3-(3-hydroxyphenyl)-5-ethyl-1-morpholino-6-thioxo-5,6,8,9,10,10a-hexahydropyrido[3,2-e]pyrrolo[1,2-c]pyrimidine-2-carbonitrile

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 3-(3-hydroxyphenyl)-5-ethyl-1-morpholino-6-thioxo-5,6,8,9,10,10a-hexahydropyrido[3,2-e]pyrrolo[1,2-c]pyrimidine-2-carbonitrile
• 英文别名: 8-Ethyl-11-(3-hydroxyphenyl)-13-morpholin-4-yl-7-sulfanylidene-6,8,10-triazatricyclo[7.4.0.02,6]trideca-1(9),10,12-triene-12-carbonitrile；8-ethyl-11-(3-hydroxyphenyl)-13-morpholin-4-yl-7-sulfanylidene-6,8,10-triazatricyclo[7.4.0.02,6]trideca-1(9),10,12-triene-12-carbonitrile
• 化学式: C₂₃H₂₅N₅O₂S
• 分子量: 435.55
• InChiKey: YYAJASOJPAGEQE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  31
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  108
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  2-pyrrolidin-2-ylidene-malononitrile 在 sodium tetrahydroborate 、 potassium carbonate 、 三乙胺 作用下， 以 1,4-二氧六环 、 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 5.0h， 生成 3-(3-hydroxyphenyl)-5-ethyl-1-morpholino-6-thioxo-5,6,8,9,10,10a-hexahydropyrido[3,2-e]pyrrolo[1,2-c]pyrimidine-2-carbonitrile
  参考文献：
  名称：

  Design, synthesis and biological evaluation of novel condensed pyrrolo[1,2-c]pyrimidines featuring morpholine moiety as PI3Kα inhibitors

  摘要：

  Four series of condensed pyrrolo[1,2-c]pyrimidines 6a-d, 8a-d, 10a,b and 12a-e designed as PI3K alpha inhibitors were synthesized and evaluated for inhibitory activity and selectivity toward different PI3K isoforms. The tested compounds displayed PI3K alpha kinase inhibitory activity at either low micromolar or nanomolar level. In particular, the morpholino-pyrimidopyrrolopyrimidinones 8a-d and morpholinopyridopyrrolopyrimidine-2-carbonitriles 12a-e proved to be highly potent and selective PI3K alpha inhibitors (IC50 = 0.1-7.7 nM). Moreover, the target compounds exhibited considerable cytotoxic activity against cervical cancer cell line HeLa that over-expresses p110 alpha (0.21-1.99 mu M). Molecular modeling simulation revealed that, the designed compounds docked well into p110 alpha active site and their complexes are stabilized by a key H-bonding with the backbone amide of VaI851 as well as other favorable hydrophobic and H-bond interactions with different amino acids within the enzyme active site. (C) 2015 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2015.05.036

文献信息

• Design, synthesis and biological evaluation of novel condensed pyrrolo[1,2-c]pyrimidines featuring morpholine moiety as PI3Kα inhibitors
  作者：Marwa A. Ibrahim、Sahar M. Abou-Seri、Mona M. Hanna、Mohamed M. Abdalla、Nehad A. El Sayed

  DOI：10.1016/j.ejmech.2015.05.036

  日期：2015.6

  Four series of condensed pyrrolo[1,2-c]pyrimidines 6a-d, 8a-d, 10a,b and 12a-e designed as PI3K alpha inhibitors were synthesized and evaluated for inhibitory activity and selectivity toward different PI3K isoforms. The tested compounds displayed PI3K alpha kinase inhibitory activity at either low micromolar or nanomolar level. In particular, the morpholino-pyrimidopyrrolopyrimidinones 8a-d and morpholinopyridopyrrolopyrimidine-2-carbonitriles 12a-e proved to be highly potent and selective PI3K alpha inhibitors (IC50 = 0.1-7.7 nM). Moreover, the target compounds exhibited considerable cytotoxic activity against cervical cancer cell line HeLa that over-expresses p110 alpha (0.21-1.99 mu M). Molecular modeling simulation revealed that, the designed compounds docked well into p110 alpha active site and their complexes are stabilized by a key H-bonding with the backbone amide of VaI851 as well as other favorable hydrophobic and H-bond interactions with different amino acids within the enzyme active site. (C) 2015 Elsevier Masson SAS. All rights reserved.