New oxaliplatin-zoledronate derivatives with potential antitumor activity towards bone tumors and metastases

Abstract

Bone cancer can originate from any cellular element of the bone and may occur sporadically or as a result of degeneration from a precursor lesion. Bone metastases, often stemming from primary cancers such as breast and prostate cancer, are extremely painful and challenging to treat. The treatment of primary bone malignancies typically involves surgery, radiotherapy, chemotherapy and analgesics. Platinum (Pt)-based drugs are effective against bone cancers and metastases but are often limited by severe side effects due to poor specificity. To improve drug targeting and reduce systemic toxicity, bisphosphonate (BP) ligands, which selectively accumulate in bone tissue, have been combined with Pt-based drugs. The combination of Pt drugs with bisphosphonates like zoledronic acid (ZL) could lead to enhanced therapeutic outcomes due to its intrinsic pharmacological activity. In this study, we report the synthesis and full characterization of two new dinuclear Pt(II) complexes that combine ZL with clinically approved oxaliplatin and the drug-candidate kiteplatin, respectively. These complexes were tested for their stability under physiological and acidic conditions, reactivity with 5’-GMP interaction with B- and G-quadruplex DNA models and cytotoxicity against a panel of human tumor cell lines.