Dataset Information

Systematically altering the lipophilicity of rhenium(I) tricarbonyl anticancer agents to tune the rate at which they induce cell death.

ABSTRACT: Rhenium-based anticancer agents have arisen as promising alternatives to conventional platinum-based drugs. Based on previous studies demonstrating how increasing lipophilicity improves drug uptake within the cell, we sought to investigate the effects of lipophilicity on the anticancer activity of a series of six rhenium(i) tricarbonyl complexes. These six rhenium(i) tricarbonyl structures, called Re-Chains, bear pyridyl imine ligands with different alkyl chains ranging in length from two to twelve carbons. The cytotoxicities of these compounds were measured in HeLa cells. At long timepoints (48 h), all compounds are equally cytotoxic. At shorter time points, however, the compounds with longer alkyl chains are significantly more active than those with smaller chains. Cellular uptake studies of these compounds show that they are taken up via both passive and active pathways. Collectively, these studies show how lipophilicity affects the rate at which these Re compounds induce their biological activities.

SUBMITTER: Konkankit CC

PROVIDER: S-EPMC8108609 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Systematically altering the lipophilicity of rhenium(I) tricarbonyl anticancer agents to tune the rate at which they induce cell death.

Konkankit Chilaluck C CC Vaughn Brett A BA Huang Zhouyang Z Boros Eszter E Wilson Justin J JJ

Dalton transactions (Cambridge, England : 2003) 20201101 45

Rhenium-based anticancer agents have arisen as promising alternatives to conventional platinum-based drugs. Based on previous studies demonstrating how increasing lipophilicity improves drug uptake within the cell, we sought to investigate the effects of lipophilicity on the anticancer activity of a series of six rhenium(i) tricarbonyl complexes. These six rhenium(i) tricarbonyl structures, called Re-Chains, bear pyridyl imine ligands with different alkyl chains ranging in length from two to twe ...[more]

PMID: 32319485

Similar Datasets

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:The excellent π-accepting azodicarboxylic esters adcOR (R = Et, iPr, tBu, Bn (CH2-C6H5) and Ph) and the piperidinyl amide derivative adcpip were used as bridging chelate ligands in dinuclear Re(CO)3 complexes [{Re(CO)3Cl}2(µ-adcOR)] and [{Re(CO)3Cl}2(µ-adcpip)]. From the adcpip ligand the mononuclear derivatives [Re(CO)3Cl(adcpip)] and [Re(CO)3(PPh3)(µ-adcpip)]Cl were also obtained. Optimised geometries from density functional theory (DFT) calculations show syn and anti isomers for the dinuclear fac-Re(CO)3 complexes at slightly different energies but they were not distinguishable from experimental IR or UV–Vis absorption spectroscopy. The electrochemistry of the adc complexes showed reduction potentials slightly below 0.0 V vs. the ferrocene/ferrocenium couple. Attempts to generate the radicals [{Re(CO)3Cl}2(µ-adcOR)]•− failed as they are inherently unstable, losing very probably first the Cl− coligand and then rapidly cleaving one [Re(CO)3] fragment. Consequently, we found signals in EPR very probably due to mononuclear radical complexes [Re(CO)3(solv)(adc)]•. The underlying Cl−→solvent exchange was modelled for the mononuclear [Re(CO)3Cl(adcpip)] using DFT calculations and showed a markedly enhanced Re-Cl labilisation for the reduced compared with the neutral complex. Both the easy reduction with potentials ranging roughly from −0.2 to −0.1 V for the adc ligands and the low-energy NIR absorptions in the 700 to 850 nm range place the adc ligands with their lowest-lying π* orbital being localised on the azo function, amongst comparable bridging chelate N^N coordinating ligands with low-lying π* orbitals of central azo, tetrazine or pyrazine functions. Comparative (TD)DFT-calculations on the Re(CO)3Cl complexes of the adcpip ligand using the quite established basis set and functionals M06-2X/def2TZVP/LANL2DZ/CPCM(THF) and the more advanced TPSSh/def2-TZVP(+def2-ECP for Re)/CPCMC(THF) for single-point calculations with BP86/def2-TZVP(+def2-ECP for Re)/CPCMC(THF) optimised geometries showed a markedly better agreement of the latter with the experimental XRD, IR and UV–Vis absorption data.

Dataset Information

Systematically altering the lipophilicity of rhenium(I) tricarbonyl anticancer agents to tune the rate at which they induce cell death.

Publications

Systematically altering the lipophilicity of rhenium(I) tricarbonyl anticancer agents to tune the rate at which they induce cell death.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets