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.
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