Bridging pyrimidine hemicurcumin and Cisplatin: Synthesis, coordination chemistry, and in vitro activity assessment of a novel Pt(II) complex

In the upcoming decades, the incidence and mortality rates of cancer are expected to rise globally, with colorectal and prostate cancers among the most prevalent types. Despite advancements in molecular targeted therapy, platinum-based chemotherapies remain the cornerstone of treatment, especially for colorectal and prostate cancer, with oxaliplatin and cisplatin being extremely effective due to their DNA-targeting capabilities. In our pursuit of new platinum-based chemotherapeutics that are potentially less toxic and more effective, we have explored the combination of the Pt-binding groups of the diaminocyclohexane ring used in oxaliplatin, with the stable amino-pyrimidine hemicurcumin moiety. This new derivative exhibit improved stability in physiological conditions and increased solubility in aqueous media, demonstrating promising effects on cell proliferation of both colorectal and prostate cells. We report herein the complete synthesis and chemical characterization in solution of the new derivative [(1 R ,2 R )-N1-(3-(4-(( E )-2-(2-Amino-6-methylpyrimidin-4-yl)vinyl)-2-methoxyphenoxy) propyl) cyclohexane-1,2-diamine] (MPYD). Our analysis includes an examination of its acid-base equilibria, speciation and stability in physiological conditions. The synthesis and in situ formation of Pt(II) complexes were investigated by nuclear magnetic resonance spectroscopy, while density functional theory calculations were employed to elucidate the chemical structure in solution. Results on the biological activity were obtained through cell viability assays on different colorectal and prostate cell lines (HCT116, HT29, PC3 and LNCaP). A new N,N chelator for Pt(II): Amino-pyrimidine hemicurcumin bridged to diaminocyclohexane. Is the match improving or detrimental to the anticancer activity? How chemical investigations can rationally help to address this task. • Amino-pyrimidine hemicurcumin bridging diaminocyclohexane: a new N,N chelator for Pt(II). • Greater stability in physiological conditions than the lead compound Curcumin. • Pt(II) complex formation in solution by NMR and DFT calculations. • Amino-pyrimidine hemicurcumin moiety enhances cellular uptake of Pt complex. • Pt complex mainly affects replication phase in HCT116 cancer cells.