Gold(I) somplexes of the type [AuL{κC-2-C6H4P(S)Ph2}] [L = PTA, PPh3, PPh2(C6H4-3-SO3Na) and PPh2(2-py)]: Synthesis, characterisation, crystal structures, and In Vitro and In Vivo anticancer properties

T Srinivasa Reddy; Steven H Privér; Ruchika Ojha; Nedaossadat Mirzadeh; Ganga Reddy Velma; Ranjithkumar Jakku; Tayebeh Hosseinnejad; Rodney Luwor; Sistla Ramakrishna; Donald Wlodkowic; Magdalena Plebanski; Suresh K Bhargava

doi:10.1016/j.ejmech.2024.117007

Gold(I) somplexes of the type [AuL{κC-2-C₆H₄P(S)Ph₂}] [L = PTA, PPh₃, PPh₂(C₆H₄-3-SO₃Na) and PPh₂(2-py)]: Synthesis, characterisation, crystal structures, and In Vitro and In Vivo anticancer properties

Eur J Med Chem. 2024 Oct 30:281:117007. doi: 10.1016/j.ejmech.2024.117007. Online ahead of print.

Affiliations

¹ School of Health and Biomedical Sciences, STEM College, RMIT University, Bundoora, Victoria, 3083, Australia.
² School of Science, STEM College, RMIT University, Melbourne, Victoria, 3001, Australia.
³ Department of Surgery, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, 3050, Australia.
⁴ Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India.
⁵ The Neurotox Laboratory, School of Science, RMIT University, Bundoora, Victoria, 3083, Australia.
⁶ School of Health and Biomedical Sciences, STEM College, RMIT University, Bundoora, Victoria, 3083, Australia. Electronic address: magdalena.plebanski@rmit.edu.au.
⁷ School of Science, STEM College, RMIT University, Melbourne, Victoria, 3001, Australia. Electronic address: suresh.bhargava@rmit.edu.au.

PMID: 39500067
DOI: 10.1016/j.ejmech.2024.117007

Abstract

Four new mononuclear gold (I) compounds of the type [AuL{κC-2-C₆H₄P(S)Ph₂}] {L = PTA (1), PPh₃ (2), PPh₂(C₆H₄-3-SO₃Na) (3), and PPh₂(2-py) (4)} were prepared by scission of the dinuclear compound [Au₂{μ-2-C₆H₄P(S)Ph₂}₂] by L or via a transmetalation reaction using the organotin reagent 2-Me₃SnC₆H₄P(S)Ph₂ and a suitable gold halide precursor. The cytotoxic potential of complexes 1-4 was evaluated against four human cancer cell lines of diverse cellular origin: cervical (HeLa), prostate (PC-3), non-small cell lung adenocarcinoma (A549), and fibrosarcoma (HT-1080). The in vitro cytotoxicity results showed that 1 demonstrated exceptional anticancer activity with IC₅₀ values ranging from 0.08 to 3.5 μM. Complex 3, which contains a sulfonated triphenyl phosphine ligand, displayed the weakest anticancer activity with IC₅₀ values ranging from 3.1 to >50 μM. When compared to the standard chemotherapeutic drug cisplatin, 1 displayed approximately 27-fold greater cytotoxic activity against cervical cancer cells and 3.5- and 7.5-fold greater activities against prostate and fibrosarcoma cancer cells, respectively. Additionally, 1 exhibited 3-fold selectivity for cervical cancer cells compared to non-cancerous HEK-293 cells. Mechanistic investigations revealed that 1 induced apoptosis, which was associated with elevated reactive oxygen species (ROS) and inhibition of the intracellular enzyme thioredoxin reductase. Furthermore, 1 exhibited notable antiangiogenic characteristics in an in vivo model using transgenic zebrafish Tg(fli1a:EGFP). In vivo studies using mouse xenograft models showed that complex 1 displayed superior inhibition of tumour growth (82 %) compared to the clinical drug cisplatin (29 %). Overall, these results highlight the potential of gold (I) compounds as novel antitumour agents.

Keywords: Anticancer activity; Apoptosis; Gold (I) complexes; Organophosphine ligands; Thioredoxin reductase.