State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China.
Eur J Med Chem. 2010 Jul;45(7):3184-90. doi: 10.1016/j.ejmech.2010.02.056. Epub 2010 Mar 1.
Indolizine and annulated indolizine derivatives incorporating a cyclopropylcarbonyl group were synthesized in a one pot procedure by the tanden reactions of [3+2] cycloaddition of the corresponding N-ylide with electron deficient alkene. Seventeen indolizine derivatives were reported for the first time. All the compounds were examined for their antiproliferative activity against the human hepatocellular liver carcinoma (Hep-G2) cell line by MTT method. Among the compounds tested, 5a, 5d, 5 g and 5 j showed the most favorable activities with IC(50) values of 0.39, 0.48, 0.29 and 0.20 microg/mL. Especially, compound 5 j displayed potent antiproliferative activities with IC(50) value of 0.20 microg/mL, and showed significant EGFR kinase inhibitory activity with IC(50) value of 0.085 microM. Docking simulations of 5 j were carried out to illustrate the binding mode of the molecular into the EGFR active site.
将环丙甲酰基引入到吲唑及并吲唑衍生物中的反应，是通过相应的 N-叶立德与缺电子烯烃的[3+2]环加成的串联反应，一锅法合成的。本文首次报道了 17 个吲唑衍生物。采用 MTT 法，测试了所有化合物对人肝癌（Hep-G2）细胞系的抗增殖活性。在测试的化合物中，5a、5d、5g 和 5j 的活性最好，IC50 值分别为 0.39、0.48、0.29 和 0.20μg/mL。特别是，化合物 5j 表现出很强的抗增殖活性，IC50 值为 0.20μg/mL，并且对 EGFR 激酶表现出显著的抑制活性，IC50 值为 0.085μM。对 5j 进行了对接模拟，以说明分子进入 EGFR 活性部位的结合模式。
