NMR-SPECTROSCOPY AS A TOOL TO INVESTIGATE THE STRUCTURAL BASIS OF ANTICANCER DRUGS

NMR spectroscopy has been shown to be useful in determining the struct ures of nucleic acid fragments in solution. Over the last several year s NMR spectroscopy, in conjunction with restrained molecular dynamics, has been employed to understand the 3D structures of a number of anti cancer drugs and to rationalize their DNA binding behavior. In this re view we address the methodologies used most frequently to determine nu cleic acid structures in solution. In subsequent sections, we examine how these methods have been applied to rationalize the activities of a number of anticancer agents that target duplex DNA such as cisplatin, bleomycin and calicheamicin. Non-duplex DNA and RNA also represent in teresting nucleic acid targets for anticancer drug design and applicat ions of solution NMR spectroscopy to understanding the structures of t hese types of molecules (e.g. Okazaki fragments, DNA tetraplexes) are also reviewed. In the final sections, advances in NMR methodologies (e .g. linear prediction, superconducting probes) that are likely to impa ct the research conducted in this area are reviewed. The success of NM R spectroscopy in understanding the structural basis for clinically us eful anticancer drugs bodes well for future applications of this metho dology not only in rationalization of existing biological activity, bu t in the design of novel agents that will be useful in treating neopla stic disease.