喹喔啉/喹唑啉类磷脂酰肌醇3-激酶（PI3K）小分子抑制剂的设计、合成和活性研究
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摘要
恶性肿瘤正成为威胁人类健康的头号疾病。临床应用的直接作用于细胞有丝分裂或DNA合成修复等过程的传统抗肿瘤药物往往存在疗效不佳、毒副作用大等缺点。作用于细胞内信号通路上关键靶点的小分子抑制剂是一类新型的抗肿瘤药物。这些小分子抑制剂和传统的肿瘤治疗药物相比往往具有更好的疗效和较小的毒副作用。磷脂酰肌醇3-激酶(P13K)是细胞内参与调控包括细胞增殖、存活、生长、转移、凋亡等重要生命活动的一类脂激酶。大量研究表明P13K家族中的α亚型和肿瘤的发生发展关系最为密切,是有希望的肿瘤治疗靶点。近年来,P13K小分子抑制剂由于其在肿瘤治疗方面的潜在应用前景而备受关注。
本文根据文献报道的P13K抑制剂的结构特征及它们与P13K的作用模式,结合该位点抑制剂中出现的喹喔啉结构母核,利用理性药物设计原理,通过在喹喔啉环的2位引入不同的芳胺片段并在喹喔啉环的3位引入不同的芳磺酰基或芳磺酰肼基片段,设计、合成了53个结构全新的N-芳基喹喔啉胺类衍生物。体外抗肿瘤活性筛选结果表明：大部分化合物的细胞增殖抑制活性优于阳性对照,其中部分化合物(如化合物1-27、1-51和1-61)对部分受试细胞株增殖抑制的IC50达到了纳摩尔级。初步构效关系研究显示,3-芳磺酰基取代优于3-芳磺酰肼基取代；2-芳胺基芳环上引入甲氧基、氨基、羟基等取代基时对活性有利。目标化合物的P13Ka抑制实验表明,化合物1-27(IC50：0.07μM)和化合物1-61(IC50：0.47μM)具有较强的P13Ka抑制活性。
在上述实验基础上,进而利用计算机辅助药物设计方法,通过Catalyst软件包构建了P13Kα的药效团模型Hypol,并对数据库进行虚拟筛选。根据筛选得到的高活性吗啉喹喔啉类化合物WR01(2-30)的结构特征,结合生物电子等排和类似物设计等方法,进一步设计合成了93个2-脂环胺取代的喹喔啉类化合物。体外细胞抗肿瘤活性测试的结果表明,大部分化合物显示了优于阳性对照的细胞增殖抑制活性。构效关系研究表明喹喔啉2位不同的脂环胺片段对活性有不同影响：吡咯烷和氢化异喹啉环取代时活性较差、吗啉环取代时活性较好、羟基哌啶和各种哌嗪环取代时活性最好,达纳摩尔级。PI3Kα抑制实验表明,羟基哌啶喹喔啉类化合物(如2-72,IC50：0.077μM;2-75,IC50：0.025μM)和各种哌嗪喹喔啉类化合物显示了良好的PI3Ka抑制活性,以上结果和药效团Hypol预测的活性基本一致,验证了Hypol的可靠性。Akt蛋白磷酸化抑制实验表明,化合物2-75显示了明显的Akt蛋白磷酸化抑制作用,再次证明了该化合物是通过作用于PI3K信号通路而发挥其抗肿瘤活性的。以上结果表明化合物2-75是有潜力的P13Kα中制剂。
此外,本文根据文献报道的2-苯基-4-吗啉基喹唑啉类PI3K抑制剂,利用拼合原理,通过在吗啉喹唑啉母核的6位引入芳亚甲胺侧链、芳磺酰胺基侧链、吡咯烷二酮氨基侧链和马来酰亚胺基侧链共设计合成了五类49个结构新颖的吗啉喹唑啉类衍生物。体外抗肿瘤活性测试结果表明,喹唑啉2位苯基的存在有利于抗肿瘤活性的提高；芳磺酰胺基侧链取代的化合物活性好于芳亚甲胺侧链取代的化合物;吡咯烷二酮氨基侧链取代的化合物活性中等；具有马来酰亚胺基侧链的化合物显示了良好的细胞增殖抑制活性(如化合物3-68和3-69)。该研究为喹唑啉类抗肿瘤药物的开发提供了新的思路。
Cancer is becoming the number-one threat to human health worldwide. Traditional anti-cancer agents, which directly interfere with mitosis, DNA synthesis, and repair systems, are often connected with drawbacks such as low efficacy and high toxicity. Small-molecule inhibitors targeting key knots of cellular signaling pathways are new class of anti-cancer agents. These small-molecule inhibitors may be more effective than current anti-cancer treatments and less harmful to normal cells. Phosphoinositide3-kianses (PI3Ks) are family of lipid kinases that regulate crucial cellular events such as proliferation, survival, growth, metastasis and apoptosis. Extensive studies have established the close connection between tumor genesis&progression and the a isoform of PI3Ks, making PI3Kα a promising target for cancer treatment. Consequently, the research on small-molecule PI3K inhibitors has attracted considerable attention in recent years.
Enlightened by the structural features and binding mode of PI3K inhibitors, using the quinoxaline core presented in reported inhibitors, target compounds were constructed through the introduction of different arylamino moiety into the2-position and either arylsulfonyl or arylsulfonylhydrazide group at the3-position of the quinoxaline core. Herein, series of53novel N-arylquinoxalinylamine derivatives were synthesized and biologically evaluated for their in vitro anti-tumor activities, the result of which showed that most target compounds exhibited better anti-proliferation activity against tested cell lines than that of the positive control and some compounds (e.g.1-27,1-51and1-61) exhibited nanomolar potency. Preliminary SAR study revealed that compounds with a3-arylsulfonyl substituent exhibited better activity than that with a3-arylsulfonylhydrazide substitutent and the introduction of methoxy, amino, and hydroxyl group at the2-arylamino group was beneficial for potency. Enzymatic assay against PI3Ka showed that compound1-27(IC50:0.07μM) and compound1-61(IC50:0.47μM) exhibited potent PI3Ka inhibitory activity.
Based on the results obtained above, a PI3Ka pharmacophore model Hypol was established using Catalyst software package, followed by virtual screening against databases. Then series of93aliphatic-cyclic-aminoquinoxalines were designed and synthesized based on the structural features of a virtual-screening identified potent morpholinoquinoxaline compound WR01(2-30) according to principles of bioisosterism and design of analogues. In vitro evaluation against human cancer cell lines showed that most target compounds exhibited better anti-proliferative activity than that of the positive control. PI3Ka assay showed that hydroxylpiperidinylquinoxaline (e.g.2-72, IC50:0.077μM;2-75, IC50:0.025μM) and various piperazinylquinoxaline derivatives exhibited potent inhibitory activity against PI3Ka. The experimental data of PI3Ka assay were consistent well with the pharmacophore-based predicted values, which validated the accuracy of the established model Hypol. A following assay showed that2-75exhibited significant suppressive effect against Akt phosphorylation. The above results demonstrate that2-75is a promising PI3Ka inhibitor.
Besides, based on reported2-phenyl-4-morpholinoquinazoline PI3K inhibitors, five series of49novel morpholinoquinazoline derivatives were designed and synthesized in this study according to combination principle through the introduction of arylideneamino, arylsulfonylamino, dioxopyrrolidinylamino, and maleinimide chains into the6-position of the morpholinoquinazoline core. In vitro anti-tumor evaluation revealed that the presence of the2-phenyl group was beneficial for potency, compounds with an arylsulfonylamino chain showed better activity than that with an arylideneamino chain, dioxopyrrolidinylamino substituted compounds showed moderate potency, and compounds substituted by maleinimide chains (e.g.3-68and3-69) showed potent inhibitory anti-tumor activity. This study provides new insights for the development of quinazolines as anti-cancer agents.
本文根据文献报道的P13K抑制剂的结构特征及它们与P13K的作用模式,结合该位点抑制剂中出现的喹喔啉结构母核,利用理性药物设计原理,通过在喹喔啉环的2位引入不同的芳胺片段并在喹喔啉环的3位引入不同的芳磺酰基或芳磺酰肼基片段,设计、合成了53个结构全新的N-芳基喹喔啉胺类衍生物。体外抗肿瘤活性筛选结果表明：大部分化合物的细胞增殖抑制活性优于阳性对照,其中部分化合物(如化合物1-27、1-51和1-61)对部分受试细胞株增殖抑制的IC50达到了纳摩尔级。初步构效关系研究显示,3-芳磺酰基取代优于3-芳磺酰肼基取代；2-芳胺基芳环上引入甲氧基、氨基、羟基等取代基时对活性有利。目标化合物的P13Ka抑制实验表明,化合物1-27(IC50：0.07μM)和化合物1-61(IC50：0.47μM)具有较强的P13Ka抑制活性。
在上述实验基础上,进而利用计算机辅助药物设计方法,通过Catalyst软件包构建了P13Kα的药效团模型Hypol,并对数据库进行虚拟筛选。根据筛选得到的高活性吗啉喹喔啉类化合物WR01(2-30)的结构特征,结合生物电子等排和类似物设计等方法,进一步设计合成了93个2-脂环胺取代的喹喔啉类化合物。体外细胞抗肿瘤活性测试的结果表明,大部分化合物显示了优于阳性对照的细胞增殖抑制活性。构效关系研究表明喹喔啉2位不同的脂环胺片段对活性有不同影响：吡咯烷和氢化异喹啉环取代时活性较差、吗啉环取代时活性较好、羟基哌啶和各种哌嗪环取代时活性最好,达纳摩尔级。PI3Kα抑制实验表明,羟基哌啶喹喔啉类化合物(如2-72,IC50：0.077μM;2-75,IC50：0.025μM)和各种哌嗪喹喔啉类化合物显示了良好的PI3Ka抑制活性,以上结果和药效团Hypol预测的活性基本一致,验证了Hypol的可靠性。Akt蛋白磷酸化抑制实验表明,化合物2-75显示了明显的Akt蛋白磷酸化抑制作用,再次证明了该化合物是通过作用于PI3K信号通路而发挥其抗肿瘤活性的。以上结果表明化合物2-75是有潜力的P13Kα中制剂。
此外,本文根据文献报道的2-苯基-4-吗啉基喹唑啉类PI3K抑制剂,利用拼合原理,通过在吗啉喹唑啉母核的6位引入芳亚甲胺侧链、芳磺酰胺基侧链、吡咯烷二酮氨基侧链和马来酰亚胺基侧链共设计合成了五类49个结构新颖的吗啉喹唑啉类衍生物。体外抗肿瘤活性测试结果表明,喹唑啉2位苯基的存在有利于抗肿瘤活性的提高；芳磺酰胺基侧链取代的化合物活性好于芳亚甲胺侧链取代的化合物;吡咯烷二酮氨基侧链取代的化合物活性中等；具有马来酰亚胺基侧链的化合物显示了良好的细胞增殖抑制活性(如化合物3-68和3-69)。该研究为喹唑啉类抗肿瘤药物的开发提供了新的思路。
Cancer is becoming the number-one threat to human health worldwide. Traditional anti-cancer agents, which directly interfere with mitosis, DNA synthesis, and repair systems, are often connected with drawbacks such as low efficacy and high toxicity. Small-molecule inhibitors targeting key knots of cellular signaling pathways are new class of anti-cancer agents. These small-molecule inhibitors may be more effective than current anti-cancer treatments and less harmful to normal cells. Phosphoinositide3-kianses (PI3Ks) are family of lipid kinases that regulate crucial cellular events such as proliferation, survival, growth, metastasis and apoptosis. Extensive studies have established the close connection between tumor genesis&progression and the a isoform of PI3Ks, making PI3Kα a promising target for cancer treatment. Consequently, the research on small-molecule PI3K inhibitors has attracted considerable attention in recent years.
Enlightened by the structural features and binding mode of PI3K inhibitors, using the quinoxaline core presented in reported inhibitors, target compounds were constructed through the introduction of different arylamino moiety into the2-position and either arylsulfonyl or arylsulfonylhydrazide group at the3-position of the quinoxaline core. Herein, series of53novel N-arylquinoxalinylamine derivatives were synthesized and biologically evaluated for their in vitro anti-tumor activities, the result of which showed that most target compounds exhibited better anti-proliferation activity against tested cell lines than that of the positive control and some compounds (e.g.1-27,1-51and1-61) exhibited nanomolar potency. Preliminary SAR study revealed that compounds with a3-arylsulfonyl substituent exhibited better activity than that with a3-arylsulfonylhydrazide substitutent and the introduction of methoxy, amino, and hydroxyl group at the2-arylamino group was beneficial for potency. Enzymatic assay against PI3Ka showed that compound1-27(IC50:0.07μM) and compound1-61(IC50:0.47μM) exhibited potent PI3Ka inhibitory activity.
Based on the results obtained above, a PI3Ka pharmacophore model Hypol was established using Catalyst software package, followed by virtual screening against databases. Then series of93aliphatic-cyclic-aminoquinoxalines were designed and synthesized based on the structural features of a virtual-screening identified potent morpholinoquinoxaline compound WR01(2-30) according to principles of bioisosterism and design of analogues. In vitro evaluation against human cancer cell lines showed that most target compounds exhibited better anti-proliferative activity than that of the positive control. PI3Ka assay showed that hydroxylpiperidinylquinoxaline (e.g.2-72, IC50:0.077μM;2-75, IC50:0.025μM) and various piperazinylquinoxaline derivatives exhibited potent inhibitory activity against PI3Ka. The experimental data of PI3Ka assay were consistent well with the pharmacophore-based predicted values, which validated the accuracy of the established model Hypol. A following assay showed that2-75exhibited significant suppressive effect against Akt phosphorylation. The above results demonstrate that2-75is a promising PI3Ka inhibitor.
Besides, based on reported2-phenyl-4-morpholinoquinazoline PI3K inhibitors, five series of49novel morpholinoquinazoline derivatives were designed and synthesized in this study according to combination principle through the introduction of arylideneamino, arylsulfonylamino, dioxopyrrolidinylamino, and maleinimide chains into the6-position of the morpholinoquinazoline core. In vitro anti-tumor evaluation revealed that the presence of the2-phenyl group was beneficial for potency, compounds with an arylsulfonylamino chain showed better activity than that with an arylideneamino chain, dioxopyrrolidinylamino substituted compounds showed moderate potency, and compounds substituted by maleinimide chains (e.g.3-68and3-69) showed potent inhibitory anti-tumor activity. This study provides new insights for the development of quinazolines as anti-cancer agents.
引文
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