A series of diarylureas and diarylamides possessing pyrrolo[3,2-c]pyridine scaffold was designed and synthesized. Their in vitro antiproliferative activities were tested against a panel of 49 cell lines of eight diffe...A series of diarylureas and diarylamides possessing pyrrolo[3,2-c]pyridine scaffold was designed and synthesized. Their in vitro antiproliferative activities were tested against a panel of 49 cell lines of eight different cancer types at the NCI and compared with Sorafenib as a reference compound. Most of the compounds showed strong and broad-spectrum antiproliferative activities with superior potencies to Sorafenib. Compounds 8a, 9d and 9f showed lethal effect with mean %inhibition more than 100% over the 49 tested cell lines. In addition, the mean %inhibition results of compounds 8d, 8e, 9e, 9g and 9h were more than 80%. And most of the IC50 values of the target compounds were in submicromolar scale. Compounds 8a, 9b and 9e demonstrated high selectivity towards cancer cell lines compared with NIH3T3 fibroblasts.展开更多
细胞外信号相关激酶(ERK)是恶性肿瘤发生发展中的关键激酶,为了寻找新型结构的ERK抑制剂,采用拼合原理设计合成了两类共12个含有吗啉环的脲类化合物,其结构经1 H NMR、13C NMR和HRMS确证.ERK激酶活力和细胞增殖测试结果表明,大部分目标...细胞外信号相关激酶(ERK)是恶性肿瘤发生发展中的关键激酶,为了寻找新型结构的ERK抑制剂,采用拼合原理设计合成了两类共12个含有吗啉环的脲类化合物,其结构经1 H NMR、13C NMR和HRMS确证.ERK激酶活力和细胞增殖测试结果表明,大部分目标化合物对人结直肠癌细胞SW480和HCT-116具有中等强度的抑制作用,尤其是1-(4-氟苄基)-3-(5-(4-吗啉代苯基)吡啶-2-基)脲(18f)的IC50分别达到0.36和0.55µmol/L,对正常细胞L02毒性较低(>10µmol/L).同时,18f能抑制ERK的激酶活力(IC50=0.051µmol/L)和磷酸化水平,但不影响总ERK表达和上游丝裂原活化的细胞外信号调节激酶(MEK)的激活.上述结果为新型苄基吡啶基脲类ERK抑制剂的深入研究提供了重要参考信息.展开更多
文摘A series of diarylureas and diarylamides possessing pyrrolo[3,2-c]pyridine scaffold was designed and synthesized. Their in vitro antiproliferative activities were tested against a panel of 49 cell lines of eight different cancer types at the NCI and compared with Sorafenib as a reference compound. Most of the compounds showed strong and broad-spectrum antiproliferative activities with superior potencies to Sorafenib. Compounds 8a, 9d and 9f showed lethal effect with mean %inhibition more than 100% over the 49 tested cell lines. In addition, the mean %inhibition results of compounds 8d, 8e, 9e, 9g and 9h were more than 80%. And most of the IC50 values of the target compounds were in submicromolar scale. Compounds 8a, 9b and 9e demonstrated high selectivity towards cancer cell lines compared with NIH3T3 fibroblasts.
文摘细胞外信号相关激酶(ERK)是恶性肿瘤发生发展中的关键激酶,为了寻找新型结构的ERK抑制剂,采用拼合原理设计合成了两类共12个含有吗啉环的脲类化合物,其结构经1 H NMR、13C NMR和HRMS确证.ERK激酶活力和细胞增殖测试结果表明,大部分目标化合物对人结直肠癌细胞SW480和HCT-116具有中等强度的抑制作用,尤其是1-(4-氟苄基)-3-(5-(4-吗啉代苯基)吡啶-2-基)脲(18f)的IC50分别达到0.36和0.55µmol/L,对正常细胞L02毒性较低(>10µmol/L).同时,18f能抑制ERK的激酶活力(IC50=0.051µmol/L)和磷酸化水平,但不影响总ERK表达和上游丝裂原活化的细胞外信号调节激酶(MEK)的激活.上述结果为新型苄基吡啶基脲类ERK抑制剂的深入研究提供了重要参考信息.
