Anticancer activity of a chelating nitrogen mustard bearing tetrachloridoplatinum(iv) complex: better stability yet equipotent to the Pt(ii) analogue

Abstract

Two Pt(IV) complexes cis,cis,trans-[Pt^IV(L1)Cl₄] (1a) & cis,cis,trans-[Pt^IV(L2)Cl₄] (2a) containing the nitrogen mustard moieties –N(CH₂CH₂Cl)₂ & –NHCH₂CH₂Cl, were prepared in a single step from the Pt(II) complexes containing –N(CH₂CH₂OH)₂ (1) & –NHCH₂CH₂OH (2) moieties respectively using only thionyl chloride. The characterization of both the Pt(IV) complexes was performed by NMR, IR, UV and elemental analysis. Complex 1a was also characterized by single crystal X-ray diffraction. 1a crystallized in the I2/a space group. 1a exhibited much higher solution stability than 2a in kinetic studies by ¹H NMR. 1a shows a prodrug like activity as it converts to its Pt(II) congener, [Pt^II(L1)Cl₂] (3) after 2 days in buffered solution. The binding experiment of 1a with model nucleobase 9-ethylguanine (9-EtG), showed that 1a converts to 3 and forms mono-adducts with 9-EtG. In the presence of reduced glutathione (GSH), the formation of 3 from 1a is quicker and upon the formation of 3 it binds almost instantaneously to GSH to form cis-[PtCl(L1)SG] (3c). Complex 3c transformed within a day to give a free aziridinium ion of L1 (3b) by dissociation. The in vitro cytotoxicity of the complexes and the clinical anticancer drug cisplatin show that 1a is potent against MCF-7, A549, HepG2 and MIA PaCa-2. The potency is highest against MIA PaCa-2 exhibiting an IC₅₀ value of 4.4 ± 0.5 μM. The in vitro cytotoxicity data also showed that between the two complexes only 1a is active against MCF-7, A549 and MIA PaCa-2 in normoxia and hypoxia, both in the presence and absence of added GSH. Even in the presence of excess GSH in hypoxia, 1a exhibits significant cytotoxicity against MIA PaCa-2 and MCF-7 with IC₅₀ values of 4.5 ± 0.3 and 11.2 ± 1.8 μM respectively. Platinum accumulation studies by ICP-MS display greater internalization of 1a, than 2a, 3 and cisplatin inside MCF-7 cells. 1a arrests cell cycle at the G2/M phase in MCF-7, exhibits capability to inhibit metastasis, induces apoptotic cell death and displays blood compatibility with human blood.