Background: Many rhenium (Re) complexes with potential anticancer properties have been synthesized in the recent years with the aim to overcome the clinical limitations of platinum agents. Re(I) tricarbonyl complexes are the most common but Re compounds with higher oxidation states have also been investigated, as well as hetero-metallic complexes and Re-loaded self-assembling devices. Many of these compounds display promising cytotoxic and phototoxic properties against malignant cells but all Re compounds are still at the stage of preclinical studies. Methods: The present review focused on the rhenium based cancer drugs that were in preclinical and clinical trials were examined critically. The detailed targeted interactions and experimental evidences of Re compounds reported by the patentable and non-patentable research findings used to write this review. Results: In the present review, we described the most recent and promising rhenium compounds focusing on their potential mechanism of action including, phototoxicity, DNA binding, mitochondrial effects, oxidative stress regulation or enzyme inhibition. Many ligands have been described that modulating the lipophilicity, the luminescent properties, the cellular uptake, the biodistribution, and the cytotoxicity, the pharmacological and toxicological profile. Conclusion: Re-based anticancer drugs can also be used in targeted therapies by coupling to a variety of biologically relevant targeting molecules. On the other hand, combination with conventional cytotoxic molecules, such as doxorubicin, allowed to take into profit the targeting properties of Re for example toward mitochondria. Through the example of the diseleno-Re complex, we showed that the main target could be the oxidative status, with a down-stream regulation of signaling pathways, and further on selective cell death of cancer cells versus normal cells.

Hetero-topic self-assembly of Re₂(CO)₁₀ with oxamide ligands and ester-functionalised flexible ditopic-tectons afforded dinuclear metallacycles resembling a stirrup. The metallastirrups showed promising cytotoxic activity against few cancer cell lines in vitro.

Six mononuclear copper(II), nickel(II) and zinc(II) complexes, [ML¹Cl₂] (1–3) and [M(L²)₂Cl₂] (4–6), of two biologically active tetrazolo[1,5-a]pyrimidine core ligands, ethyl 5-methyl-7-pyridine-2-yl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate (L¹) and ethyl-5-methyl-7-pyridine-4-yl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate (L²), have been synthesized and characterized. The molecular structure of the ligands (L^1&2) and complex 6 were determined by single crystal X-ray diffraction. The X-ray crystal structure of 6 confirms that it has a distorted tetrahedral structure with a ZnN₂Cl₂ coordination environment. All of the complexes exhibit an unusually strong luminescence at room temperature. Electroparamagnetic resonance spectra of copper(II) complexes (2 and 5) show four lines, characteristic of square planar geometry, with nuclear hyperfine spin 3/2. DNA binding studies of complexes with calf-thymus DNA suggest that complexes 2 and 5 bind in the grooves of the DNA. These results were further supported by molecular docking studies. In vitro cytotoxic activities of the ligands (L^1&2) and complexes (1–6) against human cancer cell lines such as lung (A549), cervical (HeLa), colon (HCT-15) and a non-cancer human embryonic kidney cell line revealed that the complexes selectively inhibit the growth of cancer cells and are inactive against non-cancer cell lines, whereas the ligands were found to be inactive with both cancer and non-cancer cell lines. The IC₅₀ values of the complexes revealed that the copper(II) complexes (2 and 5) exhibit high cytotoxic activity against colon (HCT-15) cells when compared to the standard drug cisplatin. Furthermore, the live cell and fluorescent imaging of cancer cells show that complexes 2 and 5 induce cell death through apoptosis.