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）：该提案在生物协调化学，分子结构生物学和抗癌药物开发的界面上概述了跨学科研究计划。这项研究的动机源于我们最近发现的细胞毒性铂 - acridinylthiourea conjugate [Martins，E。T.等，J。Med。化学44，4492（2001）]，表现出几种不寻常的（生物）化学和生物学特性。与许多基于CIS-DIAM（M）Inedichloroplatinum（Cisplatin）基序的交联剂不同，我们的共轭有望成为第一个真正的非甘氧氨酸特异性铂基的共价DNA修饰剂。癌症化学疗法的主要目标是确定避免各种抗药性的替代治疗方法，并能够与肿瘤异质性和多药抗性抗衡。为了实现这一目标，在我们的实验室中开发了新的混合分子，该分子旨在通过在DNA水平上建立的损伤机制的结合或前所未有的作用方式来起作用。该提案的一个目标是通过系统地探索这种新化合物中的结构 - 活性关系来确定基于未来（前）临床研究的原型结构的铅化合物。这将通过使用克隆生存测定法测试新合成的结构衍生物（白血病，大脑，结肠，卵巢，肺和乳腺）的新合成结构衍生物的库来实现。 另一方面，拟议的研究涉及对小分子-DNA相互作用的基本理解及其对核酸结构和识别的后果。具体而言，我们将证明，如果金属的共价结合由束缚的互嵌套单元（Acridine）而不是简单的静电，则可以将二价铂袋从其自然目标鸟嘌呤N7劫持。因此，该提案的第二部分旨在充分表征原型结合物的DNA加合物曲线，并了解其在分子水平上的（原子特异性）DNA相互作用。这将是使用各种生化，分析和光谱法（包括）来实现的。复制映射，液相色谱 - 质谱法和与分子建模结合的高分辨率NMR光谱。这项研究的结果将揭示对药物发现和生物无机化学涉及的科学社区的广泛重要性和兴趣的新颖概念。