Thiosemicarbazones are compounds characterized by a broad range of biological activities, with a particular relevance for their anticancer potential[1]. In this study, we synthesized a thiosemicarbazone bearing a carboxy group to improve its aqueous solubility and enable bioconjugation with peptides, thereby enhancing selectivity toward cancer cells. The anticancer activity of thiosemicarbazones is closely related to their ability to modulate reactive oxygen species (ROS), chemically reactive molecules generated during cellular metabolism, especially as byproducts of aerobic respiration. Although ROS play essential physiological roles, excessive ROS accumulation can trigger cellular apoptosis, and despite being extensively investigated, remains a promising strategy for cancer therapy[2]. On this basis, we synthesized a metal complex with copper(II) with our bioconjugable thiosemicarbazone. The ligand was prepared starting from 4-aminobenzoic acid, with the thiosemicarbazide as intermediate (also characterized by SC-XRD). Since the use of trifluoroacetic acid is a common cleavage method in peptide synthesis, a study of its stability in the presence of trifluoroacetic acid was carried out. The metal complex is characterized by IR, ESI-MS, elemental analysis, UV-Vis studies (Titrations, Job Plot, Stability in 24 hours), CV, EPR, DLS. We also performed DFT studies on the geometry of the metal center. Eventually, we performed UV-Vis studies of interactions with ROS (DPPH, H2O2, OH.-) and with biomolecules (DNA, albumin) via circular dichroism and fluorescence spectroscopy. Cytotoxic assays on cancer cell lines HT29 and A549 showed a remarkable activity of the metal complex, supporting the high potential of this compound for antitumoral application. [1] X-G. Bai et al., Frontiers in Pharmacology, 2022, 13, 1018951. [2] C. Glorieux et al., Nat Rev Drug Discov 2024, 23, 583–606.
Design and Antitumoral Evaluation of a Bioconjugable Copper(II)-Thiosemicarbazone Complex: ROS Targeting and Cytotoxicity in HT29 and A549 Cell Lines / Squadrini, A., Verderi, L., Pinelli, S., Mozzoni, P., Saponara, V., Cenci, G., Fortunati, S., Giannetto, M., Lajnef, S., Peyrot, F., Diaz, J., Policar, C., Pelosi, G., Bisceglie, F.. - (2026). (ItaBIC 26 ).
Design and Antitumoral Evaluation of a Bioconjugable Copper(II)-Thiosemicarbazone Complex: ROS Targeting and Cytotoxicity in HT29 and A549 Cell Lines
Attilio Squadrini;Lorenzo Verderi;Silvana Pinelli;Paola Mozzoni;Veronica Saponara;Gloria Cenci;Simone Fortunati;Marco Giannetto;Giorgio Pelosi;Franco Bisceglie
2026-01-01
Abstract
Thiosemicarbazones are compounds characterized by a broad range of biological activities, with a particular relevance for their anticancer potential[1]. In this study, we synthesized a thiosemicarbazone bearing a carboxy group to improve its aqueous solubility and enable bioconjugation with peptides, thereby enhancing selectivity toward cancer cells. The anticancer activity of thiosemicarbazones is closely related to their ability to modulate reactive oxygen species (ROS), chemically reactive molecules generated during cellular metabolism, especially as byproducts of aerobic respiration. Although ROS play essential physiological roles, excessive ROS accumulation can trigger cellular apoptosis, and despite being extensively investigated, remains a promising strategy for cancer therapy[2]. On this basis, we synthesized a metal complex with copper(II) with our bioconjugable thiosemicarbazone. The ligand was prepared starting from 4-aminobenzoic acid, with the thiosemicarbazide as intermediate (also characterized by SC-XRD). Since the use of trifluoroacetic acid is a common cleavage method in peptide synthesis, a study of its stability in the presence of trifluoroacetic acid was carried out. The metal complex is characterized by IR, ESI-MS, elemental analysis, UV-Vis studies (Titrations, Job Plot, Stability in 24 hours), CV, EPR, DLS. We also performed DFT studies on the geometry of the metal center. Eventually, we performed UV-Vis studies of interactions with ROS (DPPH, H2O2, OH.-) and with biomolecules (DNA, albumin) via circular dichroism and fluorescence spectroscopy. Cytotoxic assays on cancer cell lines HT29 and A549 showed a remarkable activity of the metal complex, supporting the high potential of this compound for antitumoral application. [1] X-G. Bai et al., Frontiers in Pharmacology, 2022, 13, 1018951. [2] C. Glorieux et al., Nat Rev Drug Discov 2024, 23, 583–606.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
