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. 2019, 25, 9206), 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.