Evaluation of DNA Cross-Linking by Aziridinomitosenes

氮丙啶有丝分裂 DNA 交联的评价

• 批准号: 6899647
• 负责人: Don L Warner
• 金额: $ 19.6万
• 依托单位: BOISE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6899647
• 关键词: DNA; acidity /alkalinity; alkylation; analog; chemical synthesis; crosslink; mass spectrometry; mitomycin C; nitrogen; nuclear magnetic resonance spectroscopy; nucleic acid structure; reduction; solvolysis; ultraviolet spectrometry

DESCRIPTION (provided by applicant): An aziridinomitosene, a compound related to the clinically used anticancer agent mitomycin C, has recently been shown to form DNA interstrand cross-links under non-reductive conditions. The occurrence of the cross-link is significant for two reasons. First, mitomycin C's antitumor activity is the result of the formation of rare interstrand DNA cross-links. Second, aziridinomitosenes were previously thought to be responsible solely for formation of less toxic DNA monoadducts. Several factors may facilitate this previously unobserved cytotoxic event, including the presence of two additional electrophilic sites located on the quinone ring at C-6 and C-7. Evidence suggests that the C-1 and C-10 electrophilic sites are key to crosslink formation, as is the case with mitomycin C, but the molecular structure of the cross-link is not known. The mechanism of DNA cross-linking by the synthetic aziridinomitosene is hypothesized to involve first monoalkylation of DNA at the C-1 aziridine site followed by a second event that activates the C-10 site for a second alkylation. The C-10 activation event is proposed to involve nucleophilic attack at the C-6 or C-7 atoms. This proposal aims to identify the molecular structure of the DNA-aziridinomitosene interstrand cross-link, determine the role of the four electrophilic sites, and investigate the physical properties required to induce cross-link formation. The proposed research involves three specific aims: 1) identify and prepare relevant mitosene analogs; 2) characterize mitosenes with respect to reduction potential, aziridine nitrogen pKa, and solvolytic stability; 3) conduct an in vitro assessment of DNA alkylation by mitosene derivatives. Upon completion of the studies, a thorough understanding of the significant structural features with respect to DNA alkylating ability will be understood. The information will serve to clarify existing literature observations and allow for future studies that exploit the most significant characteristics.

描述（由申请人提供）：氮丙啶基丝裂烯是一种与临床使用的抗癌剂丝裂霉素C相关的化合物，最近已被证明在非还原条件下形成DNA链间交联。交联的发生具有重要意义，原因有二。首先，丝裂霉素 C 的抗肿瘤活性是罕见的链间 DNA 交联形成的结果。其次，氮丙啶有丝分裂烯此前被认为是毒性较小的 DNA 单加合物形成的唯一原因。有几个因素可能促进了这种以前未观察到的细胞毒性事件，包括位于醌环 C-6 和 C-7 处的两个额外亲电子位点的存在。有证据表明，C-1 和 C-10 亲电子位点是交联形成的关键，就像丝裂霉素 C 的情况一样，但交联的分子结构尚不清楚。假设合成氮丙啶基核糖烯的 DNA 交联机制涉及 DNA 在 C-1 氮丙啶位点的第一次单烷基化，然后是激活 C-10 位点进行第二次烷基化的第二个事件。 C-10 活化事件被认为涉及 C-6 或 C-7 原子的亲核攻击。该提案旨在鉴定 DNA-氮丙啶核糖烯链间交联的分子结构，确定四个亲电子位点的作用，并研究诱导交联形成所需的物理性质。拟议的研究涉及三个具体目标：1）识别和制备相关的有丝分裂烯类似物； 2) 表征线粒体的还原电位、氮丙啶氮 pKa 和溶剂分解稳定性； 3) 对有丝分裂烯衍生物的 DNA 烷基化进行体外评估。研究完成后，将彻底了解与 DNA 烷基化能力相关的重要结构特征。这些信息将有助于澄清现有的文献观察结果，并允许未来的研究利用最重要的特征。