Novel DNA-metalating Hybrid Anticancer Agents

新型 DNA 金属化混合抗癌剂

• 批准号: 6761792
• 负责人: Ulrich Bierbach
• 金额: $ 22.46万
• 依托单位: WAKE FOREST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6761792
• 关键词: DNA; DNA damage; SDS polyacrylamide gel electrophoresis; acridines; adduct; antineoplastics; autoradiography; chemical conjugate; chemical models; chemical structure function; chemical synthesis; cisplatin; conformation; covalent bond; cytotoxicity; gel mobility shift assay; guanine; intermolecular interaction; liquid chromatography mass spectrometry; multidrug resistance; neoplasm /cancer chemotherapy; platinum; tissue /cell culture

DESCRIPTION (provided by applicant): This proposal outlines a cross-disciplinary research program at the interface of biocoordination chemistry, molecular structural biology, and anticancer drug development. The motivation of this research stems from our recent discovery of a cytotoxic platinum-acridinylthiourea conjugate [Martins, E. T., et al., J. Med. Chem. 44, 4492 (2001)] that exhibits several unusual (bio)chemical and biological properties. Unlike the many cross-linking agents based on the cis-diam(m)inedichloroplatinum (cisplatin) motif, our conjugate holds promise of being the first truly non-guanine specific platinum-based covalent DNA modifier. A major goal in cancer chemotherapy is to identify alternative treatments that circumvent the various types of resistance and are able to contend with tumor heterogeneity and multi-drug resistance. Toward this objective, new hybrid molecules are developed in our laboratory that are designed to act either via a combination of established damage mechanisms at the DNA level or an unprecedented mode of action unknown of its individual components. One goal of this proposal is to identify a lead compound based on the prototypical structure for future (pre)clinical studies by systematically exploring the structure-activity relationships within this new class of compounds. This will be achieved by testing a library of newly synthesized structural derivatives in a broad range of cell lines (leukemia, brain, colon, ovarian, lung, and breast) using clonogenic survival assays. On the other hand, the proposed research is concerned with the fundamental understanding of small molecule-DNA interactions and their consequences for nucleic acid structure and recognition. Specifically, we will demonstrate that divalent platinum can be hijacked away from its natural target, guanine-N7, if the covalent binding of the metal is dominated by the tethered intercalating unit (acridine) rather than simple electrostatics. The second part of the proposal therefore aims to fully characterize the DNA adduct profile of the prototypical conjugate and to understand its (atom-specific) DNA interactions at the molecular level. This will be achieved using various biochemical, analytical, and spectroscopic methods, incl. replication mapping, liquid chromatography-mass spectrometry, and high-resolution NMR spectroscopy in conjunction with molecular modeling. The results expected from this study will reveal novel concepts of wide importance and interest to the scienific communities involved both in drug discovery and bioinorganic chemistry.

描述（由申请人提供）：该提案概述了生物配位化学、分子结构生物学和抗癌药物开发交叉学科的研究计划。这项研究的动机源于我们最近发现的一种细胞毒性铂-吖啶基硫脲缀合物[Martins, E. T., et al., J. Med.化学。 44, 4492 (2001)] 表现出几种不寻常的（生物）化学和生物特性。与许多基于顺式二氯铂（顺铂）基序的交联剂不同，我们的缀合物有望成为第一个真正的非鸟嘌呤特异性铂基共价 DNA 修饰剂。癌症化疗的一个主要目标是确定替代疗法，以规避各种类型的耐药性，并能够应对肿瘤异质性和多药耐药性。为了实现这一目标，我们的实验室开发了新的混合分子，这些分子旨在通过 DNA 水平上已建立的损伤机制的组合发挥作用，或者通过其各个成分未知的前所未有的作用模式发挥作用。该提案的一个目标是通过系统地探索此类新化合物中的结构-活性关系，根据未来（前）临床研究的原型结构确定先导化合物。这将通过使用克隆生存测定在广泛的细胞系（白血病、脑、结肠、卵巢、肺和乳腺）中测试新合成的结构衍生物库来实现。 另一方面，拟议的研究涉及小分子-DNA 相互作用的基本理解及其对核酸结构和识别的影响。具体来说，我们将证明，如果金属的共价结合由束缚嵌入单元（吖啶）而不是简单的静电主导，那么二价铂可以被劫持远离其天然靶标鸟嘌呤-N7。因此，该提案的第二部分旨在全面表征原型缀合物的 DNA 加合物谱，并了解其在分子水平上的（原子特异性）DNA 相互作用。这将通过各种生化、分析和光谱方法来实现，包括。复制图谱、液相色谱-质谱分析、高分辨率核磁共振波谱与分子建模相结合。这项研究的预期结果将揭示对涉及药物发现和生物无机化学的科学界具有广泛重要性和兴趣的新概念。