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

摘要

Two Pt(IV) complexes cis, cis, trans-Pt-IV(L1)Cl-4 (1a) cis, cis, trans-Pt-IV(L2)Cl-4 (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 H-1 NMR. 1a shows a prodrug like activity as it converts to its Pt(II) congener, Pt-II(L1)Cl-2 (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 mu M. 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 mu M 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.