DNA Alkylation by Leinamycin

描述(由申请人提供)： 表征DNA分子识别和化学修饰的新过程对包括药物化学、毒理学和生物技术在内的各种科学领域都很重要。在这方面，天然产物雷诺霉素特别令人感兴趣，因为它通过以前从未见过的化学机制有效地破坏DNA。当雷诺霉素遇到富含硫醇的环境时，如在细胞内发现的那样，天然产物通过独特的反应序列转化为DNA烷化的表面硫离子。重要的是，雷诺霉素的不同寻常的化学性质赋予了该化合物极强的细胞毒性特性(IC-50值为0.014微克/毫升-这意味着IC-50为27纳米)。我们相信，对雷诺霉素的持续研究将揭示关于诱变剂、毒素和抗癌剂与DNA相互作用的不同方式的新的、根本上重要的概念。拟议的实验旨在检查雷诺霉素的特性，这些特性是其有效的DNA烷基化特性的核心，但目前尚不清楚。本工作分为四个具体目标：目标1，表征雷诺霉素与DNA的非共价相互作用。这些研究之所以令人感兴趣，是因为雷诺霉素以非共价方式与DNA结合，但不具有任何典型的与这种性质相关的结构元素。目的2.研究雷诺霉素衍生的表硫离子能否通过抗生素的C8-醇基提供的邻基稳定来实现DNA的有效烷基化。这些研究可能会揭示有效地将表硫离子烷基化试剂通过细胞范围输送到DNA所需的结构特征。目的3.研究雷诺霉素是否是可逆性DNA烷基化试剂。这种不同寻常的性质可能会使DNA加合物平衡或“洗牌”到热力学上有利的位置。目的4.考察影响雷诺霉素1，2-二硫杂环-3-酮-1-氧化物“触发装置”稳定性的因素。雷诺霉素中的这种独特的结构单元用于在进入富含硫醇的环境时启动天然产物向烷化剂的转化。我们计划确定雷诺霉素中稳定这种天生脆弱的杂环的官能团。

DESCRIPTION (provided by applicant): Characterization of new processes for the molecular recognition and chemical modification of DNA is important to a variety of scientific fields including medicinal chemistry, toxicology, and biotechnology. In this regard the natural product leinamycin is of special interest because it efficiently damages DNA by chemical mechanisms that have not been seen previously. When leinamycin encounters a thiol-rich environment such as that found inside cells, the natural product is converted to a DNA-alkylating episulfonium ion via unique sequence of reactions. Importantly, the unusual chemical properties of leinamycin endow the compound with extremely potent cytotoxic properties (IC-50 values of 0.014 micrograms/mL - this translates to an IC-50 of 27 nM). We believe that continued study of leinamycin will reveal new, fundamentally important concepts regarding the diverse ways that mutagens, toxins, and anticancer agents can interact with DNA. The proposed experiments are designed to examine properties of leinamycin that are central to its efficient DNA-alkylating properties, but which are currently not well understood. The work is divided into Four Specific Aims: Aim 1, Characterize noncovalent interactions of leinamycin with DNA. These studies are of interest because leinamycin associates noncovalently with DNA but does not possess any structural elements typically associated with this property. Aim 2. Examine whether efficient DNA alkylation by the leinamycin-derived episulfonium ion is made possible by neighboring-group stabilization provided by the C8-alcohol group of the antibiotic. These studies may reveal structural features necessary for the efficient delivery of episulfonium ion alkylating agents through the cellular mileau to DNA. Aim 3. Investigate whether leinamycin is a reversible DNA-alkylating agent. This unusual property may allow the equilibration or "shuffling" of DNA adducts to thermodynamically favored sites. Aim 4. Investigate factors that control the stability of leinamycin's 1,2-dithiolan-3-one-1-oxide "triggering device". This unique structural unit in leinamycin serves to initiate conversion of the natural product to an alkylating agent upon entering a thiol-rich environment. We plan to identify functional groups in leinamycin that stabilize this inherently fragile heterocycle.