Dithiole thiones and ones--Chemistry to Biochemistry

描述：(申请人提供)本提案的长期目标是 了解癌症化学防腐剂的详细分子基础 1，2-二硫醇-3-硫酮和1，2-二硫醇-3-酮的作用。一位有希望的成员 这类药物中的奥替拉兹正处于人民医院的二期临床试验中 中国共和国。目前，许多组织正在进行大量调查 关于这些化合物在生化、细胞和 生物体水平。到目前为止的总体情况是，这些化合物 优先刺激第二相代谢酶的诱导， 防止电击。然而，不确定的一个主要领域是 第二相酶启动步骤的分子本质 归纳法。如本提案所述，这在一定程度上是由于缺乏 关于这类化合物的化学和新陈代谢的信息。 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。这个 另一种选择是这些化合物，或它们分解的产物， 产生与氧化还原敏感的活性氧物种(ROS)相互作用 转录因子，然后引起诱导。解决这个问题 在对该化学物质进行详细分析之前，绝对需要一分为二 机制的关键过程可以承接。这个问题的解决将 也极大地有助于集中努力寻找目标生物分子 ROS的亲选民。最后，了解归纳的化学基础 二期酶诱导的实质是对构建新的 具有增强效力和疗效的癌症化学防护剂。

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.