Multifunctional platinum(iv) complex bearing HDAC inhibitor and biotin moiety exhibits prominent cytotoxicity and tumor-targeting ability

Abstract

Despite the wide clinical use of platinum drugs in cancer treatment, their severe side effects and lack of tumor selectivity seriously limit their further clinical application. To address the limitations of the current platinum drugs, herein a multifunctional platinum(IV) compound 1 containing a histone deacetylase (HDAC) inhibitor (4-phenylbutyric acid, 4-PBA) and a tumor-targeting group (biotin) has been designed and prepared. An in vitro cytotoxicity study indicated that compound 1 exhibits comparable or superior cytotoxicity to cisplatin against the tested cancer cell lines, but greatly reduced toxicity in human normal liver LO2 cells, implying the potential tumor-targeting ability of compound 1. Molecular docking results indicate that compound 1 can effectively interact with a biotin-specific receptor (streptavidin) through its biotin moiety, enabling potential tumor-targeting capability. Further studies indicated that compound 1's cytotoxicity stems from inducing DNA damage via the mitochondrial apoptotic pathway and inhibiting HDACs. Consequently, this compound can not only take advantage of the tumor selectively of biotin to improve its tumor-targeting ability but also strengthen its anticancer activity via simultaneously targeting DNA and HDACs.