Novel Silver Complexes Based on Phosphanes and Ester Derivatives of Bis(pyrazol-1-yl)acetate Ligands Targeting TrxR: New Promising Chemotherapeutic Tools Relevant to SCLC Management

Maura Pellei; Carlo Santini; Luca Bagnarelli; Miriam Caviglia; Paolo Sgarbossa; Michele De Franco; Mirella Zancato; Cristina Marzano; Valentina Gandin

doi:10.3390/ijms24044091

Novel Silver Complexes Based on Phosphanes and Ester Derivatives of Bis(pyrazol-1-yl)acetate Ligands Targeting TrxR: New Promising Chemotherapeutic Tools Relevant to SCLC Management

Int J Mol Sci. 2023 Feb 17;24(4):4091. doi: 10.3390/ijms24044091.

Authors

Maura Pellei¹, Carlo Santini¹, Luca Bagnarelli¹, Miriam Caviglia¹, Paolo Sgarbossa², Michele De Franco³, Mirella Zancato³, Cristina Marzano³, Valentina Gandin³

Affiliations

¹ School of Science and Technology, Chemistry Division, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
² Department of Industrial Engineering, University of Padova, Via Marzolo 9, 35131 Padova, Italy.
³ Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, 35131 Padova, Italy.

Abstract

Bis(pyrazol-1-yl)acetic acid (HC(pz)₂COOH) and bis(3,5-dimethyl-pyrazol-1-yl)acetic acid (HC(pz^Me2)₂COOH) were converted into the methyl ester derivatives 1 (L^OMe) and 2 (L^2OMe), respectively, and were used for the preparation of silver(I) complexes 3-5. The Ag(I) complexes were prepared by the reaction of AgNO₃ and 1,3,5-triaza-7-phosphaadamantane (PTA) or triphenylphosphine (PPh₃) with L^OMe and L^2OMe in methanol solution. All Ag(I) complexes showed a significant in vitro antitumor activity, proving to be more effective than the reference drug cisplatin in the in-house human cancer cell line panel containing examples of different solid tumors. Compounds were particularly effective against the highly aggressive and intrinsically resistant human small-cell lung carcinoma (SCLC) cells, either in 2D and 3D cancer cell models. Mechanistic studies revealed their ability to accumulate into cancer cells and to selectively target Thioredoxin (TrxR), thus leading to redox homeostasis unbalance and ultimately inducing cancer cell death through apoptosis.

Keywords: TrxR; anticancer activity; bis(pyrazolyl)acetate ligands; oxidative stress; silver.

MeSH terms

Acetates
Antineoplastic Agents* / pharmacology
Coordination Complexes* / pharmacology
Humans
Ligands
Silver
Thioredoxins

Substances

phosphine
Silver
Ligands
Acetates
Thioredoxins
Antineoplastic Agents
Coordination Complexes

Grants and funding

This work was supported by Unione Europea—NextGenerationEU, “MUR-Fondo Promozione e Sviluppo—D.M. 737/2021, An innovative platform against SARS-CoV-2 and other emerging viruses grounded on copper-based materials (INVIRCuM)” (University of Camerino, FAR 2022 PNR) and the University of Padova (PRID BIRD225980). We are grateful to CIRCMSB (Consorzio Interuniversitario di Ricerca in Chimica dei Metalli nei Sistemi Biologici).