MOLECULAR MECHANISMS OF ANTICANCER DRUGS

这个项目的总体目标是研究分子基础。 几种重要的抗癌/抗肿瘤药物与药物的相互作用 使用单晶x射线衍射法和其他生物物理方法的DNA 技巧。这些结果将为分子水平的研究提供有价值的见解。 药物的作用机制。我们的方法是让这些 抗癌/抗癌药物与精心设计的DNA和 使用复杂结晶技术的RNA寡核苷酸 在派的实验室里研发的。我们建议研究以下药物 分子： 1.嵌入剂和双嵌入剂：苯类抗生素； 喹啉类抗生素；喹恶啉类抗生素；合成椭圆形 双键插层剂；其他合成插层剂；苯恶宗 抗生素。 2.次要沟槽结合药物：含吡咯的抗生素和 合成槽粘结剂。 3.与DNA共价作用的药物：微小沟槽结合剂(CC- 1065及其衍生物)和主要沟槽粘结剂(顺铂)。 4.抗癌核苷：Arac和araA。 这些天然和合成的抗肿瘤药物大多已经上市。 在派的实验室里。所述范围内的几种药物-DNA络合物 以上都已结晶，它们正处于不同的结构阶段 分析。更多的DNA和RNA寡核苷酸将被合成用于 以上列出的各种药物的结晶实验。这个 我们将比较从溶液和固态衍生出来的结构 它们将成为进一步使用 强大的计算机资源，包括一台Cray 2超级计算机和一流 伊利诺伊大学的图形设施，以充分了解 主宰结构、动力学和相互作用的分子力 药物-核酸复合体。我们的长期目标是利用这些结果 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结合亲和力和 以及它们的特异性，它们将被合成并进一步研究。

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.