抗肿瘤先导化合物990209孪药的设计合成及活性

Design,synthesis and biological activity of twin drugs of antitumor compound 990209

目的改善抗肿瘤先导化合物990209的药效学性质。方法基于孪药的设计原理,设计并合成不同连接臂的990209孪药,采用MTT法测定目标化合物对人肝癌细胞Bel-7402增殖的影响。结果与结论设计合成了6种不同连接臂的990209孪药,其结构经核磁共振氢谱、核磁共振碳谱以及高分辨质谱确证;初步体外活性评价结果表明,孪药6的抗肿瘤活性优于先导化合物990209,具有进一步研究的价值。

Compound 990209, a novel kind of dithiocarbamate, has entered preclinical study as potent antitumor agent. However, the high dose and poor water solubility limited its further development. In order to increase the activity, six twin drugs of 990209 were designed and synthesized based on the principle of twin drugs design. Except for twin drug 3, all twin drugs were prepared with 990209 as the starting material. The base of 990209 was reacted with corresponding linkers affording twin drugs 1, 2 and 4. The N- chloroformylation intermediate （5＇） of 990209 was respectively reacted with ethane-1, 2-diamine and 2- （aminooxy）-N,N-dimethylethan-l-amine to give the corresponding twin drugs 5 and 6. Twin drug 3 was synthesized from 1-Boc-piperazine through three steps. 1-Boc-piperazine was firstly reacted with linker affording the intermediate 3＇. Then, the 3＇ was removed protecting group and reacted with CS2 and 4-bromo- 2,2-diphenylbutanenitrile to afford the twin drug 3. All the target compounds were confirmed by NMR and HR-MS and evaluated for their antitumor activity against Bel-7402 by MTT assay. It was found that the twin drug 6 was ten-fold potent than alone compound 990209. This result showed that the linker of the twin drug 6 was suitable and the twin drug 6 was worthy of further study.