cis-Pt I₂(NH₃)₂: a reappraisal

Abstract

The investigation of cis-PtI 2 (NH 3 ) 2 , the diiodido analogue of cisplatin (cisPtI 2 hereafter), has been unjustly overlooked so far mainly because of old claims of pharmacological inactivity. Some recent -but still fragmentary -findings prompted us to reconsider more systematically the chemical and biological profile of cisPtI 2 in comparison with cisplatin. Its solution behaviour, interactions with DNA and cytotoxic properties versus selected cancer cell lines were thus extensively analysed through a variety of biophysical and computational methods. Notably, we found that cisPtI 2 is highly cytotoxic in vitro toward a few solid tumour cell lines and that its DNA platination pattern closely reproduces that of cisplatin; cisPtI 2 is also shown to completely overcome resistance to cisplatin in a platinum resistant cancer cell line. The differences in the biological actions of these two Pt complexes are most likely related to slight but meaningful differences in their solution behaviour and reactivity. Overall, a very encouraging and unexpected pharmacological profile emerges for cisPtI 2 with relevant implications both in terms of mechanistic knowledge and of prospective clinical application. An ab initio DFT study is also included to support the interpretation of the solution behaviour of cisPtI 2 under physiological and slightly acidic pH conditions.

A first-in-class and a fished out anticancer platinum compound: cis-[PtCl2(NH3)2] and cis-[PtI2(NH3)2] compared for their reactivity towards DNA model systems

“…In agreement with previous studies, 6 the two metal complexes show in general a similar reactivity towards the selected single strand ODNs (cfr. panel A with panel B of Fig.…”

“…Proved to be internalised by cells in a far greater amount than cisplatin, this compound has also been found to interact with calf thymus DNA through an interaction mode very similar to that well documented for CDDP, though showing a slower reactivity. 6 Following these intriguing results, we have here investigated the interaction of cisdiamminediiodoplatinum (II), the closest iodido analogue of CDDP, with selected DNA models; thus several oligonucleotide sequences, either in unstructured or structured (duplex and Gquadruplex) form, have been reacted under pseudo-physiological conditions with this Pt complex, using CDDP as a control, and then studied by CD and UV-vis spectroscopy, as well as by ESI-MS analysis.…”

“…Indeed, some of us recently showed that it reacts with proteins or ammonia ligands. 6,7 The X-ray structure of the adduct formed in the reaction between the model protein hen egg white lysozyme and cis- towards DNA is analogous to that of CDDP and its activation occurs upon displacement of both iodido ligands with water molecules. 7 Notably, in vitro biological assays proved that cis-[PtI 2 (NH 3 ) 2 ] is able to produce cytotoxic effects comparable or even greater than those caused by CDDP, also overcoming resistance in a cisplatin-resistant cancer cell line, where it is internalised in far greater amounts than in healthy and cisplatin-sensitive cancer cells.…”

Platinum(II) Iodido Complexes of 7-Azaindoles with Significant Antiproliferative Effects: An Old Story Revisited with Unexpected Outcomes

“…cis -[PtI 2 (NH 3 ) 2 ], an iodido analogue of cisplatin ), thus declaring iodide as unsuitable ligand for development of novel platinum-based metallotherapeutics [3–4]. Remarkably, several complexes previously declared to be inactive, were more recently reported as antitumour active [5–6]. For example, cis -[PtI 2 (NH 3 ) 2 ] showed in vitro antitumour activity against various cancer cell lines including both cisplatin -sensitive (IC 50 = 13.4 μM) and cisplatin -resistant (IC 50 = 4.2 μM) HCT116 colon cancer cell lines (IC 50 = 7.6, and 22.0 μM, respectively, for cisplatin ) [6].…”

“…Remarkably, several complexes previously declared to be inactive, were more recently reported as antitumour active [5–6]. For example, cis -[PtI 2 (NH 3 ) 2 ] showed in vitro antitumour activity against various cancer cell lines including both cisplatin -sensitive (IC 50 = 13.4 μM) and cisplatin -resistant (IC 50 = 4.2 μM) HCT116 colon cancer cell lines (IC 50 = 7.6, and 22.0 μM, respectively, for cisplatin ) [6]. Apart from that, many other platinum(II) iodido complexes of various types (monofunctional [7–8], bifunctional [9–11], mixed-ligand [12–13] and multinuclear [14] complexes) showed considerable potency connected with different mechanism of action from those of the clinically used platinum-based drugs.…”