MOLECULAR MECHANISMS OF ANTICANCER DRUGS

抗癌药物的分子机制

• 批准号: 3197252
• 负责人: ANDREW H WANG
• 金额: $ 14.96万
• 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/3197252
• 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; 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.

该项目的总体目标是研究分子基础 几种重要的抗癌/抗肿瘤药物的相互作用 DNA使用单晶X射线衍射方法和其他生物物理方法 技术。 这些结果将为分子生物学提供有价值的见解。 药物的作用机制。 我们的方法是让这些 抗癌/抗肿瘤药物与精心设计的DNA共结晶 使用先进的结晶技术的 RNA 寡核苷酸 PI实验室开发。 我们建议研究以下药物 分子： 1. 嵌入剂和双嵌入剂：蒽环类抗生素； 喹啉类抗生素；喹喔啉类抗生素； 合成玫瑰树碱 双嵌入剂；其他合成嵌入剂；苯恶腙 抗生素。 2.小​​沟结合药物：含吡咯类抗生素和 合成凹槽粘合剂。 3. 与DNA共价相互作用的药物：小沟结合剂（CC- 1065 及其衍生物）和大沟粘合剂（顺铂）。 4.抗癌核苷：araC和araA。 大多数天然和合成抗肿瘤药物已经可用 在PI的实验室里。 所描述范围内的几种药物-DNA复合物 以上已经结晶，并且处于不同的结构阶段 分析。 更多的 DNA 和 RNA 寡核苷酸将被合成 上面列出的各种药物的结晶实验。 这 将比较来自溶液和固态的结构 它们将成为进一步理论分析的基础 强大的计算机资源，包括CRAY 2超级计算机和精湛的 图形设施，在伊利诺伊大学充分了解 控制结构、动力学和相互作用的分子力 药物-核酸复合物。 我们的长期目标是利用结果 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 特异性，它们将被合成并进一步研究。