Chou Li-Chen, Huang Li-Jiau, Yang Jai-Sing, Lee Fang-Yu, Teng Che-Ming, Kuo Sheng-Chu
Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan.
Bioorg Med Chem. 2007 Feb 15;15(4):1732-40. doi: 10.1016/j.bmc.2006.12.001. Epub 2006 Dec 6.
As part of our continuing search for potential anticancer drug candidates in YC-1 analogs, several 1-benzyl-3-(substituted aryl)-5-methylfuro[3,2-c]pyrazoles were synthesized and evaluated for their cytotoxicity against HL-60 cell line. Among these compounds, 1-benzyl-3-(5-hydroxymethyl-2-furyl)-5-methylfuro[3,2-c]pyrazole (1) showed more potency than YC-1. Through investigation of action mechanism, it was found that compound 1 induced terminal differentiation of HL-60 cells toward granulocyte lineage and promoted HL-60 cell differentiation by regulation of Bcl-2 and c-Myc proteins. Meanwhile, compound 1 also demonstrated apoptosis inducing effect. Such anti-leukemia mechanism of action is apparently different from that of YC-1 which mainly works by inducing apoptosis, but not cell differentiation. Therefore, compound 1 is identified here as a new lead compound of cell differentiating agent and apoptosis inducer for further development of new anti-leukemia agents.
作为我们持续寻找 YC-1 类似物中潜在抗癌药物候选物的一部分，合成了几种 1-苄基-3-(取代芳基)-5-甲基呋喃并[3,2-c]吡唑，并评估了它们对 HL-60 细胞系的细胞毒性。在这些化合物中，1-苄基-3-(5-羟甲基-2-呋喃基)-5-甲基呋喃并[3,2-c]吡唑(1)显示出比 YC-1 更强的效力。通过作用机制研究发现，化合物 1 诱导 HL-60 细胞向粒细胞系终末分化，并通过调节 Bcl-2 和 c-Myc 蛋白促进 HL-60 细胞分化。同时，化合物 1 也表现出诱导凋亡的作用。这种抗白血病作用机制明显不同于 YC-1，后者主要通过诱导凋亡而非细胞分化发挥作用。因此，化合物 1 在此被鉴定为一种新的细胞分化剂和凋亡诱导剂的先导化合物，用于进一步开发新型抗白血病药物。
