Synthesis of furopyrazole analogs of 1-benzyl-3-(5-hydroxymethyl-2-furyl)indazole (YC-1) as novel anti-leukemia agents |
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Authors: | Chou Li-Chen Huang Li-Jiau Yang Jai-Sing Lee Fang-Yu Teng Che-Ming Kuo Sheng-Chu |
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Institution: | Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan. |
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Abstract: | As part of our continuing search for potential anticancer drug candidates in YC-1 analogs, several 1-benzyl-3-(substituted aryl)-5-methylfuro3,2-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-methylfuro3,2-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. |
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