Host-guest inclusion systems of Pt(IV)-bis(benzoato) anticancer candidates and cyclodextrins

Two small series of Pt(IV) complexes of general formula cis,cis,trans-[PtA2Cl2L2] (A = 2×NH3 or cyclohexane-1R,2R-diamine, dach; L = aromatic carboxylate of different chain length, i.e. - OCO(CH2)nC6H5, n = 0, 1, and 2) were synthesized and fully characterized (including the X-ray structure of one of them). The antiproliferative activity of the complexes was evaluated on a panel of eight cell lines (including a cisplatin-resistant and a nonmalignant cell line) and their cellular accumulation was determined in HCT 116 human colon cancer cells. In contrast with Pt(IV) complexes bearing aliphatic carboxylates where the antiproliferative potency increases as the number of carbon atoms increases as well, in the bis(benzoato) series a clear structure-activity relationship cannot be drawn, pointing out that the aromatic portion plays a role not simply predictable. In order to increase their water solubility, inclusion reactions with cyclodextrins (CDs) were attempted. Phase-solubility tests demonstrated the ability of b-CD to solubilize the [Pt(NH3)2Cl2L2] series only, offering the best result for the prototype [Pt(NH3)2Cl2(C6H5COO)2]. In the case of [Pt(dach)Cl2L2] series completely insoluble adducts were obtained. Two different ways to prepare the host-guest inclusion systems (i.e. simple solubilization at room temperature of [Pt(NH3)2Cl2(C6H5COO)2] in solution containing excess of b-CD or thermal reaction and subsequent isolation of a solid adduct) were exploited and the resulting products were tested for cytotoxicity against cancer cell lines. The presence of b-CD in solution, increasing the water solubility of [Pt(NH3)2Cl2(C6H5COO)2], does not significantly alter its antitumor activity. The solid inclusion system, albeit very soluble itself, has clearly undergone an extensive aggregation, that resulted detrimental for the Pt cellular accumulation and the overall cytotoxicity.