ANTITUMOR ACTIVITY OF FAGARONINE AND ANALOGUES

该项目旨在研究 已知抗肿瘤的苯并菲啶生物碱的作用 活性，fagarestine和两面针碱。 一系列类似物已经被 合成，以确定这些分子的活性中心， 为了将生物效应与分子 结构 鉴于我们在设计和合成 一种潜在有用的抗肿瘤剂，基于结构 已知药物中存在的显示这种性质的特征，我们计划 继续并扩大我们的研究计划， 合成新的NBQ、fagarestine和两面针碱类似物。 这 为设计更有效的抗肿瘤药物提供依据 毒品 在我们的研究中，我们发现，fagarestine和相关的类似物， 干扰DNA模板功能的直接后果 双链DNA的嵌入过程。 NBQ，最 这些类似物的活性已被证明可以诱导分化 HL-60早幼粒细胞白血病的治疗 剂量 我们的研究发现，NBQ作为分化诱导剂， 问题：这种药物通过什么机制表达其 分化效应？ 了解有多少的 这些药物的生物活性可归因于细胞因子， 与分化诱导相反， 一种潜在的癌症化疗新模式的见解。

This project has been designed to study the molecular basis of action of the benzophenanthridinum alkaloid of known antitumor activity, fagaronine and nitidine. A series of analogues has been synthesized to determine the active centre of these molecules in order to correlate the biological effect with the molecular structure. In view of our success in the design and synthesis of a potentially useful antitumor agent, based on the structural features present in known drugs displaying this property, we plan to continue and expand our research program directed towards the synthesis of new NBQ, fagaronine, and nitidine analogues. This will provide the basis for the design of more effective antitumor drugs. In our studies we have found that fagaronine and related analogues interfere with the DNA template function as a direct consequence of the intercalation process to double-stranded DNA. NBQ, the most active of these analogues, has been shown to induce differentiation of HL-60 promyelocytic leukemia at lower-than-chemotherapeutic doses. Our findings with NBQ as differentiation inducer raises the question: By what mechanism(s) does this drug expresses its differentiation effect? The understanding of how much of the biologic activity of these drugs can be attributed to cytocydal effect in contrast to differentiation induction will give us an insight of a potentially new mode of cancer chemotherapy.