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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. 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.

SUBMITTER: Marker SC

PROVIDER: S-EPMC8114230 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Seven rhenium(I) complexes of the general formula fac-[Re(CO)3(NN)(OH2)]+ where NN = 2,2'-bipyridine (8), 4,4'-dimethyl-2,2'-bipyridine (9), 4,4'-dimethoxy-2,2'-bipyridine (10), dimethyl 2,2'-bipyridine-4,4'-dicarboxylate (11), 1,10-phenanthroline (12), 2,9-dimethyl-1,10-phenanthroline (13), or 4,7-diphenyl-1,10-phenanthroline (14), were synthesized and characterized by 1H NMR spectroscopy, IR spectroscopy, mass spectrometry, and X-ray crystallography. With the exception of 11, all complexes exhibited 50% growth inhibitory concentration (IC50) values that were less than 20 μM in HeLa cells, indicating that these compounds represent a new potential class of anticancer agents. Complexes 9, 10, and 13 were as effective in cisplatin-resistant cells as wild-type cells, signifying that they circumvent cisplatin resistance. The mechanism of action of the most potent complex, 13, was explored further by leveraging its intrinsic luminescence properties to determine its intracellular localization. These studies indicated that 13 induces cytoplasmic vacuolization that is lysosomal in nature. Additional in vitro assays indicated that 13 induces cell death without causing an increase in intracellular reactive oxygen species or depolarization of the mitochondrial membrane potential. Further studies revealed that the mode of cell death does not fall into one of the canonical categories such as apoptosis, necrosis, paraptosis, and autophagy, suggesting that a novel mode of action may be operative for this class of rhenium compounds. The in vivo biodistribution and metabolism of complex 13 and its 99mTc analogue 13* were also evaluated in naı̈ve mice. Complexes 13 and 13* exhibited comparable biodistribution profiles with both hepatic and renal excretion. High-performance liquid chromatography inductively coupled plasma mass-spectrometry (HPLC-ICP-MS) analysis of mouse blood plasma and urine postadministration showed considerable metabolic stability of 13, rendering this potent complex suitable for in vivo applications. These studies have shown the biological properties of this class of compounds and demonstrated their potential as promising theranostic anticancer agents that can circumvent cisplatin resistance.

Project description:New Re(I) carbonyl complexes are proposed as candidates for photodynamic therapy after investigating the effects of the pyridocarbazole-type ligand conjugation, addition of substituents to this ligand, and replacement of one CO by phosphines in [Re(pyridocarbazole)(CO)3(pyridine)] complexes by means of the density functional theory (DFT) and time-dependent DFT. We have found, first, that increasing the conjugation in the bidentate ligand reduces the highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) energy gap of the complex, so its absorption wavelength red-shifts. When the enlargement of this ligand is carried out by merging the electron-withdrawing 1H-pyrrole-2,5-dione heterocycle, it enhances even more the stabilization of the LUMO due to its electron-acceptor character. Second, the analysis of the shape and composition of the orbitals involved in the band of interest indicates which substituents of the bidentate ligand and which positions are optimal for reducing the HOMO-LUMO energy gap. The introduction of electron-withdrawing substituents into the pyridine ring of the pyridocarbazole ligand mainly stabilizes the LUMO, whereas the HOMO energy increases primarily when electron-donating substituents are introduced into its indole moiety. Each type of substituents results in a bathochromic shift of the lowest-lying absorption band, which is even larger if they are combined in the same complex. Finally, the removal of the π-backbonding interaction between Re and the CO trans to the monodentate pyridine when it is replaced by phosphines PMe3, 1,4-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane (DAPTA), and 1,4,7-triaza-9-phosphatricyclo[5.3.2.1]tridecane (CAP) causes another extra bathochromic shift due to the destabilization of the HOMO, which is low with DAPTA, moderate with PMe3, but especially large with CAP. Through the combination of the PMe3 or CAP ligands with adequate electron-withdrawing and/or electron-donating substituents at the pyridocarbazole ligand, we have found several complexes with significant absorption at the therapeutic window. In addition, according to our results on the singlet-triplet energy gap, all of them should be able to produce cytotoxic singlet oxygen.

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

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