A Non-Metallic DNA Intercalator from Pyronine-Aloperine Conjugation Reverses Cisplatin Resistance in Ovarian Cancer

Abstract

Cisplatin (DDP) resistance remains a key factor contributing to the high mortality rate among ovarian cancer patients. The Pt(II)−DNA covalent adduct is prone to removal through changes in gene expression in tumor cells, resulting in DDP resistance. To address this challenge, developing a non-metallic DNA intercalator is crucial. In this study, we incorporate the alkaloid aloperine (Alo) into a traditional RNA-binding agent, pyronine (PY), yielding a pyronine−aloperine conjugate (PY−Alo) as a nucleus-targeted DNA intercalator. In the PY−Alo structure, the PY scaffold intercalates between DNA base pairs, and the bridged nitrogen atom in the Alo moiety forms an additional hydrogen bond with DNA bases. PY−Alo can induce synergistic apoptosis and autophagy in A2780/DDP cells. In vivo evaluations demonstrate that PY−Alo significantly inhibits the progression of cisplatin-resistant ovarian cancer, with favorable biosafety. This study also illustrates a feasible strategy for converting a natural alkaloid into a DNA intercalator as a chemotherapeutic agent.