ANTINEOPLASTIC POLYAMINE ANALOGUES

抗肿瘤多胺类似物

• 批准号: 6745968
• 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 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6745968
• 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治疗中化疗干预的一个有吸引力的新靶点。干扰该途径通常导致细胞生长速率降低，但在某些特定情况下导致表型特异性细胞毒性。我们已经开发了一些合成路线，提供了一个途径，以各种各样的新的不对称取代的多胺类似物，许多具有独特的生物化学活性。迄今为止，已经合成了43种新的类似物，并对其抗增殖活性进行了研究，目的是阐明其作用机制。初步结果表明，这些独特的类似物的研究提供的主要结果。1)多胺类似物诱导的过氧化氢（H_2O_2）的产生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起重要作用：2）由类似物产生的细胞毒性通过半胱天冬酶依赖性和非依赖性程序性细胞死亡途径产生; 3）发现了多胺类似物的全新活性机制，特别是产生G2/M阻滞、改变微管蛋白聚合和作为纺锤体毒物的能力; 4）对这些独特的多胺类似物的研究发现，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，在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。

项目成果

Studies of the mechanism by which increased spermidine/spermine N1-acetyltransferase activity increases susceptibility to skin carcinogenesis.

研究亚精胺/精胺 N1-乙酰转移酶活性增加增加皮肤癌易感性的机制。

• DOI: 10.1093/carcin/bgm162
• 发表时间: 2007
• 期刊: Carcinogenesis
• 影响因子: 4.7
• 作者: Wang,Xiaojing;Feith,DavidJ;Welsh,Pat;Coleman,CatherineS;Lopez,Christina;Woster,PatrickM;O'Brien,ThomasG;Pegg,AnthonyE
• 通讯作者: Pegg,AnthonyE

Alkyl-substituted polyaminohydroxamic acids: a novel class of targeted histone deacetylase inhibitors.

烷基取代的聚氨基异羟肟酸：一类新型的靶向组蛋白脱乙酰酶抑制剂。

• DOI: 10.1021/jm0505009
• 发表时间: 2005
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Varghese,Sheeba;Gupta,Deepak;Baran,Tiffany;Jiemjit,Anchalee;Gore,StevenD;CaseroJr,RobertA;Woster,PatrickM
• 通讯作者: Woster,PatrickM

Novel Pt(II) and Pd(II) complexes with polyamine analogues: synthesis and vibrational analysis.

新型 Pt(II) 和 Pd(II) 与多胺类似物的配合物：合成和振动分析。

• DOI: 10.1016/j.jinorgbio.2011.11.021
• 发表时间: 2012
• 期刊: Journal of inorganic biochemistry
• 影响因子: 3.9
• 作者: Silva,TM;Oredsson,S;Persson,L;Woster,P;Marques,MPM
• 通讯作者: Marques,MPM

A small molecule polyamine oxidase inhibitor blocks androgen-induced oxidative stress and delays prostate cancer progression in the transgenic adenocarcinoma of the mouse prostate model.

• DOI: 10.1158/0008-5472.can-08-2472
• 发表时间: 2009-10-01
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Basu HS;Thompson TA;Church DR;Clower CC;Mehraein-Ghomi F;Amlong CA;Martin CT;Woster PM;Lindstrom MJ;Wilding G
• 通讯作者: Wilding G

Polyamine-based analogues as biochemical probes and potential therapeutics.

基于多胺的类似物作为生化探针和潜在的治疗方法。

• DOI: 10.1042/bst0350356
• 发表时间: 2007
• 期刊: Biochemical Society transactions
• 影响因子: 3.9
• 作者: Boncher,T;Bi,X;Varghese,S;CaseroJr,RA;Woster,PM
• 通讯作者: Woster,PM