Transition metals have major advantages over organic compounds for the development of new therapeutic drugs, including varying geometries, coordination numbers, oxidation states, and thermodynamic–kinetic characteristics [[1], [2], [3]]. Metal complexes may be used as scaffolds, and a desired therapeutic value can be obtained by incorporating different metal ions and active organic ligands. In vivo, metal ions exist in the form of electron-deficient cations and are readily linked to biological targets of electron-rich biomolecules, such as proteins and DNA, through noncovalent interactions [3,4]. In the 1960s, cisplatin was accidently discovered and demonstrated to possess potent anticancer properties [1,5]. Since then, metal-based chemotherapeutic drugs have gained widespread attention from chemists. Although the rhodium (Rh)(III) center is kinetically inert, a few studies have examined its biological effects [6]. Recent studies have indicated that the incorporation of appropriate ligands increases the reactivity of Rh complexes toward biological targets [6]. These complexes exhibit promising anticancer activity and distinct mechanisms of action (MoAs) compared with platinum drugs. For example, several Rh(III) complexes inhibit cell proliferation through various mechanisms, such as mitochondrial dysfunction, autophagy, or immunological pathways [[6], [7], [8], [9], [10], [11], [12], [13]]. Rh-based anticancer complexes can be categorized into two types based on their structure: half-sandwich complexes and cyclometalate complexes [14]. Notably, Guo et al. synthesized a series of organometallic half-sandwich Rh(III) complexes with the structural formula [(η6-arene)/(η5-Cp*)Rh(XY)Cl]0/+ (Cp*: C5(CH3)5; XY: bidentate chelating ligands), which resulted in cell cycle arrest, disruption of lysosomal integrity [15], and generation of reactive oxygen species (ROS) [12,16].

A survey by Njardarson revealed that nitrogen heterocycles account for 59 % of the small molecule drugs approved by the FDA in 2014 [17], with each drug containing at least one nitrogen heterocycle. The compound 8-hydroxyquinoline (8-OHQ) contains a pyridine ring that provides an N-donor ligand fused with a phenol, which further provides an O-donor ligand; 8-OHQ is the backbone of drugs that form (N, O) five-membered chelate rings with metal ions [[18], [19], [20]]. Derivatives of 8-OHQ exhibit biological activity in several diseases (e.g., 5-nitro-8-OHQ for infectious diseases and 5-chloro-7-iodo-8-OHQ for neuropathies) [[18], [19], [20]]. Recently, many novel quinoline metal complexes, which have shown promising anticancer activity in vitro and in vivo, have been reported, including ruthenium(II) [[21], [22], [23], [24]], copper(II) [[25], [26], [27]], cobalt(II) [25,28], nickel(II) [25,29], zinc(II) [26,30], lanthanide(III) [31], iron(III) [32], platinum(II) [33], vanadium(IV) [34], and Rh(III) [8,[35], [36], [37], [38]] complexes. Enyedy reported the activity of 8-OHQ–amino acid hybrids and their [Rh(η5-C5Me5) (H2O)3]2+ complexes, which exhibited high stability and were more effective in treating drug-resistant Colo 320 cells than drug-sensitive Colo 205 cells [35]. Moreover, they interacted with calf thymus DNA (ct-DNA) as well as human serum albumin, but DNA cleavage was not observed [36]. In addition, Chen and Liang synthesized the novel 8-OHQ–Rh complex and found that the unsubstituted and methyl-substituted 8-OHQ–Rh(III) complex can induce tumor cell death by disrupting mitochondrial-related mechanisms [37,38]; however, the specific underlying MoAs remain unknown.

Compounds conjugated to lipophilic cations, such as triphenylphosphine (Ph3P+, TPP), can accumulate in the mitochondria driven by plasma membrane potential (Δψp) and mitochondrial membrane potential (Δψm) [[39], [40], [41], [42]]. Thus, TPP has been used as a mitochondrial targeting moiety. In this study, we synthesized and characterized four mitochondria-targeting Rh(III) complexes: [Rh(XR1)2(TPP)Cl]·(TPP=O) (YNU-1a), [Rh(XR2)2(TPP)Cl] (YNU-1b), [Rh(XR3)2(TPP)Cl] (YNU-1c), and [Rh(XR4)2(TPP)Cl] (YNU-1d), bearing 2-methylquinolin-8-ol (H-XR1), 5,7-dichloro-8-OHQ (H-XR2), 5,7-dichloro-2-methyl-8-OHQ (H-XR3), 2-methyl-5,7-dibromo-quinoline-8-ol (H-XR4), and (TPP)3RhCl. The anti-proliferative activities of these complexes on Hep-G2 and HCC1806 tumor cells and human normal liver HL-7702 cells were evaluated via the MTT assay, and a series of in vitro and in vivo experiments were performed using YNU-1a–YNU-1d compounds with promising activity.