Further Approaches in the Design of Antitumor Agents with Response to Cell Resistance: Looking toward Aza Crown Ether-dtc Complexes

Abstract

The dianionic aza crown ether-dtc N,N'-bis(dithiocarbamate)-1,10-diaza-18-crown-6 (L^2-) is a versatile ligand capable of yielding binuclear complexes with group 10 elements, also known as Ni-triade, [μ-(κ²-S,-S'-L)M₂(PPh₃)₄]Cl₂ (M = Pd (1), Pt (2)), [μ-(κ²-S,-S'-L)M₂(PPh₃)₄](BPh₄)₂ (M = Pd (3), Pt (4)), and μ-(κ-S,-S'-L)Ni₂(PPh₃)₂Cl₂ (5), and has proven to be an excellent option to the design of metal-based drugs able to provide multiple response to cell resistance. Palladium and platinum complexes, 1 and 2, were tested for cytotoxicity in the human cervix carcinoma cell line HeLa-229, the human ovarian carcinoma cell line A2780, and the cisplatin-resistant mutant A2780cis, finding significant activity toward all three cancer cell lines, with low micromolar IC₅₀ values, comparable to cisplatin. Markedly, against the cisplatin resistant cell line A2780cis, compound 2 exhibits better cytotoxic activity than the clinical drug (IC₅₀ = 2.3 ± 0.2 μM for 2 versus 3.6 ± 0.5 μM for cisplatin). Moreover, an enhancement of the antitumor response is achieved when adding an equimolar amount of alkali metal chloride (NaCl or KCl) to the medium, for instance, testing compound 1 against the cisplatin-resistant A2780cis cells, the IC₅₀ decreases from 9.3 ± 0.4 to 7.4 ± 0.3 and 5.4 ± 0.1 μM, respectively, after addition of the salt solution. For the platinum derivative 2, the IC₅₀ improves by ca. 40% reaching 1.3 ± 0.1 μM when potassium chloride is added. Likewise, the resistant factor found for 2 (RF = 1) confirms that this complex circumvents cisplatin-resistance in A2780cis and is improved with the addition of potassium chloride (RF = 0.65). The presence of the aza crown ether moiety as linker in the systems studied herein is a key point since, in addition to allowing and facilitating interaction with alkali metal ions, this unit is flexible enough to adapt to a variety of environments, as confirmed by the X-ray crystal structures described, where different conformations and ways to fold in are found. In order to gain insight into the electronic and structural facts involved in the interaction of complex 2 with the alkali metal ions, a DFT study was performed, and the description of the molecular electrostatic potentials (MEPs) is also presented.