Evaluation of DNA Cross-Linking by Aziridinomitosenes

氮丙啶有丝分裂 DNA 交联的评价

• 批准号: 7845922
• 负责人: Don L Warner
• 金额: $ 3.49万
• 依托单位: BOISE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7845922
• 关键词: Adverse effects; Antineoplastic Agents; Apoptosis; Aziridines; Bacteria; Binding; Binding Sites; Biological; Biological Factors; Biological Process; Bladder; Cancer cell line; Cancerous; Carbamates; Carbon; Cell Death; Cells; Chemicals; Cisplatin; Clinical; Clinical Trials; Colorectal; DNA; DNA Alkylation; DNA Binding; DNA Modification Process; DNA Sequence; DNA biosynthesis; Drug usage; Enzyme Activation; Evaluation; Exhibits; Foundations; Future; Generations; Head and neck structure; In Vitro; Investigation; Knowledge; Lead; Life; Link; Literature; Lung; Malignant Neoplasms; Mechlorethamine; Methods; Mitomycins; Molecular; Non-Small-Cell Lung Carcinoma; Oxidation-Reduction; Pattern; Pharmaceutical Preparations; Property; Protein Biosynthesis; Proteins; Public Health; Quinones; Reactive Oxygen Species; Reporting; Research; Role; Site; Solid; Spectrum Analysis; Stomach; Structure; Testing; Therapeutic; Toxic effect; adduct; analog; cancer cell; chemotherapeutic agent; chemotherapy; crosslink; cytotoxicity; design; drug candidate; drug development; in vivo; insight; interest; member; novel; prevent; protein complex; public health relevance; research study

DESCRIPTION (provided by applicant): Aziridinomitosenes (AZMs) are related to the clinically useful anti-cancer agent mitomycin C (MC). The search for compounds related to MC that display an increase in efficacy and a decrease in side-effects has led to the study and synthesis of numerous analogs, several of which have advanced to clinical trials. Reductively activated MC forms DNA interstrand cross-links (ICLs), which block DNA replication and protein synthesis and result in cell death. Several synthetic AZMs have been found to form, without prior activation, ICLs and DNA/protein cross-links (DPCLs). Although drug development is beyond the scope of the current proposal, AZM analogs capable of forming ICLs without prior reductive activation are intriguing drug candidates since literature reports have shown that there is a direct correlation between mitomycin toxicity and reduction potential. In addition, AZM-induced DPCLs may have increased therapeutic importance as a result of their ability to obstruct DNA-associated protein complexes and disrupt key biological processes. Since several chemotherapeutic agents have been reported to form DPCLs, including cisplatin and several nitrogen mustards, the ability of synthetic AZMs to form DPCLs is clearly worth future evaluation. Objective/Hypothesis/Aims. Evidence suggests that synthetic AZMs covalently modify DNA to form interstrand cross-links (ICLs) and DNA/protein cross-links (DPCLs). Given that these AZMs, unlike MC, do not require reductive activation prior to DNA binding, adduct formation by AZMs may be occurring via a novel mechanism. Since the primary structural difference between these and previously reported AZMs is the substitution pattern on the quinone ring, a hypothesis for activation is proposed to involve attack by a cellular nucleophile into the quinone ring. To test this hypothesis, the proposed research includes the following specific aims: 1) Identify and prepare relevant AZMs, 2) Characterize AZMs and reactive intermediates with respect to solvolytic stability and correlate with DNA-alkylating and cytotoxicity studies, 3) Conduct an in vitro assessment of DNA alkylation, including experiments that probe for the formation of ICLs and DPCLs, and 4) Investigate the cytotoxicity of AZM derivatives in cancer cell lines, including experiments that examine the mechanism of cell death upon exposure of cancer cells to AZMs. The projects described herein aim to gain a thorough understanding of the unique chemical and biological properties of AZMs that facilitate ICL and DPCL formation, which will ultimately provide a solid foundation for future research that may lead to more efficacious chemotherapy treatments. PUBLIC HEALTH RELEVANCE: Many of the most significant anticancer agents in use today exhibit their biological properties through the covalent modification of DNA. The aziridinomitosenes described within this proposal are novel DNA-modifying agents with as of yet undetermined therapeutic potential. The purpose of the described projects is to determine the manner in which these compounds manifest their potency in order to provide a solid foundation for future research leading to more efficacious chemotherapy treatments.

描述(申请人提供)：阿齐利诺米松(AZM)与临床上有用的抗癌药物丝裂霉素C(MC)有关。寻找与MC相关的化合物，显示出疗效的提高和副作用的减少，导致了许多类似物的研究和合成，其中一些已经进入临床试验。还原激活的MC形成DNA链间交联链(ICL)，阻止DNA复制和蛋白质合成，导致细胞死亡。已发现几种人工合成的AZM在没有事先激活的情况下形成ICL和DNA/蛋白质交联链(DPCL)。虽然药物开发超出了当前提议的范围，但能够在不事先还原激活的情况下形成ICL的Azm类似物是耐人寻味的候选药物，因为文献报道表明丝裂霉素毒性和还原潜力之间存在直接关联。此外，AZM诱导的DPCL可能由于其阻止DNA相关蛋白复合体和扰乱关键生物学过程的能力而增加了治疗重要性。由于已经报道了几种化疗药物形成DPCL，包括顺铂和几种氮芥菜，合成AZM形成DPCL的能力显然值得进一步评估。目标/假设/目的。有证据表明，合成的AZM可以共价修饰DNA，形成链间交联物(ICL)和DNA/蛋白质交联物(DPCL)。鉴于这些AZMS与MC不同，在DNA结合之前不需要还原活化，AZMS的加合物形成可能通过一种新的机制发生。由于这些AZM与以前报道的AZM之间的主要结构差异是醌环上的取代模式，因此提出了一个激活假说，涉及到细胞亲核分子对醌环的攻击。为了验证这一假说，拟议的研究包括以下具体目标：1)确定和制备相关的AZM，2)表征AZM和活性中间体的溶解稳定性，并与DNA烷基化和细胞毒性研究相关，3)进行DNA烷基化的体外评估，包括探索ICL和DPCL形成的实验，以及4)研究AZM衍生物对癌细胞的细胞毒性，包括研究癌细胞暴露于AZM时细胞死亡的机制。本文描述的项目旨在彻底了解AZM独特的化学和生物学特性，这些特性有助于ICL和DPCL的形成，最终将为未来可能导致更有效的化疗治疗的研究提供坚实的基础。与公共健康相关：当今使用的许多最重要的抗癌药物通过DNA的共价修饰展示了它们的生物学特性。本提案中描述的氮杂环丁二烯是一种新型的DNA修饰剂，具有尚未确定的治疗潜力。所述项目的目的是确定这些化合物显示其效力的方式，以便为未来导致更有效的化疗治疗的研究提供坚实的基础。