金が化学療法薬としてプラチナに勝るという新しい研究結果が発表された(Gold beats platinum for chemo drugs in new lab study)

2024-11-28 ロイヤルメルボルン工科大学(RMIT)

<関連情報>

• https://www.rmit.edu.au/news/all-news/2024/nov/gold-cancer
• https://www.sciencedirect.com/science/article/abs/pii/S0223523424008894

AuL{κC-2-C6H4P(S)Ph2}] [L = PTA, PPh3, PPh2(C6H4-3-SO3Na) and PPh2(2-py)]タイプの金(I)錯体: 合成、キャラクタリゼーション、結晶構造、インビトロおよびインビボ抗がん特性 Gold(I) complexes 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
European Journal of Medicinal Chemistry  Available online: 30 October 2024
DOI:https://doi.org/10.1016/j.ejmech.2024.117007

Graphical abstract

Highlights

• Successfully synthesised four gold(I) complexes with diverse organophosphine ligands.
• Complex 1, exhibited selective and superior potency against cervical cancer cells.
• Complex 1 inhibited thioredoxin reductase, leading to ROS accumulation, cell cycle arrest, and apoptosis.
• Complex 1 demonstrated substantial antiangiogenic effects in zebrafish embryos.
• In a mouse cervical cancer xenograft model, complex 1 outperformed cisplatin (82 % inhibition vs. 29 %).

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.