pocket of the complex crystal, several new FXR-99analogs with improved physicochemical property were designed, synthesized and evaluated with its FXR antagonist activity. However, these analogs turned out to show reduced antagonist activity.
During the SAR studies of DCW229, we serepiditiouly found that aromatic aldehydes could react with acylidenemalononitriles via Stetter-cyclization process to form2-amino furan derivatives. The reaction conditions and substrates scope were investigated and found that aromatic aldehydes with electron-deficient substitution afford the desired product in good yields while electron-donating substituted aromatic aldehydes give moderate yields.
The second part of this dissertation explored the reactivity of aryne in the multicomponent and cascade reaction with nitrogen containing nucleophilic compounds. Arynes are very reactive intermediates, which had been studied more than60years. However, aryne had not been widely used in constructing biological moleculars or natural products which mainly due to harsh conditions required to generate arynes. Most recently, the using of o-silyl aryl triflates as aryne precursors reported by Kobayashi has attracted great attention for the stability of these compounds and mild condition required to generate arynes.
In segement2chapter2, we described the multicomponent reaction involving arynes, N-heteroaromatic compounds and aldehydes or ketones to give benzo-annulated1,3-oxazine derivatives in moderate to high yields. The reaction conditions and substrates scope were investigated thoroughly and a possible mechanism was also proposed to illustrate the regioselectivity and distereoselectivity when3-OMe benzyne was used in this reaction. It worth to be mentioned that aldehydes or ketones with a hydrogen reacted smoothly in our conditions to generate the desired products while Cheng et. al. had reported in their conditions to give1,2-disubstituted N-aromatic compounds.
During the optimization of the multicomponent reaction, we found dichloromethane could efficiently react with arynes and N-hetaroaromatic compounds to form the 1,2-disubstituted pyridine, quinoline or isoquinoline derivatives. Trichloromethane and dibromomethane could also participate in this reaction to afford the corresponding products.
Segement2chapter3investigated the cascade reaction of aza-Morita-Baylis-Hillman adducts with arynes to generate the3-methylene-2,3-dihydroquinolin-4(1H)-one derivatives with TMAF as the fluride sources. Initial efforts were focused on the direct reaction of Morita-Baylis-Hillman adducts with aryne. However, no desried product was obtained which probably due to the low nucleophilic of hydroxyl group with aryne. n-Butylamine derivate178a reacted with benzyne smoothly to afford the desired product in low yield, with the N-Ph derivative as main byproduct. The low yield of desried product might be attributed to the stable configuration of the intermediate in which Phenyl anion is prone to attack proton rather than carbonyl group. To overcome this problem, a-Phenyl derivative180a was used in this reaction and the yield of the desried product was improved to moderate.
FXR(法尼酯衍生物X受体)是一种重要的配体激活转录因子,是核受体超家族的成员。FXR参与了体内胆固醇代谢、脂代谢和糖代谢等多种生理过程,与糖尿病、肥胖和血脂紊乱等代谢类疾病有密切的联系。现有研究表明FXR拮抗剂在治疗代谢类疾病方面可能具有潜在的应用。目前文献报道的FXR拮抗剂普遍存在活性较低、获取困难等缺点。为了得到高活性的FXR拮抗剂,我们利用高通量筛选得到的两个FXR拮抗剂AA7和DCW229作为先导化合物,对其开展结构优化并取得一些成果。
AA7的构效关系研究：设计、合成了33个AA7类似物,系统研究了AA7结构中各部分对其拮抗FXR活性的影响；获得了比AA7活性提高近30倍、比阳性对照化合物GS提高80倍的新衍生物AA7-2。遗憾的是AA7-2只能在分子水平上拮抗FXR,在细胞水平上对CDCA激活的FXR无显著影响。
DCW229的构效关系研究：经过多轮的结构优化,设计、合成了100多个衍生物；衍生物FXR-21在分子水平具有中等FXR抑制活性,在细胞水平上对FXR及其下游基因具有一定的抑制活性,对FXR有较高的选择性,动物药效学实验揭示其可以有效的降低总胆固醇的水平；在此基础上又进行了深入的结构优化进而发现了衍生物FXR-99,其分子水平拮抗FXR的IC5o为0.3μM,超过了目前文献报道的所有FXR拮抗剂,FXR-99在细胞水平对FXR及其下游基因也具有很强的拮抗活性,对FXR具有较高的选择性,但动物水平的实验却显示对高脂喂养小鼠的胆固醇水平影响不大,分析可能是水溶性太低所致。
随后药理研究小组成功培育出FXR-99与FXR的共晶复合物,并解析了其结构,该晶体复合物是首个拮抗剂与FXR的晶体复合物。通过分析该晶体结构中FXR-99与结合口袋中氨基酸残基的相互作用,设计并合成了一批提高化合物水溶性的衍生物,遗憾的是这些化合物与FXR-99相比FXR抑制活性有较大幅度的下降。进一步的研究还有待开展。
在DCW229衍生物合成过程中,我们发现芳香醛在氮杂卡宾的催化下与苄烯丙二腈或苄烯腈乙酸乙酯发生Stetter反应时可以发生环合得到2-氨基呋喃类衍生物。底物适应性研究发现,芳香醛取代基对该反应影响较大,吸电子的取代基通常具有较高的收率而给电子取代基只能得到中等收率。
芳炔是一类极活泼的化合物,早在1953年就有文献报道。随后也有一些利用芳炔构建复杂分子片段、合成天然产物的研究报道,但由于其制备条件苛刻、反应活性过高,芳炔在有机合成中的应用一直不广。直到上世纪末,众多温和条件制备芳炔的方法被报道和应用,其中Kobayashi报道的邻三甲基硅基三氟甲磺酸酚酯类芳炔前体,因其制备容易、性质稳定且转化成芳炔条件温和而应用最广。
本论文第二部分第二章研究Kobayashi芳炔前体与含氮杂环及醛或酮在氟化铯存在下直接制备苯并噁嗪类化合物,该反应收率较高、底物适用较广。特别值得注意的是,在我们的反应条件下,含α氢的酮也可以得到苯并噁嗪类化合物,而并非郑建鸿所报道的1,2-二取代吡啶或喹啉衍生物。在条件优化过程中,我们意外发现二氯甲烷可以替代醛或酮有效的参与该反应。二氯甲烷中极弱的酸性氢可以被苯基负离子捕获,失去氢的二氯甲烷负离子进而进攻含氮杂环中的亚胺结构,得到1,2-二取代的吡啶、喹啉及异喹啉衍生物。
第二部分第三章研究氮杂Morita-Baylis-Hillman产物与芳炔发生串联反应得到3-亚甲基-2,3-二氢喹啉酮类衍生物。由于羟基对苯炔亲核性较低,初始利用MBH产物与苯炔反应并没有得到目标化合物。将其替换为含氨基的衍生物178a,可以得到目标化合物,但收率较低。分析原因可能是反应中间体优势构型中苯基负离子与羰基相距较远,苯基负离子更倾向于捕获质子得到N-苯基副产物。通过增加氨基邻位取代基的大小,在邻位引入苯基的衍生物180a可以得到收率中等的目标产物。
This dissertation mainly focuses on two parts. The first is the medicinal chemistry research, two HTS (high-throughput screening) hits of FXR antagonists were selected for SAR studies and nearly150derivatives were designed, synthesized and evaluated with biological activity. The second part is the methodological research, several heterocyclic backbones were constructed via multicomponent reaction or cascade reaction involving arynes and nitrogen containing nucleophilic compounds.
FXR (Farnesoid X receptor) is a ligand-acitivated transcriptional factor which is a number of the nuclear receptor superfamilay. FXR is involved in the regulation of bile acid and cholesterol homeostasis, lipoprotein and glucose metabolism as a bile acid sensor. FXR has been thought to be involved in the formation of metabolic syndrome which including obesity, dyslipidemia, diabetes and so on. FXR antagonists lower the contents of triglyceride and cholesterol and increase the high-density lipoprotein (HDL) in HepG2cells and in high-fat diet C57BL/6mice. Despite the promising perspective of FXR antagonists in the regulation of numerous biological processes and related diseases development, the FXR antagonists reported in the literature are limited in low potency and difficulty in obtaining. Two moderate FXR antagonists AA7and DCW229obtained via HTS were selected for further modification and the results are shown as follows.
To exploring the structure-activity relationship of AA7,33analogs were designed, synthesized and evaluated with FXR antagonist activities. The most potent derivative AA7-2was almost30-fold more potent than the hit AA7and more than80-fold stronger than the positive control FXR antagonist GS. To our great disappointment, further evaluation of AA7-2in hepatic cell shown no positive effect on inhibition of FXR.
As for another FXR antagonist DCW229, more than100analogs were designed, synthesized and test with its FXR antagonist activities. The analog FXR-21was found to inhibit the CDCA induced coactivator recruitment of FXR and its downstream target genes in hepatic cells with moderate potency. Besides that, FXR-21also exhibited a high selectivity over other nuclear receptors. Further evaluation in high-fat diet mice found it could efficiently reduced the total level of cholesterol, which implied its promising prospective in the treatment of metabolism disorders. To further improve its potency, several rounds of design, synthesis and evaluation were carried out and more potent FXR antagonist FXR-99was discovered with IC_(50)=0.3μM. FXR-99also showed potent inhibition of FXR and its downstream target genes and high selectivity over other nuclear receptors in hepatic cells. However, FXR-99showed no positive effect on the regulation of total cholesterol in high-fat diet mice. Considering the high Log P value and low water solubility of FXR-99, we supposed the failure in the high-fat diet mice might be attributed to its low solubility and poor physicochemical property.
After the discovery of the potent FXR antagonist FXR-99, our cooperators successfully cultivated the cocrystal complex of FXR-99with FXR and elucidated its structure, which is the first cocrystal complex of FXR with FXR antagonist. Based on the binding pocket of the complex crystal, several new FXR-99analogs with improved physicochemical property were designed, synthesized and evaluated with its FXR antagonist activity. However, these analogs turned out to show reduced antagonist activity.
During the SAR studies of DCW229, we serepiditiouly found that aromatic aldehydes could react with acylidenemalononitriles via Stetter-cyclization process to form2-amino furan derivatives. The reaction conditions and substrates scope were investigated and found that aromatic aldehydes with electron-deficient substitution afford the desired product in good yields while electron-donating substituted aromatic aldehydes give moderate yields.
The second part of this dissertation explored the reactivity of aryne in the multicomponent and cascade reaction with nitrogen containing nucleophilic compounds. Arynes are very reactive intermediates, which had been studied more than60years. However, aryne had not been widely used in constructing biological moleculars or natural products which mainly due to harsh conditions required to generate arynes. Most recently, the using of o-silyl aryl triflates as aryne precursors reported by Kobayashi has attracted great attention for the stability of these compounds and mild condition required to generate arynes.
In segement2chapter2, we described the multicomponent reaction involving arynes, N-heteroaromatic compounds and aldehydes or ketones to give benzo-annulated1,3-oxazine derivatives in moderate to high yields. The reaction conditions and substrates scope were investigated thoroughly and a possible mechanism was also proposed to illustrate the regioselectivity and distereoselectivity when3-OMe benzyne was used in this reaction. It worth to be mentioned that aldehydes or ketones with a hydrogen reacted smoothly in our conditions to generate the desired products while Cheng et. al. had reported in their conditions to give1,2-disubstituted N-aromatic compounds.
During the optimization of the multicomponent reaction, we found dichloromethane could efficiently react with arynes and N-hetaroaromatic compounds to form the 1,2-disubstituted pyridine, quinoline or isoquinoline derivatives. Trichloromethane and dibromomethane could also participate in this reaction to afford the corresponding products.
Segement2chapter3investigated the cascade reaction of aza-Morita-Baylis-Hillman adducts with arynes to generate the3-methylene-2,3-dihydroquinolin-4(1H)-one derivatives with TMAF as the fluride sources. Initial efforts were focused on the direct reaction of Morita-Baylis-Hillman adducts with aryne. However, no desried product was obtained which probably due to the low nucleophilic of hydroxyl group with aryne. n-Butylamine derivate178a reacted with benzyne smoothly to afford the desired product in low yield, with the N-Ph derivative as main byproduct. The low yield of desried product might be attributed to the stable configuration of the intermediate in which Phenyl anion is prone to attack proton rather than carbonyl group. To overcome this problem, a-Phenyl derivative180a was used in this reaction and the yield of the desried product was improved to moderate.
引文
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