The potency of cisplatin in cancerous cells has been complicated by its toxicity to normal cells. Cisplatin can be modified in a number of ways with ligands of varied sizes, polarities, and charges. These features can affect the kinetics of interaction with nucleic acids, the types of adducts formed, the preferred sites of coordination, and cell cytotoxicity. In this study, amino acids were reacted with platinum to form a series of cisplatin analogues. Arginine-linked platinum (ArgPt) is active in prostate cancer cell line and show a balance between potency and reduced toxicity. RNA is a competitive target of cisplatin and is able to accumulate inert platinum adducts. Aquated cisplatin may have preferential target residues in RNA as observed with DNA. Further, kinetic studies showed that ornithine-linked platinum (OrnPt) and ArgPt are reactive towards both RNA and DNA nucleosides but with different selectivities. The two amino acid complexes have selectivity towards A/dA residues, in contrast to cisplatin which targets dG. Inductively coupled plasma mass spectrometry (ICPMS) quantification reveals higher accumulation of OrnPt and ArgPt on RNA over DNA. ArgPt also forms platinum adducts with poly(A) RNA. Platination by amino-acid-linked platinum analogues at particular sites on the ribonucleosides (<i>i.e</i>., N1, N3, or N7) is found to have varying impacts on their glycosidic bond stabilities. Weak glycosidic bonds accelerate depurination and could ultimately contribute to cell cytotoxicity. Such adducts may affect the biological roles of RNA such as mRNA maturation and protein synthesis. Therefore, amino-acid-linked platinum(II) analogues may have alternative targets and selective potency compared to cisplatin.

Interactions of platinum(II) small molecules with RNA and implications of platination on RNA depurination and cell cytotoxicity

255th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.