Antitumor active trans‑platinum complexes through metabolic stability and enhanced cellular accumulation

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Oncology

Background:

• Platinum-based chemotherapy, including cisplatin, remains a cornerstone in cancer treatment.
• Development of novel platinum compounds is crucial to overcome resistance and improve therapeutic outcomes.
• Trans-planar amine (TPA) platinum complexes offer an alternative structural motif for drug design.

Purpose of the Study:

• To synthesize and evaluate novel trans-planar amine (TPA) platinum carboxylate compounds with isoquinoline ligands.
• To optimize cytotoxic and metabolic efficiency by varying the leaving carboxylate group.
• To compare the pharmacological properties of TPA compounds with cisplatin.

Main Methods:

• Systematic biophysical and biological studies including substitution reactions with N-acetyl-methionine (NAM).
• Assessment of DNA structural perturbation, cytotoxicity, cellular accumulation, metabolic stability, and cell cycle effects.
• In vivo evaluation in a human ovarian cancer mouse model (A2780 cells).

Main Results:

• TPA compounds exhibited micromolar cytotoxic activity with minimal DNA binding and unaltered cell cycle.
• Reactivity trend with NAM followed: hydroxyacetate > lactate > acetate, correlating with cytotoxicity and DNA binding.
• TPA compounds demonstrated superior efficacy to cisplatin in vitro and prolonged survival in vivo.
• Significant decrease in tumor burden was observed in mice treated with TPA compounds.

Conclusions:

• The TPA platinum compounds show enhanced cellular efficacy and distinct cytotoxic profiles compared to cisplatin.
• Varying the leaving carboxylate group influences reactivity, cytotoxicity, and DNA binding.
• TPA compounds represent a promising class of non-traditional platinum drugs with potential for clinical translation.