Cervical cancer is the fourth most common cancer in the world next to breast, colorectal, and lung cancers [1]. Each year, over 600,000 new cases and 300,000 deaths of cervical cancer are reported worldwide [2,3]. In recent years, developing countries have seen a rise in cervical cancer incidence, particularly among younger individuals [4,5]. It is widely held that radical surgery or radiotherapy is effective for early-stage cases, while advanced-stages cervical cancer often requires chemotherapy or radiotherapy combined with cis-platin-based treatment [6]. However, the use of cis-platin is frequently associated with nephrotoxicity, ototoxicity, neurotoxicity, drug resistance and other toxic side effects. Consequently, investigators have endeavored to discover more efficient or more discriminating chemotherapy drugs for the management of cervical cancer.

Gene-controlled apoptosis is an active mode of cell suicide that is integral to cancer therapy [7]. Chemotherapeutic drugs that inhibit the proliferation of malignant tumor cells by promoting apoptosis are one of the effective methods for cancer treatment [8,9]. Currently, there are two types of cervical cancer treatments: targeted apoptosis therapy and natural product-based drug development. Targeted apoptosis therapy work by reducing the expression level of anti-apoptotic protein and up-regulate the expression of pro-apoptotic protein, as exemplified by MiRNA373 [10] and ribonuclease binase [11]. Exploring natural products as new tumor-suppressors is another main direction of current cervical cancer drug research [12,13]. For instance, some phenolic and terpenoid complexes from Baccharis trimera have been found to be good anti-proliferative properties against SiHa cell line [14]. Semi-purified alligator flowers were reported to promote the expression of pro-apoptotic proteins in cervical cancer cells [15], However, these natural complexes have potential side effect and are difficult to extract. Therefore, there are currently limited synthetic drugs available for the treatment of cervical cancer. The current research focuses on the development of affordable drugs that are safer and more effective in treating this form of cancer [16].

Nitrogen-containing organic-metal complexes have garnered rising attention due to their ability to readily bind with biomacromolecules in the human body. As organic ligands containing multiple nitrogen, terpyridine and its derivatives show excellent potential in pharmaceutical research owing to their multi-dentate coordination properties and flatness [17]. For example, some silver-terpyridine complexes were found to have a robust inhibitory impact on the propagation of Hela cells [18]. Mechanistic studies find that some terpyridine complexes work in the treatment of cervical cancer by binding to DNA [19]. Our research group has also demonstrated that the complexes formed by different substituted terpyridines with different metals have excellent broad-spectrum anti-proliferation ability on diverse cancer cells [[20], [21], [22], [23], [24], [25], [26], [27]]. Nickel has attracted much attention because of its low price, easy availability and the better water solubility of its complexes than platinum complexes. Nickel-containing complexes such as flavonoid complexes were found to reduce the survival and expression levels of anti-apoptotic proteins and Bcl-2, thereby effectively inhibit the proliferation of Hela cell lines. We hope that the coordination of nickel and terpyridine will combine both of their advantages to develop potential candidates as anticancer drug. Herein, a series of nickel nitrate-terpyridine complexes, including [Ni(4′-phenyl-2,2′:6′,2″-terpyridine)2](NO3)2 (1), [Ni(4′-(p-methoxyl-phenyl)-2,2′:6′,2″-terpyridine)2](NO3)2 (2), [Ni(4′-(p-mesyl-phenyl)-2,2′:6′,2″-terpyridine)2](NO3)2 (3), [Ni(4′-(p-fluoro-phenyl)-2,2′:6′,2″-terpyridine)2](NO3)2 (4), [Ni(4′-(p-bromo-phenyl)-2,2′:6′,2″-terpyridine)2](NO3)2 (5), [Ni(4′-(p-iodo-phenyl)-2,2′:6′,2″-terpyridine)2](NO3)2 (6), were prepared from methanol-dichloromethane solution. Three suitable single crystals (1, 2 and 4) were obtained through solvent evaporation method. Single-crystal X-ray diffraction determination shows that they feature a coordination mode that Ni atom locates in center to connect with two terpyridine ligands and form a 1:2 coordinated molecule, and the molecules are packed together by π-π interactions. Their anti-proliferative activities on SiHa, Bel-7402, and Eca-109 indicate that they show high anti-proliferative activity. The cytotoxicity of these complexes against HL-7702 cell line shows that complex 5 can significantly inhibit the proliferation of the SiHa cell line but is less toxicity to the normal HL-7702 cell line, implying an obvious specific inhibition effect. In addition, the binding ability and binding modes of these complexes to biomacromolecules were studied by molecular docking simulation, UV–Vis spectroscopy and circular dichroism (CD).