New Pt-NNSO core anticancer agents: Structural optimization and investigation of their anticancer activity

A series of new platinum Pt(II) compounds possessing a bidentate leaving ligand modified from oxaliplatin has been synthesized, with one of the oxygen ligating atom substituted for a sulphur atom (resulting in a Pt-NNSO coordination core structure). The general structures are R,R-diaminocyclohexane (DACH)-Pt-(methylthio)acetic acid (K4) and DACH-Pt-(thiophenylacetic acid) (K4 derivatives). Substitution of an electron donating or withdrawing group at the ortho or para position on the phenyl ring of K4 derivatives was found to affect the complexes' stability, reactivity with the biological molecules (5'-guanosine monophosphate (5'-GMP) and L-methionine (L-Met)) and anticancer activity. ¹H NMR experiments demonstrated that Pt-NNSO complexes formed a mixture of mono- and diadduct with 5'-GMP in various ratios, which are different from the classical Pt drugs (forming mainly diadduct). In addition, all of the K4 derivatives with improved lipophilicity are less deactivated by L-Met in comparison to cisplatin (CDDP) and oxaliplatin. Biological assessments showed that all Pt-NNSO complexes are less toxic than CDDP in normal porcine kidney cells and are minimally affected by drug resistance. Some of the new compounds also displayed comparable anticancer activity to CDDP or better than carboplatin in a few cancer cell lines. The lower reactivity of the Pt-NNSO compounds than CDDP towards thiol molecules, presumably leading to less efflux in resistant cancer cells, and the ability to inhibit autophagy were believed to allow the new compounds to be less affected by Pt resistance.