Exploring the In Vivo and In Vitro Anticancer Activity of Rhenium Isonitrile Complexes

Abstract

The established platinum-based drugs form covalent DNA adducts to elicit their cytotoxic response. Although they are widely employed, these agents cause toxic side-effects and are susceptible to cancer-resistance mechanisms. To overcome these limitations, alternative metal complexes containing the rhenium­(I) tricarbonyl core have been explored as anticancer agents. Based on a previous study (Chem. Eur. J.2019259206), a series of highly active tricarbonyl rhenium isonitrile polypyridyl (TRIP) complexes of the general formula fac-[Re­(CO)3(NN)­(ICN)]+, where NN is a chelating diimine and ICN is an isonitrile ligand, that induce endoplasmic reticulum (ER) stress via activation of the unfolded protein response (UPR) pathway are investigated. A total of 11 of these TRIP complexes were synthesized, modifying both the equatorial polypyridyl and axial isonitrile ligands. Complexes with more electron-donating equatorial ligands were found to have greater anticancer activity, whereas the axial ICN ligands had a smaller effect on their overall potency. All 11 TRIP derivatives trigger a similar phenotype that is characterized by their abilities to induce ER stress and activate the UPR. Lastly, we explored the in vivo efficacy of one of the most potent complexes, fac-[Re­(CO)3(dmphen)­(ptolICN)]+ (TRIP-1a), where dmphen = 2,9-dimethyl-1,10-phenanthroline and ptolICN = para-tolyl isonitrile, in mice. The 99mTc congener of TRIP-1a was synthesized, and its biodistribution in BALB/c mice was investigated in comparison to the parent Re complex. The results illustrate that both complexes have similar biodistribution patterns, suggesting that 99mTc analogues of these TRIP complexes can be used as diagnostic partner agents. The in vivo antitumor activity of TRIP-1a was then investigated in NSG mice bearing A2780 ovarian cancer xenografts. When administered at a dose of 20 mg/kg twice weekly, this complex was able to inhibit tumor growth and prolong mouse survival by 150% compared to the vehicle control cohort.

Therapeutic and Diagnostic Applications of Multimetallic Rhenium(I) Tricarbonyl Complexes

“…A large library of complexes of this type was studied for their anticancer activities (16-37) (Figure 5). [41][42][43][44] An early example is a library of metallacyclophanes with ester linkages (16)(17)(18)(19)(20). Within this class of compounds, those containing longer alkyl chains exhibit higher cytotoxicity (16 < 18 < 20).…”

“…[8][9][10][11][12][13][14][15] For instance, our group has described the anticancer activity of a series of tricarbonyl rhenium isonitrile polypyridyl complex (TRIP) complexes. [16][17][18] TRIP kills cancer cells via the induction of endoplasmic reticulum (ER) stress, marking a notable divergence from the well-established DNA-binding mechanism of Pt(II) chemotherapeutics. Moreover, the rich photophysical properties of the Re(CO) 3 core have given rise to promising new photodynamic therapy (PDT) and photoactivated chemotherapy (PACT) agents, owing to their ability to generate singlet oxygen ( 1 O 2 ) and carbon monoxide (CO) upon irradiation.…”

“…With respect to their therapeutic applications, Re(CO) 3 complexes act via mechanisms of action that are significantly different from those of classical platinum‐based chemotherapeutics [8–15] . For instance, our group has described the anticancer activity of a series of tricarbonyl rhenium isonitrile polypyridyl complex (TRIP) complexes [16–18] . TRIP kills cancer cells via the induction of endoplasmic reticulum (ER) stress, marking a notable divergence from the well‐established DNA‐binding mechanism of Pt(II) chemotherapeutics.…”

ReI Tricarbonyl Complexes as Coordinate Covalent Inhibitors for the SARS‐CoV‐2 Main Cysteine Protease

“…Among the docked binding poses, the fragment with the lowest energy was found to coordinate to Cys145 and not the other surface Cys residues. Previous studies have discussed the application of Re I tricarbonyl as anticancer agents, luminescent probes, or radio‐imaging agents, suggesting the biocompatibility of such compounds [32–37] . Additional docking studies were performed with the scaffold that possessed symmetric substituents in all positions of the 2,2′‐bipyridine ligand (vide infra).…”

The effect of sodium thiosulfate on cytotoxicity of a diimine Re(i) tricarbonyl complex

“…30 Such complexes show cytotoxicity in a range of human cancer cell lines, highlighting their potential as chemotherapeutic agents. [31][32][33][34][35][36][37] The mechanism of action in which the complexes initiate cell death is not yet fully understood, although in many cases such complexes have been localized in the cytoplasm and mitochondria. 30,38 The emissive properties of rhenium-based complexes in the visible region facilitate their cellular localization with confocal and fluorescence microscopy.…”