DNA Alkylation by Leinamycin

描述（由申请人提供）： 表征DNA的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，天然产物雷那霉素是特别令人感兴趣的，因为它通过以前没有见过的化学机制有效地破坏DNA。当雷那霉素遇到富含巯基的环境（如细胞内发现的环境）时，天然产物通过独特的反应序列转化为DNA烷基化表锍离子。重要的是，莱那霉素的不寻常的化学性质赋予该化合物极强的细胞毒性（IC-50值为0.014微克/mL -这意味着IC-50为27 nM）。我们相信，对雷那霉素的继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、根本性的重要概念。拟议的实验旨在研究莱那霉素的性能是其有效的DNA烷基化性能的核心，但目前还没有很好地理解。本论文的工作分为四个具体的目的：目的1，研究雷那霉素与DNA的非共价相互作用。这些研究是有意义的，因为来那霉素与DNA非共价结合，但不具有任何与此性质相关的结构元件。目标2.检查抗生素的C8-醇基提供的邻基稳定性是否使来那霉素衍生的表锍离子有效地进行DNA烷基化成为可能。这些研究可能揭示了通过细胞里程碑有效递送表锍离子烷化剂至DNA所必需的结构特征。目标3.研究来那霉素是否是一种可逆的DNA烷基化剂。这种不寻常的性质可能允许DNA加合物平衡或“洗牌”到生物学上有利的位点。目标4。研究控制雷那霉素1，2-二硫戊环-3-酮-1-氧化物“触发装置”稳定性的因素。在莱那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。我们计划确定来那霉素中稳定这种固有脆弱杂环的官能团。

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.