Background & Aims: Patients with cholangiocarcinoma (CCA) have poor prognosis. Current first-line chemotherapy, including Cisplatin and Gemcitabine, provides limited survival benefits due to the development of chemoresistance. Cisplatin induces single-strand DNA breaks, activating DNA repair mechanisms that diminish its effectiveness. In this study, we present the design, chemical synthesis, and therapeutic evaluation of a new generation of chemotherapeutic agents with unique polyelectrophilic properties, capable of inducing high frequency of double-strand DNA breaks, thereby inhibiting DNA repair and promoting cancer cell death. Methods: Two novel compounds, Aurkine 16 and Aurkine 18, were designed and evaluated for their antitumour effects in both naïve and Cisplatin-resistant CCA cells, cancer-associated fibroblasts (CAFs), healthy cholangiocytes, and xenograft models. Results: Aurkines effectively induced double-strand DNA breaks, leading to increased DNA damage and elevated levels of reactive oxygen species, resulting in greater cytotoxicity compared to Cisplatin in CCA cells. Unlike Cisplatin, Aurkines did not activate key proteins involved in single-strand DNA repair, such as ATR and CHK1 phosphorylation. Importantly, these compounds also triggered apoptosis in Cisplatin-resistant CCA cells and CAFs without harming healthy cholangiocytes. Additionally, Aurkines demonstrated cytotoxicity in other Cisplatin-resistant cancers, such as breast and ovarian cancer. This selective action against malignant cells was attributed to differences in histone deacetylase (HDAC)-dependent DNA packaging between normal and cancer cells. In vivo, Aurkines inhibited the growth of both naïve and Cisplatin-resistant CCA tumours without adverse effects. Transport studies revealed that Aurkines were selectively taken up by transport proteins OCT1, OCT3, CTR1, and OATP1A2, whereas Cisplatin only modestly utilizes CTR1.