Organotin(IV) Compounds with Potent Cytotoxicity, DNA Damage, Cell Cycle Arrest, and Pro-Apoptotic Effects

Abstract

Platinum-based anticancer agents exert their activity through DNA cross-linking but are limited by systemic toxicity, poor selectivity, and the emergence of drug resistance, underscoring the need for alternative mechanisms of action. We have selected organotin(IV) center with intrinsic cytotoxic potential and combined it with multifunctional ligands containing functional moieties that could enhance the anticancer efficacy, and synthesised two organotin(IV) complexes, Bu₂SnL and Ph₂SnL (L= Benzyl 2-(Diphenylphosphoryl)hydrazine-1-carbodithioate), to explore a non-cross-linking DNA-damaging strategy. Cellular uptake studies revealed substantial intracellular accumulation of both complexes, with preferential nuclear localization. In vitro cytotoxicity assays demonstrated potent antiproliferative activity against breast cancer T-47D cells, with Bu₂SnL exhibiting an IC₅₀ value of 0.32 ± 0.04 μM, representing an ≈88-fold increase in potency relative to cisplatin. Mechanistic investigations indicated that these complexes induce pronounced DNA damage, G1-phase cell cycle arrest, and intracellular ATP depletion, ultimately leading to apoptotic cell death. The DNA interaction studies suggest the possibility of a distinct binding mode compared to cisplatin, and we propose that the complex is coordinating to phosphate groups rather than nucleobase cross-linking. These findings indicate that organotin(IV) complexes are promising anticancer candidates that may offer a different mechanism of action, potentially overcoming the limitations of cisplatin.