Metal anti-cancer drug activity (Pt, Ru) is generally attributed to DNA cross-linking which distorts the DNA structure in ways that are recognized by proteins. Such cross-links also cause mutations by Pt and possibly other heavy metals (Hg). The 5' pair of GpG and ApG cross-links, the major DNA lesions caused by the widely used Pt anti- cancer drugs, is uniquely distorted. This 5' site has been difficult to characterize because of its fluxional nature. The site is highly mutagenic, a factor likely contributing to cancer in long-term survivors of drug treatment. Pt(NH) H-bonding to the DNA, nucleobase orientation, and ease of rotation about the Pt-base bond influence the formation, the structure, and the fluxionality of the DNA adducts with active or mutagenic cross-links. The goals of this proposal are to elucidate and then control these factors. Achieving these goals would allow investigators to test many hypotheses related to the mechanism of action of clinically used Pt drugs; this knowledge could lead to the design of superior Pt drugs forming the most active adducts in the optimal DNA conformation for protein binding. In previous work, the PI has designed and initiated investigations into new Pt(diamine)X(2) complexes for assessing and controlling structure and fluxional properties of PtDNA adducts. A conceptual advance in this design is the incorporation of the Pt(NH) groups in rings which simultaneously fix NH orientation and impart chirality. The attendant bulk, for example of 2,2'-bipiperidine (BiP) complex limits rotation about the Pt-N(nucleopurine) bond. In preliminary studies, these complexes show promise for investigating how cross-linked adducts are formed. Such knowledge may be helpful in assessing the controversies concerning (a) whether PtDNA adducts convert readily from B- to A-form, a form hypothesized to be involved in protein binding of adducts and (b) whether the intra- or inter-strand type of cross-link leads to Pt drug anti-cancer activity. A recent hypothesis suggests intrastrand cross-links convert to interstrand cross-links, and these are more mutagenic in the long-term, through displacement by Cl(- ); in the adducts developed in this work, this process could be slowed or eliminated by fixing nucleobase orientation in the adducts to obscure the Pt axial sites from nucleophilic attack. Octahedral anti-cancer drugs form cross-links less readily than square planar Pt drugs. If factors inhibiting cross-links can be understood, many more types of metal anti-cancer drugs could be designed. Approaches to be used include synthetic chemistry, spectroscopy, gel electrophoresis, and computational methods.
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