MOLECULAR MECHANISMS OF ANTICANCER DRUGS

抗癌药物的分子机制

• 批准号: 3197253
• 负责人: ANDREW H WANG
• 金额: $ 15.59万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-07-01 至 1995-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3197253
• 关键词: DNA; X ray crystallography; adduct; anthracyclines; antineoplastic antibiotics; antineoplastics; chemical binding; chemical structure function; circular dichroism; cis platinum compound; computer graphics /printing; computer simulation; conformation; covalent bond; cytosine arabinoside; daunorubicin; doxorubicin; drug interactions; intermolecular interaction; isomorphous substitution; molecular dynamics; netropsin; nuclear magnetic resonance spectroscopy; nucleic acid chemical synthesis; nucleic acid structure; oligonucleotides; quinoline; synthetic nucleotide

The overall objective of this project is to investigate the molecular basis of the interactions of several important anticancer/antitumor drugs with DNA using single crystal x-ray diffraction methods and other biophysical techniques. These results will provide valuable insights on the molecular mechanisms of the drugs. Our approach is to have these anticancer/antitumor drugs co-crystallized with carefully designed DNA and RNA oligonucleotides using the sophisticated crystallization technique developed in PI's laboratory. We propose to study the following drug molecules: 1. Intercalators and Bis-intercalators: Anthracylcine antibiotics; Quinoline antibiotics; Quinoxaline antibiotics; Synthetic ellipticine bis-intercalator; Other synthetic intercalators; Phenoxazone antibiotics. 2. Minor groove binding drugs: Pyrrole-containing antibiotics and Synthetic groove binders. 3. Drugs that interact with DNA covalently: Minor groove binder (CC- 1065 and derivatives) and Major groove binder (Cisplatin). 4. Anticancer Nucleosides: araC and araA. Most of these natural and synthetic antitumor drugs are already available in PI's laboratory. Several drug-DNA complexes in the scope described above have been crystallized and they are in various stages of structural analysis. Many more DNA and RNA oligonucleotides will be synthesized for the crystallization experiments with various drugs listed above. The structure derived both from solution and from solid states will be compared and they will be the basis for further theoretical analysis using the powerful computer resource, including a CRAY 2 supercomputer and superb graphic facilities, at the University of Illinois to fully understand the molecular forces that govern the structure, dynamics and interactions of the drug-nucleic acid complexes. Our long range goal is to use the results from these structural studies as the basis for designing new compounds. These new compounds will have unique DNA/RNA binding affinity and specificity and they will be synthesized and further studied.

该项目的总体目的是研究分子基础 几种重要的抗癌/抗肿瘤药物与 DNA使用单晶X射线衍射方法和其他生物物理 技术。 这些结果将为分子提供宝贵的见解 药物的机制。 我们的方法是拥有这些 与精心设计的DNA共结晶的抗癌/抗肿瘤药物 RNA寡核苷酸使用复杂的结晶技术 在Pi的实验室中开发。 我们建议研究以下药物 分子： 1。介导者和双互换器：蒽仑抗生素； 喹啉抗生素； Quinoxaline抗生素； 合成椭圆氨酸 双交换器；其他合成的介入剂；苯氧唑 抗生素。 2。较小的凹槽结合药：含吡咯的抗生素和 合成凹槽粘合剂。 3。共价与DNA相互作用的药物：较小的凹槽粘合剂（CC- 1065和衍生物）和主要的凹槽粘合剂（顺铂）。 4。抗癌核苷：ARAC和ARAA。 这些天然和合成抗肿瘤药物中的大多数已经可用 在Pi的实验室中。 描述的范围中的几个药物-DNA复合物 以上已经结晶，它们处于结构的各个阶段 分析。 将合成更多更多的DNA和RNA寡核苷酸 上面列出的各种药物的结晶实验。 这 将比较从溶液和固态得出的结构 它们将是使用 功能强大的计算机资源，包括Cray 2超级计算机和出色 伊利诺伊大学的图形设施，以完全了解 控制结构，动力学和相互作用的分子力 药物核酸复合物。 我们的远距离目标是使用结果 从这些结构研究作为设计新化合物的基础。 这些新化合物将具有独特的DNA/RNA结合亲和力，并且 特异性将合成并进一步研究。