A trans-dichloridoplatinum(II) complex of a monodentate nitrogen mustard: Synthesis, stability and cytotoxicity studies

摘要

A trans-dichloridoplatinum(II) complex, trans-[(PtCl2)-Cl-II(L)(DMSAO)1 (1) of a monodentate nitrogen mustard, bis(2-chloroethyl)amine (L), was synthesized by the reaction of cis-(PtCl2)-Cl-II(L)(DMSAO)(2)] & L.HCl in presence of Et3N. 1 was characterised by NMR, FT-IR and elemental analysis. L is unstable in aqueous solution while 1 displayed moderate stability. In aqueous buffer solution of pD 7.4, 1 starts to loose L slowly upon dissolution and even after 48 h there is still intact/aquated complex present in solution. 1 interacts with the model nucleobase 9-ethyl guanine. The ligand L was non-toxic against MCF-7, A549, HepG2 & MIA PaCa-2 up to 200 mu M. In contrast, the Pt(II) complex 1 showed an excellent IC50 (ca. 600 nM) against MIA PaCa-2 and also displayed good IC50, value (3-7 mu M) against the other cancer cell lines probed. The in vitro cytotoxicity of 1 is better than cisplatin against each of the treated cancer cell lines and it is not affected by hypoxia as per the in vitro studies. Complex 1 displays higher cellular accumulation than cisplatin and arrests the cell cycle in both S & G2/M phase inducing apoptotic cell death. The G2/M phase arrest is dominant at higher concentrations. The depolarisation of mitochondria by 1 combined with activation of caspase-7 indicates apoptotic cell death. Complex 1 induces low hemolysis of human blood signifying excellent blood compatibility.