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 ( <i>Chem. Eur. J.</i> 2019, 25, 9206), a series of highly active tricarbonyl rhenium isonitrile polypyridyl (TRIP) complexes of the general formula <i>fac</i>-[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, <i>fac</i>-[Re(CO)₃(dmphen)(<i>p</i>tolICN)]⁺ (<b>TRIP-1a</b>), where dmphen = 2,9-dimethyl-1,10-phenanthroline and <i>p</i>tolICN = <i>para</i>-tolyl isonitrile, in mice. The ^99mTc congener of <b>TRIP-1a</b> 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 <b>TRIP-1a</b> 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.