Wang Jeh-Jeng, Shen Yu-Kai, Hu Wan-Ping, Hsieh Ming-Chu, Lin Fu-Lung, Hsu Ming-Kuan, Hsu Mei-Hui
Faculty of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung City 807, Taiwan.
J Med Chem. 2006 Feb 23;49(4):1442-9. doi: 10.1021/jm050956q.
A series of novel pyrrolo[2,1-c][1,4]benzodiazepine (PBD) hybrids linked with indole carboxylates is described. These compounds were prepared by linking C-8 of 3 (DC-81) with an indole 2-carbonyl moiety (9) through carbon chain linkers to afford PBD hybrid agents 17-21 in good yields. Preliminary in vivo tests show that these hybrid agents have potent antitumor activity. The cytotoxic studies of the hybrid agents on human melanoma A2058 cells indicate most of the hybrids induced higher cytotoxicity, better DNA-binding ability, an increase in the apoptotic sub-G1 population, and a significant reduction in deltapsi(mt) relative to compound 3. In addition, DNA flow cytometric analysis shows that hybrids actively induce a marked loss of cells from the G2/M phase of the cell cycle, which progresses to early apoptosis as detected by flow cytometry after double-staining with annexin V and propidium iodide (PI). Thus, we suggest that the hybrid agents are potent inducers of cell apoptosis in A2058 cells.
描述了一系列与吲哚羧酸盐相连的新型吡咯并[2,1-c][1,4]苯并二氮杂卓（PBD）杂化物。这些化合物是通过将3（DC-81）的C-8与吲哚2-羰基部分（9）通过碳链连接基相连而制备的，以良好的产率得到PBD杂化剂17-21。初步体内试验表明这些杂化剂具有强大的抗肿瘤活性。杂化剂对人黑素瘤A2058细胞的细胞毒性研究表明，相对于化合物3，大多数杂化物诱导更高的细胞毒性、更好的DNA结合能力、凋亡亚G1期细胞群体增加以及线粒体膜电位（Δψ(mt)）显著降低。此外，DNA流式细胞术分析表明，杂化物能积极诱导细胞从细胞周期的G2/M期显著丢失，在用膜联蛋白V和碘化丙啶（PI）双重染色后通过流式细胞术检测发现其进展为早期凋亡。因此，我们认为这些杂化剂是A2058细胞中细胞凋亡的有效诱导剂。
