Neutral and charged phosphine/scorpionate copper(I) complexes: Effects of ligand assembly on their antiproliferative activity

• Published in: European journal of medicinal chemistry 2013-01, Vol.59, p.218-226
• Main Authors: Porchia, Marina, Dolmella, Alessandro, Gandin, Valentina, Marzano, Cristina, Pellei, Maura, Peruzzo, Valentina, Refosco, Fiorenzo, Santini, Carlo, Tisato, Francesco
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; Copper - chemistry; Copper - pharmacology; Copper(I); Crystallography, X-Ray; Cytotoxic activity; Humans; Inhibitory Concentration 50; Ligands; Molecular Structure; Phosphine; Phosphines - chemistry; Phosphines - pharmacology; Scorpionates
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2012.11.022

Ligand-exchange reactions of copper(I) precursors ([Cu(CH3CN)4]BF4, CuCl) with a panel of bis(azolyl)borates or poly(pyrazolyl)methanes and a tertiary monodentate phosphine (PTA = 1,3,5-triaza-7-phosphaadamantane, PCN = tris(cyanoethyl)phosphine) produced two series of heteroleptic, either ‘2 + 1 + 1’- or ‘3 + 1’-type complexes, which have been characterized by elemental analysis, FT-IR, ESI-MS and multinuclear 31P and 1H NMR. ‘2 + 1 + 1’-type complexes include a N,N-bidentate chelate and two monodentate phosphines (1–8) and ‘3 + 1’-type complexes comprise a N,N,O- or N,N,N-tridentate chelate and one monodentate phosphine (9–12). All these complexes adopt a four-coordinate, tetrahedral geometry. ‘3 + 1’ complexes show better red-ox stability and a greater tendency to retain the native ‘3 + 1’ mixed-ligand structure. Conversely, ‘2 + 1 + 1’ complexes exhibit increased propensity to dissociation as shown by ESI-MS measurements and X-ray structure determination at low temperature (150 K) of the polymeric complex {[H2B(tzNO2)2]Cu[PCN]}n6b. In this complex, either the bis(triazolyl)borate and the PCN ligands act as bidentate, with PCN being also the μ2–bridiging linker between adjacent monomers. Compound 6b is the first reported example of a polymeric PCN compound with a tetra-coordinate metal centre. Cytotoxic activity of all compounds has been evaluated by MTT test against a panel of several human tumor cell lines including examples of breast (MCF-7), colon (HCT-15 and LoVo), lung (A549), cervix (A431) and ovarian (2008 and its cisplatin resistant variant, C13*) carcinoma, melanoma (A375) and promyelocytic leukemia (HL60). Copper complexes generally show in vitro antitumour activity comparable to that of cisplatin. In particular, neutral ‘3 + 1’-type complexes 9 and 10, show IC50 values appreciably lower than those exhibited by the reference metallodrug. Copper(I) complexes comprising monodentate phosphines and a bi- or a tridentate scorpionate ligand show antiproliferative activity depending on their coordination sphere and overall charge. (Compound 10 mean IC50 2.4 μM). [Display omitted] ► Cu(I) complexes containing monodentate phosphine and a bi- or a tridentate scorpionate ligand are reported. ► Novel Cu(I) complexes showed antiproliferative activity. ► Cytotoxicity was related to coordination sphere and to overall charge of the complexes. ► Neutral ‘3 + 1’ complexes demonstrated to be the most active (average IC50 4.3 μM). ► Phosphine loss from a ‘2 + 1