Dithiole thiones and ones--Chemistry to Biochemistry

描述：（由申请人提供）本提案的长期目标是 了解癌症化学预防的详细分子基础 1，2-二硫杂环戊烯-3-硫酮和1，2-二硫杂环戊烯-3-酮的影响。一个有前途的成员 这类药物中的一种是奥替普拉， 中华民国目前有许多团体正在进行调查 关于这些化合物在生物化学，细胞和 有机体水平。到目前为止，总的情况是，这些化合物 优先刺激诱导2相代谢酶， 防止亲电攻击。然而，一个主要的不确定性领域是 第二阶段酶的起始步骤的分子性质 诱导如本提案所述，部分原因是缺乏 关于这类化合物的化学和代谢的信息。 有人认为，这些化合物或它们的产物 分解，作为亲电体与蛋白质信使形成加合物， 可能是转录因子，随后激活表达。的 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物质（ROS） 然后产生诱导的转录因子。解决这一 在对化学物质进行详细分析之前， 关键过程的机制。解决这一问题将 也极大地帮助集中精力寻找目标生物分子的 ROS的亲电子体。最后，理解归纳的化学基础 第二阶段酶诱导基本上是为了思考构建新的 具有增强的效力和功效的癌症化学预防剂。

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.