Coinage Metal Compounds With 4-Methoxy-Diphenylphosphane Benzoate Ligand Inhibit Female Cancer Cell Growth

Lorenzo Luciani; Rossana Galassi; Junbiao Wang; Cristina Marchini; Alessia Cogo; Maria Luisa Di Paolo; Lisa Dalla Via

doi:10.3389/fchem.2022.924584

Coinage Metal Compounds With 4-Methoxy-Diphenylphosphane Benzoate Ligand Inhibit Female Cancer Cell Growth

Front Chem. 2022 Jul 13:10:924584. doi: 10.3389/fchem.2022.924584. eCollection 2022.

Authors

Lorenzo Luciani¹, Rossana Galassi¹, Junbiao Wang², Cristina Marchini², Alessia Cogo³, Maria Luisa Di Paolo⁴, Lisa Dalla Via³

Affiliations

¹ School of Science and Technology, University of Camerino, Camerino, Italy.
² School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy.
³ Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, Padova, Italy.
⁴ Dipartimento di Medicina Molecolare, Università degli Studi di Padova, Padova, Italy.

Abstract

In the continuous effort to find new metal-based compounds as alternatives to platinum-related anticancer drugs, 11^th group metal phosphane compounds have been thoroughly taken into consideration. Tris-arylphosphane metal derivatives have been extensively considered as heteroleptic metal compounds exhibiting remarkable cytotoxic activities. Functional groups in the aryl moieties modulate the activity reinforcing or eliminating it. Previous works have highlighted that the presence of hydrophilic groups in the phosphane ligands, such as COOH or OH, hampers the anticancer activity of gold azolate/PPh₃ compounds. To increase the polarity of the triarylphosphane ligand without affecting the activity, we considered the preparation of esters starting from the 4-diphenylphosphane-benzoic acid. The resulting phosphanes are poorer donators than the PPh₃, leading to poly-phosphane M(I) compounds, and they exhibit intense emissive properties. A homologous series of L₃MX-type compounds (where M = Au and X = Cl, M = Cu and X = BF₄, and M = Ag and X = PF₆) were obtained with the 4-methoxy-diphenylphosphane benzoate. The homologous metal compounds have been characterized by analytical and spectroscopic methods and, remarkably, their formation was associated with high frequencies of ³¹P NMR chemical shift variations (5-35 ppm in CDCl₃). The new complexes and the ligand were evaluated on sensitive and cisplatin-resistant human tumor cell lines. The ligand is ineffective on cells while the complexes exert a notable antiproliferative effect. The homologous series of the L₃MX complexes were able to significantly reduce the cell viability of human triple-negative breast cancer cells (MDA-MB-231), representing the most aggressive subtype of breast cancer, and of ovarian carcinoma (A2780). Among these coinage metal compounds, L₃AgPF₆ results the most interesting, showing the lowest GI₅₀ values in all cell lines. Interestingly, this silver complex is more cytotoxic than cisplatin, taken as reference drug. The investigation of the mechanism of action of L₃AgPF₆ in A2780 cells highlighted the induction of the apoptotic pathway, the depolarization of the mitochondrial inner membrane, and a significant accumulation in cells.

Keywords: antiproliferative activity; breast cancer; copper; gold; metal-based drug; ovarian cancer; phosphane; silver.