Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan.
Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan.
Mol Divers. 2024 Apr;28(2):595-608. doi: 10.1007/s11030-023-10605-x. Epub 2023 Feb 3.
A series of 1-benzo[1,3]dioxol-5-yl-indoles bearing 3-N-fused heteroaryl moieties have been designed based on literature reports of the activity of indoles against various cancer cell lines, synthesized via a Pd-catalyzed C-N cross-coupling, and evaluated for their anticancer activity against prostate (LNCaP), pancreatic (MIA PaCa-2), and acute lymphoblastic leukemia (CCRF-CEM) cancer cell lines. A detailed structure-activity relationship study culminated in the identification of 3-N-benzo[1,2,5]oxadiazole 17 and 3-N-2-methylquinoline 20, whose IC values ranged from 328 to 644 nM against CCRF-CEM and MIA PaCa-2. Further mechanistic studies revealed that 20 caused cell cycle arrest at the S phase and induced apoptosis in CCRF-CEM cancer cells. These 1-benzo[1,3]dioxol-5-yl-3-N-fused heteroaryl indoles may serve as a template for further optimization to afford more active analogs and develop a comprehensive understanding of the structure-activity relationships of indole anticancer molecules.
一系列含有 3-N-稠合杂芳基部分的 1-苯并[1,3]二氧杂环戊烯基吲哚类化合物是基于吲哚类化合物对各种癌细胞系活性的文献报道设计的，通过 Pd 催化的 C-N 交叉偶联合成，并对其在前列腺（LNCaP）、胰腺（MIA PaCa-2）和急性淋巴细胞白血病（CCRF-CEM）癌细胞系中的抗癌活性进行了评估。详细的构效关系研究最终确定了 3-N-苯并[1,2,5]恶二唑 17 和 3-N-2-甲基喹啉 20，它们对 CCRF-CEM 和 MIA PaCa-2 的 IC 值范围为 328-644 nM。进一步的机制研究表明，20 可使 CCRF-CEM 癌细胞的细胞周期停滞在 S 期，并诱导细胞凋亡。这些 1-苯并[1,3]二氧杂环戊烯基-3-N-稠合杂芳基吲哚类化合物可作为进一步优化的模板，提供更有效的类似物，并全面了解吲哚类抗癌分子的构效关系。
