title: Synthesis, characterization, and in vitro antitumor properties of tris(hydroxymethyl)phosphine copper(I) complexes containing the new bis(1,2,4-triazol-1-yl)acetate ligand.
abstract: The new sodium bis(1,2,4-triazol-1-yl)acetate ligand, Na[HC(CO(2))(tz)(2)], has been prepared in methanol solution by using 1,2,4-triazole, dibromoacetic acid, and NaOH. Treatment of the [Cu(CH(3)CN)(4)][PF(6)] acceptor with Na[HC(CO(2))(tz)(2)] or Na[HC(CO(2))[(pz(Me2))(2)] in the presence of the tris(hydroxymethyl)phosphine coligand in methanol/acetonitrile solutions produced unprecedented mononuclear copper(I) complexes of the [L(n)]Cu[P(CH(2)OH)(3)](2) (L(1), 2; L(2), 3) [(CH(3)CN)(2)Cu(P(CH(2)OH)(3))(2)]PF(6), 4. These compounds have been characterized by elemental analyses, FTIR, ESI-MS, and multinuclear (1H and 31P) NMR spectral data. The new copper(I) complexes were tested for their cytotoxic properties against a panel of several human tumor cell lines. The results reported here indicate that all the complexes showed in vitro antitumor activity similar or better than that of cisplatin, the most used metal-based antitumor drug. In particular, [HC(CO(2))(pz(Me2))(2)]Cu[P(CH(2)OH)(3)](2), 3 showed IC(50) values markedly lower than the reference compound against all tumor cell lines. Chemosensitivity tests performed on cisplatin sensitive and resistant cell lines have demonstrated that all these Cu(I) complexes were able to overcome cisplatin resistance, supporting the hypothesis of a different mechanism of action compared to that exhibited by the reference drug. Flow cytometric analysis on 2008 human ovarian carcinoma cells revealed that complex 3, chosen as the best candidate, induced a marked enlargement of both cell size and granularity, and a significant increase in the fraction of G2/M cells that, differently from cisplatin, was not accompanied by the appearance of a relevant sub-G1 fraction. Besides, no evidence of caspase-3 activation was detected in cells treated with complex 3. We hypothesize that the cytotoxic activity of the new copper(I) complex may be correlated to its ability to trigger paraptosis, a nonapoptotic mechanism of cell death.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Padova, via Marzolo 5, 35131 Padova, Italy. cristina.marzano@unipd.it
authors.forename: Cristina
authors.initials: C
authors.lastname: Marzano
authors.forename: Maura
authors.initials: M
authors.lastname: Pellei
authors.forename: Davide
authors.initials: D
authors.lastname: Colavito
authors.forename: Simone
authors.initials: S
authors.lastname: Alidori
authors.forename: Giancarlo Gioia
authors.initials: GG
authors.lastname: Lobbia
authors.forename: Valentina
authors.initials: V
authors.lastname: Gandin
authors.forename: Francesco
authors.initials: F
authors.lastname: Tisato
authors.forename: Carlo
authors.initials: C
authors.lastname: Santini
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology; D003300:Copper; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D006801:Humans; D008024:Ligands; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010720:Phosphines / Q000737:chemistry*; D012995:Solubility; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry*
chemical_list: C517226:(bis(3,5-dimethylpyrazol-1-yl)acetate)bis(tris(hydroxymethyl)phosphine)copper(I); D000970:Antineoplastic Agents; D002614:Chelating Agents; D008024:Ligands; D009942:Organometallic Compounds; D010720:Phosphines; D014230:Triazoles; D003300:Copper; D053148:Caspase 3; D002945:Cisplatin