ANTINEOPLASTIC POLYAMINE ANALOGUES

多胺代谢途径是肿瘤化疗干预治疗中一个有吸引力的新靶点。干扰该通路通常会导致细胞生长速率降低，但在某些特定情况下会导致表型特异性细胞毒性。我们已经开发了许多合成途径，为各种各样的新型不对称取代多胺类似物提供了途径，其中许多具有独特的生化活性。迄今为止，已经合成了43种新的类似物，并研究了它们的抗增殖活性，目的是阐明它们的作用机制。初步结果证明了这些独特的类似物研究提供的主要发现。1)由类似物诱导的多胺分解代谢产生的H2O2在对一些最有希望的类似物的表型特异性细胞毒性反应中发挥重要作用；2)类似物通过caspase依赖性和非依赖性程序性细胞死亡途径产生细胞毒性；3)发现了一种全新的多胺类似物的活性机制，特别是产生G2/M块、改变微管蛋白聚合和作为纺锤体毒物的能力；4)对这些独特的类似物的研究发现，天然多胺可能具有自由基清除剂的重要功能，可以保护染色质免受活性氧的攻击。基于这些令人兴奋的初步结果，本申请中研究的主要目标是扩展上述发现，并进行详细的结构分析，以帮助生产更有效的抗肿瘤药物。

The polyamine metabolic pathway represents an attractive and novel target for chemotherapeutic intervention in the treatment of neoplastic disease. Interference with the pathway generally leads to a decrease in cellular growth rate, but in some specific instance results in phenotype- specific cytotoxicity. We have developed a number of synthetic routes that provide a pathway to a wide variety of novel unsymmetrically substituted polyamine analogues, many with unique biochemical activities. Forty-three new analogues have been synthesized to date and examined for their anti proliferative activity with the goal of elucidating their mechanism of action. The preliminary results demonstrate major findings provided by the study of these unique analogues. 1) The production of H2O2 produced as a result of analogue induced polyamine catabolism can play a significant role in the phenotype-specific cytotoxic response to some of the most promising analogues; 2) The cytotoxicity produced by the analogues results through caspase-dependent and - independent programmed cell death pathways; 3) A completely novel mechanisms of activity for polyamine analogue have been discovered, specifically the abilities to produced a G2/M block, alter tubulin polymerization and act as spindle poisons; 4) The study of these unique analogues has led to the discovery that the natural polyamines may have the important function of acting as free radical scavengers in protecting chromatin from reactive oxygen species attack. Based on these exciting preliminary results from the major goals of the studies detained in this application are to expand upon the above finding and to perform detailed structure analyses to aid in the production of more effective anti- neoplastic agents.