Poster abstracts
Poster number 100 submitted by Bett Kimutai
Reaction kinetics, nucleoside preference, and impact of amino-acid-linked platinum analogues on RNA and DNA
Bett Kimutai (Wayne State University Chemistry), Chenchen He (Wayne State University Chemisty), Andrew Roberts (Wayne State University Chemistry), Marcel Jones (University of Detroit Mercy), M. T. Rodgers (Wayne State University Chemistry), Christine S. Chow (Wayne State University Chemistry)
Abstract:
Cisplatin is known to preferentially coordinate to deoxyguanosine residues of DNA and forms adducts that inhibit DNA functions. RNA is also a competitive target of cisplatin and aquated cisplatin may have preferential target residues in RNA as observed with DNA. Since cisplatin has a number of drawbacks that reduce its effectiveness, including repair mechanisms that remove the platinum adducts from the DNA strands, there is still a need to develop compounds that are able to coordinate to different nucleic acid sites. RNA residues may serve as ideal targets for such platinum-based drugs. Platinum compounds that target residues other than deoxyguanosine may have alternative anticancer mechanisms that circumvent the undesired inactivation pathways of cisplatin. In this study, we demonstrate that amino-acid-linked platinum(II) analogues (AlaPt, OrnPt, and ArgPt) have altered reactivity compared to cisplatin. They preferentially coordinate and form adducts with adenosine and deoxyadenosine residues. ArgPt also forms adducts with poly(A) RNA and shows selective toxicity in cancer cells. Binding of AlaPt and OrnPt to adenosine leads to destabilization of the glycosidic bond for certain adducts. This phenomenon is dependent on the site of platination and the type of ligand present in the metal complex. The weakening of the nucleoside glycosidic bond, could have important biological consequences including depurination and degradation of nucleic acids.
Keywords: cisplatin, cell toxicity