Dithiole thiones and ones--Chemistry to Biochemistry

二硫醇硫酮及其化合物--化学到生物化学

• 批准号: 6837141
• 负责人: JAMES C FISHBEIN
• 金额: $ 41.63万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE COUNTY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-11 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6837141
• 关键词: NAD(P)H dehydrogenase; cancer prevention; carcinogenesis inhibitor; cell line; chemoprevention; enzyme induction /repression; free radical oxygen; glutathione transferase; high performance liquid chromatography; neoplasm /cancer genetics; neoplasm /cancer pharmacology; oltipraz; pharmacokinetics; thiones; transcription factor

DESCRIPTION: (provided by applicant) The long term goal of this proposal is to understand the detailed molecular basis for the cancer chemopreventitive effects of 1,2-dithiole-3-thiones and 1,2-dithiole-3-ones. One promising member of this class is oltipraz which is in Phase 2 clinical trials in the People's Republic of China. There is currently much investigation by a number of groups about the mode of action of these compounds at the biochemical, cellular and organismal level. The general picture to date is that these compounds preferentially stimulate the induction of Phase 2 metabolic enzymes that protect against electrophilic assault. However, a major area of uncertainty is the molecular nature of the initiation steps involved in Phase 2 enzyme induction. As elaborated in this proposal, this is in part due to the dearth of information regarding the chemistry and metabolism of this class of compounds. One posits the notion that these compounds, or the products of their decomposition, act as electrophiles which form adducts with protein messengers, possibly transcription factors, that subsequently activate expression. The alternative is that these compounds, or the products of their decomposition, generate reactive oxygen species (ROS) that interact with redox sensitive transcription factors that then give rise to induction. Resolving this dichotomy is absolutely required before a detailed analysis of the chemical mechanism of the key process can be undertaken. Resolution of this problem will also greatly aid in focusing efforts to find the target biomolecules of the electorphiles of ROS. Finally, understanding the chemical basis for induction of Phase 2 enzyme induction is essentially for thinking about constructing new cancer chemopreventitives with enhanced potency and efficacy.

描述：（由申请人提供）该提案的长期目标是 了解癌症化学预防的详细分子基础 1,2-二硫醇-3-硫酮和1,2-二硫醇-3-酮的作用。一名有前途的成员 该类药物为吡噻硫酮（oltipraz），目前正在人民医院进行二期临床试验。 中华民国。目前多个团体正在进行大量调查 关于这些化合物在生化、细胞和 有机体水平。迄今为止的总体情况是这些化合物 优先刺激第二阶段代谢酶的诱导 防止亲电攻击。然而，一个主要的不确定性领域是 第 2 相酶涉及的起始步骤的分子性质 就职。正如本提案中所阐述的，这部分是由于缺乏 有关此类化合物的化学和代谢的信息。 人们提出这样一种观念，即这些化合物或其产物 分解，作为亲电子试剂与蛋白质信使形成加合物， 可能是转录因子，随后激活表达。这 另一种选择是这些化合物或其分解产物， 产生与氧化还原敏感物质相互作用的活性氧（ROS） 然后引起诱导的转录因子。解决这个问题 在对化学物质进行详细分析之前，绝对需要进行二分法 关键流程机制得以落实。这个问题的解决将 也极大地有助于集中精力寻找目标生物分子 ROS 的亲电体。最后，了解感应的化学基础 第二阶段酶诱导的本质是思考构建新的 具有增强效力和功效的癌症化学预防剂。

项目成果

Thiolytic chemistry of alternative precursors to the major metabolite of the cancer chemopreventive oltipraz.

癌症化学预防药物奥替普拉主要代谢物的替代前体的硫解化学。

• 发表时间: 2002-12-27
• 作者: Navamal, Mettachit;McGrath, Colleen;Stewart, Jennifer;Blans, Patrick;Villamena, Frederick;Zweier, Jay;Fishbein, James C
• 通讯作者: Fishbein, James C