Identification of Novel Thiazolo[5,4-b]Pyridine Derivatives as Potent Phosphoinositide 3-Kinase Inhibitors.
Identification of Novel Thiazolo[5,4-b]Pyridine Derivatives as Potent Phosphoinositide 3-Kinase Inhibitors.
复制标题
新型噻唑并[5,4-b]吡啶衍生物作为有效磷酸肌醇 3-激酶抑制剂的鉴定
DOI：
10.3390/molecules25204630
复制
发表时间：
2020-10-12
期刊：
影响因子：
--
通讯作者：
Xu H
中科院分区：
文献类型：
--
作者：
Xia L;Zhang Y;Zhang J;Lin S;Zhang K;Tian H;Dong Y;Xu H
本文设计并合成了一系列2-吡啶基，4-吗啉基取代的噻唑并[5，4-B]吡啶类似物。这些噻唑并[5，4-B]吡啶是由市售物质经七步以中等至良好的产率有效制备的。所有这些N-杂环化合物，其特征在于通过核磁共振（NMR）和高分辨率质谱（HRMS）分析和测试的磷酸肌醇3-激酶（PI 3 K）的酶活性测定。结果表明，这些N-杂环化合物具有较强的PI 3 K抑制活性，其中代表性化合物（19 a）的IC 50可达3.6 nm。结构-活性关系（SAR）研究表明，磺酰胺官能团对PI 3 K α抑制活性很重要，2-氯-4-氟苯基磺酰胺（19 b）或5-氯噻吩-2-磺酰胺（19 c）显示出强效抑制活性，IC 50值为纳摩尔。与噻唑并[5，4-B]吡啶连接的吡啶基是PI 3 K α抑制效力的另一个关键结构单元，被苯基取代导致活性显著降低。酶抑制结果表明，化合物19 a以纳摩尔IC 50值抑制PI 3 K α、PI 3 K γ或PI 3 K δ，但其对PI 3 K β的抑制活性降低约10倍。进一步的对接分析表明，化合物19 a的N-杂环核心通过关键的氢键作用直接参与了与激酶的结合。
A series of novel 2-pyridyl, 4-morpholinyl substituted thiazolo[5,4-b]pyridine analogues have been designed and synthesized in this paper. These thiazolo[5,4-b]pyridines were efficiently prepared in seven steps from commercially available substances in moderate to good yields. All of these N-heterocyclic compounds were characterized by nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) analysis and tested for phosphoinositide 3-kinase (PI3K) enzymatic assay. The results indicated that these N-heterocyclic compounds showed potent PI3K inhibitory activity, and the IC50 of a representative compound (19a) could reach to 3.6 nm. The structure−activity relationships (SAR) study showed that sulfonamide functionality was important for PI3Kα inhibitory activity, and 2-chloro-4-florophenyl sulfonamide (19b), or 5-chlorothiophene-2-sulfonamide (19c) showed potent inhibitory activity with a nanomolar IC50 value. The pyridyl attached to thiazolo[5,4-b]pyridine was another key structural unit for PI3Kα inhibitory potency, and replacement by phenyl lead to a significant decrease in activity. Enzymatic Inhibition results showed that compound 19a inhibited PI3Kα, PI3Kγ, or PI3Kδ with a nanomolar IC50 value, but its inhibitory activity on PI3Kβ was approximately 10-fold reduced. Further docking analysis revealed that the N-heterocyclic core of compound 19a was directly involved in the binding to the kinase through the key hydrogen bonds interaction.
登录
查看更多内容
C-H锌锌通过C-H锌的铜催化的杂种氨基化氨化。
DOI：
10.1002/anie.201311029
发表时间：
2014-04-25
期刊：
Angewandte Chemie (International ed. in English)
影响因子：
--
作者：
McDonald SL;Hendrick CE;Wang Q
通讯作者：
Wang Q
影响因子：
4.2
作者：
Burger, Matthew T.;Pecchi, Sabina;Voliva, Charles F.
通讯作者：
Voliva, Charles F.
影响因子：
2.7
作者：
Rao, Ashwin U.;Palani, Anandan;Lachowicz, Jean
通讯作者：
Lachowicz, Jean
影响因子：
7.3
作者：
Lin, Songwen;Wang, Chunyang;Xu, Heng
通讯作者：
Xu, Heng
影响因子：
4.2
作者：
Knight, Steven D.;Adams, Nicholas D.;Dhanak, Dashyant
通讯作者：
Dhanak, Dashyant