Abstract

In the current work, a new set of carbohydrazide linked benzofuran-isatin conjugates (5a–e and 7a–i) was designed and synthesised. The anticancer activity for compounds (5b–d, 7a, 7b, 7d and 7g) was measured against NCI-55 human cancer cell lines. Compound 5d was the most efficient, and thus subjected to the five-dose screen where it showed excellent broad activity against almost all tested cancer subpanels. Furthermore, all conjugates (5a–e and 7a–i) showed a good anti-proliferative activity towards colorectal cancer SW-620 and HT-29 cell lines, with an excellent inhibitory effect for compounds 5a and 5d (IC₅₀ = 8.7 and 9.4 µM (5a), and 6.5 and 9.8 µM for (5d), respectively). Both compounds displayed selective cytotoxicity with good safety profile. In addition, both compounds provoked apoptosis in a dose dependent manner in SW-620 cells. Also, they significantly inhibited the anti-apoptotic Bcl2 protein expression and increased the cleaved PARP level that resulted in SW-620 cells apoptosis.

摘要

在目前的工作中，设计并合成了一组新的碳酰肼连接的苯并呋喃-靛红缀合物（5a-e和7a-i）。针对 NCI-55 人类癌细胞系测量了化合物（5b-d、7a、7b、7d和7g）的抗癌活性。化合物5d是最有效的，因此经过五剂量筛选，它对几乎所有测试的癌症亚组都显示出极好的广泛活性。此外，所有偶联物（5a-e和7a-i）均对结直肠癌 SW-620 和 HT-29 细胞系显示出良好的抗增殖活性，对化合物5a和HT-29 具有优异的抑制作用。5d（IC ₅₀ = 8.7 和 9.4 µM（5a），以及（5d）分别为 6.5 和 9.8 µM ）。两种化合物均显示出选择性的细胞毒性和良好的安全性。此外，这两种化合物均以剂量依赖性方式在 SW-620 细胞中引起细胞凋亡。此外，它们显着抑制了抗凋亡 Bcl2 蛋白的表达，并增加了导致 SW-620 细胞凋亡的裂解 PARP 水平。