This proposal outlines a cross-disciplinary research program at the interface of biocoordination chemistry, molecular structural biology, and anticancer drug development. The motivation of this research stems from our recent discovery of a cytotoxic platinum-acridinylthiourea conjugate [Martins, E. T., et al., J. Med. Chem. 44, 4492 (2001)] that exhibits several unusual (bio)chemical and biological properties. Unlike the many cross-linking agents based on the cis-diam(m)inedichloroplatinum (cisplatin) motif, our conjugate holds promise of being the first truly non-guanine specific platinum-based covalent DNA modifier. A major goal in cancer chemotherapy is to identify alternative treatments that circumvent the various types of resistance and are able to contend with tumor heterogeneity and multi-drug resistance. Toward this objective, new hybrid molecules are developed in our laboratory that are designed to act either via a combination of established damage mechanisms at the DNA level or an unprecedented mode of action unknown of its individual components. One goal of this proposal is to identify a lead compound based on the prototypical structure for future (pre)clinical studies by systematically exploring the structure-activity relationships within this new class of compounds. This will be achieved by testing a library of newly synthesized structural derivatives in a broad range of cell lines (leukemia, brain, colon, ovarian, lung, and breast) using clonogenic survival assays. On the other hand, the proposed research is concerned with the fundamental understanding of small molecule-DNA interactions and their consequences for nucleic acid structure and recognition. Specifically, we will demonstrate that divalent platinum can be hijacked away from its natural target, guanine-N7, if the covalent binding of the metal is dominated by the tethered intercalating unit (acridine) rather than simple electrostatics. The second part of the proposal therefore aims to fully characterize the DNA adduct profile of the prototypical conjugate and to understand its (atom-specific) DNA interactions at the molecular level. This will be achieved using various biochemical, analytical, and spectroscopic methods, incl. replication mapping, liquid chromatography-mass spectrometry, and high-resolution NMR spectroscopy in conjunction with molecular modeling. The results expected from this study will reveal novel concepts of wide importance and interest to the scienific communities involved both in drug discovery and bioinorganic chemistry. ? ? ?
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