Rational design of anticancer platinum(IV) prodrugs

Platinum-based anticancer drugs such as cisplatin play a crucial role in the treatment of various malignant tumors; however, their therapeutic effects are severely hampered by drug resistance and systemic toxicities. Recently, octahedral Pt-IV prodrugs have attracted much attention as the next generation of Pt-based anticancer drug candidates. Pt-IV complexes can be easily functionalized with some biologically innocent or active ligands to tune their pharmacological properties for overcoming the drawbacks of traditional Pt-II-based drugs. This review presents a comprehensive overview on the Pt-IV anticancer complexes that have been reported in the past decades from drug design perspectives. These complexes are classified into three categories based on their different design purposes, including to conquer cisplatin resistance, to ameliorate cisplatin toxicities, and to target tumor microenvironment. Representative examples of each type are discussed in terms of design principle, chemical structure, cytotoxicity, mechanism of action, and possible limitations in medical application. In the end, future opportunities and challenges in this field are tentatively proposed. The information and views presented in this review are suggested to help generating new ideas and strategies to design and develop novel Pt-based anticancer drugs with high efficacy and low toxicity.