Cancer incidence and mortality are rising; projections estimate 35 million new global cases by 2050 [1]. Currently, the main means of cancer treatment include surgical resection, radiotherapy, chemotherapy and immunotherapy [2]. The successful development of platinum-based anticancer agents has catalyzed the expansion of metallodrug research, with several ruthenium-based complexes advancing to clinical trials as viable candidates for next-generation metal-based anticancer therapeutics [3,4]. However, the gradual emergence of drug resistance, systemic toxicity and lack of selectivity in clinical application of platinum-based drugs, especially long-term treatment leads to attenuation of efficacy, accumulation of toxic side effects and serious adverse reactions, such as dose-dependent nephrotoxicity, neurotoxicity, vomiting, etc., which prompt the scientists to seek breakthroughs in new metal-based drugs [5,6]. By designing different organic ligands coordinating with metal ions, chemists have prepared diverse complexes with novel architectures and enhanced properties [[7], [8], [9], [10], [11]]. Studies have shown that zinc-based complexes have shown to be appealing as anticancer drugs with low toxicity by inducing apoptosis or by targeting DNA or other components in the nucleus [12]. Meanwhile, Lanthanide (III) complexes have been found to have various pharmacological effects for their interaction with DNA, especially europium(III) complexes offer unparalleled advantages in theranostics due to their ideal luminescent properties for high-contrast imaging and efficient photodynamic therapy [[13], [14], [15], [16]].

Imidazoles have been described as promising drugs due to their unique biological properties, ranging from antibacterial, antifungal, anti-Alzheimer's disease, anti-malarial, and anticancer activities [[17], [18], [19], [20]]. The unique electronic configuration of imidazoles confers robust binding interactions with transition metals and rare-earth ions, and their ability to modulate key biological pathways, including apoptosis induction, enzyme inhibition, and redox homeostasis, which establishes them as valued privileged scaffolds for rational drug design. This synergistic interplay between tunable metal-binding properties and target-specific bioactivity has broadened the horizon for precision therapeutics with enhanced tumor selectivity and resistance-overcoming potential.

As a prominent member of the Schiff base family, acylhydrazone compounds exhibit distinctive chemical characteristics primarily attributed to their -CONHN=CH- functional group. These compounds demonstrate remarkable coordination capabilities facilitated by the dual electron-donating nature of their nitrogen and oxygen atoms, which provide versatile binding sites for diverse metal ions. This arrangement facilitates the creation of hydrogen bonds, bolstering the stability of the compounds and quelling a host of physiological and chemical reactions. As a result, these compounds demonstrate notable chemotherapeutic potential with versatile biological activities, including anti-inflammatory, antimycobacterial, antimicrobial, and anticancer properties [21,22]. Acylhydrazone-based complexes have emerged as versatile platforms in pharmaceutical development, agrochemical innovation, and analytical sensing technologies, with particularly significant advancements in antitumor drug discovery. Remarkably, several derivatives have been identified as leading compounds for novel chemotherapeutic agents through preclinical studies [23,24]. These advantages promote this field to become a hot spot in the cross research of coordination chemistry and medicinal chemistry. At present, most of the synthesized complexes are small molecular compounds with good solubility, which can enter tumor cells quickly through passive diffusion. However, they are also easily pumped out by tumor cells and cannot achieve the goal of long-term treatment.

Molecules with 1D chain structure has a certain degree of aggregation, which may improve the in vivo distribution of drugs and prolong their residence time in the circulatory system, thereby enhancing therapeutic efficacy. In this paper, we designed and synthesized a new Schiff base acylhydrazone ligand N′-(5-bromo-2-hydroxybenzmethylene)-4-(1-imidazole)benzoyl hydrazide (HL) containing an ONO chelating ring at one end and an imidazolyl group at the other end coordinating with metal ions to form a chain structure. As expected, two metal complexes [ZnL(CH3OH)]·NO3 (1) and [EuL(NO3)2DMF] (2) with 1D chain structure were synthesized (Scheme 1). They were characterized by X-ray single crystal diffraction, UV spectroscopy, infrared spectroscopy, and thermogravimetric analysis. Beyond assessing the complexes' antiproliferative effects in vitro, we conducted comprehensive mechanistic studies. These investigations included wound healing assays, apoptosis analysis, reactive oxygen species measurement, and cell cycle profiling to elucidate the underlying biological mechanisms. The experimental design encompassed both functional cellular assays and detailed mechanistic exploration. Finally, a xenograft tumor nude mouse model was established to evaluate its anti-tumor effect in vivo.