Synthesis and anticancer mechanisms of four novel platinum(II) 4'-substituted-2,2':6',2''-terpyridine complexes

Area of Science:

• Medicinal Chemistry
• Cancer Biology
• Mitochondrial Biology

Background:

• Mitophagy, the selective degradation of dysfunctional mitochondria, is a critical cellular process.
• Dysfunctional mitochondria play a role in cancer progression and drug resistance.
• Platinum(II)-based drugs are widely used in cancer chemotherapy but can exhibit toxicity and resistance.

Purpose of the Study:

• To design and synthesize novel platinum(II)-based chemotherapeutics with mitophagy-targeting properties.
• To evaluate the antitumor activity and mechanism of action of these compounds, particularly against cisplatin-resistant cancer cells.
• To assess the therapeutic efficiency and toxicity of the most promising compound in vivo.

Main Methods:

• Synthesis and characterization of four novel binuclear platinum(II) complexes with 4'-substituted-2,2':6',2''-terpyridine ligands.
• Evaluation of selective cytotoxicity against cisplatin-resistant (SKO3cisR) and sensitive (SKO3) ovarian cancer cells, and normal liver cells (HL-7702).
• Investigation of the mitophagy pathway involvement, including mitochondrial membrane potential, calcium levels, reactive oxygen species, mitochondrial DNA damage, ATP levels, and respiratory chain function.
• In vivo efficacy and toxicity studies of the lead compound (tpy1Pt).

Main Results:

• The synthesized platinum(II) complexes (tpy1Pt-tpy4Pt) demonstrated selective cytotoxicity against SKO3cisR cells compared to SKO3 and HL-7702 cells.
• Tpy1Pt and tpy2Pt were found to induce cancer cell death via mitophagy, evidenced by disrupted mitophagy protein expression, mitochondrial dysfunction, and altered cellular energetics.
• The dinuclear compound tpy1Pt exhibited significant therapeutic efficiency (approx. 52.4%) with negligible toxicity in in vivo models.

Conclusions:

• Novel platinum(II) complexes effectively target mitophagy and exhibit selective cytotoxicity against cisplatin-resistant ovarian cancer cells.
• Tpy1Pt represents a promising next-generation dinuclear platinum(II)-based anticancer drug candidate due to its potent efficacy and low toxicity.
• Targeting mitophagy offers a viable strategy for overcoming platinum resistance in cancer therapy.