Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths in the world [1]. The HCC incidence is the highest among all cancer types, and about half a million people are diagnosed with this disease annually [2]. Surgery, chemotherapy, and radiotherapy are currently the main clinical treatments for HCC patients. In spite of advancements in the current therapeutics, the prognosis of advanced HCC remains poor, and its 5-year survival rate is only about 18% [3]. Therefore, there is an exigent need to search for new and more effective chemotherapy drugs for HCC treatment.

Platinum-based drugs, including cisplatin, oxaliplatin, and carboplatin, have been administered in single or combination regimens used for the treatment of several solid tumors, including HCC [[4], [5], [6]]. Platinum-base drugs exert anticancer effects via multiple mechanisms, and yet their most prominent mode of action involves their interaction with genomic DNA to form platinum-DNA adducts, primarily intra-strand cross-link adducts, which activate several signal transduction pathways and culminate in the activation of apoptosis [7]. However severe toxic and side effects and acquired/intrinsic resistance seriously limit the clinical effect of platinum-based drugs in the treatment of patients with HCC [8,9]. One such kind of resistance happens because of the nucleotide excision repair (NER) mechanism, which works in nuclear DNA [10].

To overcome the deficiencies and increase the efficacy, many non-classical platinum antitumor complexes with novel mechanism of action have been reported [[11], [12], [13]]. Among them, monofunctional platinum(II) complexes have attracted much attention [[14], [15], [16]]. Unlike classical bifunctional platinum(II) drugs, the class of platinum complexes can only bind to DNA via one ligating site. Such the Pt-DNA monofunctional adducts do not greatly distort the DNA structure and they are less recognized by the NER mechanism [17]. Moreover, recent studies have reported monofunctional platinum complexes can act on other cellular targets beyond genomic DNA within a cancer cell, such as mitochondria, overexpressed receptors or protein and enzymes, which will lead to different cellular responses in favor of circumventing the drug resistance or side effects [12,18,19]. For example, Mao group developed a monofunctional platinum(II) complex featuring lonidamine as an inhibitor of mitochondrial hexokinase, which has demonstrated potent anticancer activities and good selectivity for cancerous cells over healthy ones [20]. The complex mainly located in mitochondria, caused apoptosis through a mitochondrial-dependent pathway, and also perturbed cell death associated signal pathways such as DNA damage, metabolic process, and transcription regulator activity [20]. Guo group constructed a series of mitochondria-targeting monofunctional platinum(II) complexes based on triphenylphosphonium (TPP) and these complexes have demonstrated superior anticancer activities by disrupting the mitochondrial membrane potential (MMP), damaging both nuclear and mitochondrial DNA and perturbing the bioenergetics pathways [21,22]. Another cationic monofunctional platinum(II) complex based on the DNA-intercalating moiety N-(2-ethylpyridine)-1,8-naphthalimide, which targeted both nuclear and mitochondrial DNA, exhibited higher in vitro and in vivo antitumor activities with lower systemic toxicity than cisplatin [23]. Such a class of complexes can be achieved by incorporating targeting moieties or biologically active carrier groups into the tridentate “platin” frameworks. Our group has a long-term interest in developing the class of platinum complexes [[24], [25], [26], [27]]. A series of mononuclear platinum(II) complexes have been constructed by tethering some pharmacophores or functional groups, such as thioflavin-T (ThT), benzothiazole, dansyl moiety, benzoxazole, et al., to the different tridentate chelating PtII centers. These complexes could bind to DNA through multiple binding modes involving non-covalent interaction and monofunctional platination, induce the conformational change of DNA, and exhibit potent anticancer activities against some human cancer cell lines. Nevertheless, the cellular actions of these complexes are still not clear. It is valuable for studying the cellular mechanism of anticancer monofunctional platinum(II) compounds. In this study, we continued to tether the benzothiazole derivative 2-(4-aminophenyl)benzothiazole to an N,N,O-tridentate chelating PtII center to form a novel mononuclear platinum complex [Pt(L-H)Cl] (1, Scheme 1). We investigated the antiproliferative activities in vitro of the complex against a panel of human cancer cell lines including the human cervical cancer HeLa, the human non-small-cell lung cancer A549, the human breast cancer MCF-7, the human liver cancer HepG-2 and SMMC-7221, and the human normal liver L02 cell lines. The result demonstrated the complex possessed the highest antiproliferative activity against the human liver cancer HepG-2 and SMMC-7221, and lower effect in normal liver cells. The underlying antitumor mechanism of 1 was also further explored.