ANTINEOPLASTIC POLYAMINE ANALOGUES

抗肿瘤多胺类似物

• 批准号: 6362749
• 负责人: Patrick M Woster
• 金额: $ 24.66万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6362749
• 关键词: analog; antineoplastics; athymic mouse; breast neoplasms; cysteine endopeptidases; cytotoxicity; drug design /synthesis /production; drug screening /evaluation; enzyme activity; hydrogen peroxide; lung neoplasms; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; nonhuman therapy evaluation; polyamines; prostate neoplasms; spindle pole body; tissue /cell culture; tubulin

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.

多胺代谢途径代表了肿瘤疾病化疗干预的一个有吸引力的新靶点。对该途径的干扰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。我们开发了许多合成路线，为多种新型不对称取代的多胺类似物提供了途径，其中许多类似物具有独特的生化活性。迄今为止，已合成了 43 种新的类似物，并检查了它们的抗增殖活性，目的是阐明它们的作用机制。初步结果证明了对这些独特类似物的研究所提供的主要发现。 1) 类似物诱导的多胺分解代谢产生的 H2O2 在对一些最有前途的类似物的表型特异性细胞毒性反应中发挥着重要作用； 2) 类似物产生的细胞毒性是通过 caspase 依赖性和独立的程序性细胞死亡途径产生的； 3) 发现了多胺类似物的全新活性机制，特别是产生 G2/M 阻断、改变微管蛋白聚合和充当纺锤体毒物的能力； 4）对这些独特类似物的研究发现，天然多胺可能具有作为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，本申请中保留的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剂。