ABSTRACT
The synthesis and antiproliferative activity of Mes- and iPr-substituted gold(I) bis(1,2,3-triazol-5-ylidene) complexes in various cancer cell lines are reported, showing nanomolar IC50 values of 50 nM (lymphoma cells) and 500 nM (leukemia cells), respectively (Mes < iPr). The compounds exclusively induce apoptosis (50 nM to 5 µM) instead of necrosis in common malignant blood cells (leukemia cells) and do not affect non-malignant leucocytes. Remarkably, the complexes not only overcome resistances against the well-established cytostatic etoposide, cytarabine, daunorubicin, and cisplatin but also promote a synergistic effect of up to 182% when used with daunorubicin. The present results demonstrate that gold(I) bis(1,2,3-triazol-5-ylidene) complexes are highly promising and easily modifiable anticancer metallodrugs.
Subject(s)
Antineoplastic Agents/pharmacology , Coordination Complexes/pharmacology , Gold/chemistry , Triazoles/chemistry , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Line, Tumor , Coordination Complexes/chemistry , Daunorubicin/pharmacology , Drug Resistance, Neoplasm/drug effects , Drug Synergism , HumansABSTRACT
The first diiron(iii,iv)-µ2-oxo tetracarbene complex is isolated and characterized by SC-XRD, UV/Vis, EPR, Evans' NMR and elemental analysis. CV indicates the presence of a transient high-valent diiron(iv)-µ2-oxo species. Its formation and decay is investigated via UV/Vis kinetics and NMR.
Subject(s)
Biomimetic Materials/chemistry , Coordination Complexes/chemistry , Enzymes/metabolism , Iron/chemistry , Methane/analogs & derivatives , Kinetics , Methane/chemistry , Models, Molecular , Molecular ConformationABSTRACT
Fluorescent Pd(ii) and Pt(ii) complexes bearing 4-methylene-7-methoxycoumarin (MMC) and 2,6-diispropylphenyl (Dipp) substituted NHC/1,2,3-triazole hybrid ligands are described. Depending on the reaction conditions two different ligand coordination modes are observed, i.e., bidentate solely coordinating via NHCs or tetradentate coordinating via NHCs and 1,2,3-triazoles. All Dipp substituted complexes show antiproliferative activity against cervix (HeLa) and breast (MCF-7) human carcinoma cells. The activity significantly depends on the coordination mode, with the tetradentate motif being notably more effective (HeLa: IC50 = 3.9 µM to 4.7 µM; MCF-7: IC50 = 2.07 µM to 2.35 µM). Amongst the MMC series, only the Pd(ii) complex featuring the bidentate coordination mode is active against HeLa (IC50 = 6.1 µM). In contrast to its structurally related Dipp derivative (SI = 0.6), it shows a high selectivity for HeLa (SI > 16) compared to healthy skin cells (HaCaT). According to fluorescence microscopy, this compound is presumably located in late endosomes or lysosomes.
Subject(s)
Antineoplastic Agents , Coordination Complexes , Coumarins , Organometallic Compounds , Palladium , Platinum , Triazoles , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line , Cell Proliferation/drug effects , Cell Survival/drug effects , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Coumarins/chemistry , Coumarins/pharmacology , Fluorescence , Humans , Microscopy, Fluorescence , Neoplasms/drug therapy , Organometallic Compounds/chemistry , Organometallic Compounds/pharmacology , Palladium/chemistry , Palladium/pharmacology , Platinum/chemistry , Platinum/pharmacology , Triazoles/chemistry , Triazoles/pharmacologyABSTRACT
The syn- and anti-isomers of dinuclear Au(I) complexes of the type Au2(RLOH)(PF6)2 (R = isopropyl or mesityl) bearing 2-hydroxyethane-1,1-diyl-bridged bisimidazolylidene ligands were separated by reversed phase high performance liquid chromatography (HPLC) and characterized by NMR spectroscopy, elemental analysis, ESI mass spectrometry as well as single crystal X-ray diffraction analysis. Evaluation of the antiproliferative activity of the isolated isomers has shown very small difference in their cytotoxic behavior in various cancer cell lines. Additional counter-anion exchange (hexafluorophosphate to chloride) allows to increase the water solubility of synAu2(MesLOH)(PF6)2 and leads to higher antiproliferative activity when compared to the hexafluorophosphate-complex. Both isomers were treated with l-cysteine as nucleophilic thiol source and only the anti-isomer shows dissociation of one bisimidazolylidene ligand after 24 h. In the case of the syn-isomer, density functional theory calculations indicate a lower reactivity due to the higher steric hindrance of the N-substituents and additional hydrogen bond interaction, which prevents a nucleophilic attack. When the N-substituent is replaced by the bulkier mesityl group, both conformations remain unreactive and result to be the most cytotoxic complexes in the above-mentioned cancer cell lines. Interestingly, synAu2(MesLOH)(PF6)2 exhibits a high selectivity in the MCF-7 cell line with a selectivity index (SI) of 19, which is superior to auranofin (SI < 1), making this compound an ideal candidate for further studies. Preliminary mechanistic studies reveal that the cytotoxic complexes possess mitochondrial-TrxR inhibition properties in the nanomolar range. Additionally, the cellular distribution studies by ICP-MS and nuclear microscopy have shown that the compound accumulates in the membranes. These results suggest that the mitochondrial membrane is the main target for this type of dinuclear complexes, causing oxidative stress by inhibiting mitochondrial thioredoxin reductase.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Gold/chemistry , Cell Line, Tumor , Density Functional Theory , Humans , Hydrogen Bonding , Imidazoles/chemistry , Isomerism , Ligands , Membrane Potential, Mitochondrial/drug effects , Models, Molecular , Molecular Conformation , SolubilityABSTRACT
A series of histidine derived Au(I) bis-NHC complexes bearing different ester, amide and carboxylic acid functionalities as well as wingtip substituents is synthesized and characterized. The stability in aqueous media, inâ vitro cytotoxicity in a set of cancer cell lines (MCF7, PC3 and A2780/A2780cisR) along with the cellular uptake are evaluated. Stability tests suggest hydrolysis of the ester within 8â h, which might lead to deactivation. Furthermore, the bis-NHC system shows a sufficient stability against cysteine and the thiol containing peptide GSH. The benzyl ester and amide show the highest activity comparable to the benchmark compound cisplatin, with the ester only displaying a slightly lower cytotoxicity than the amide. A cellular uptake study revealed that the benzyl ester and the amide could have different intracellular distribution profiles but both complexes induce perturbations of the cellular physiological processes. The simple modifiability and high stability of the complexes provides a promising system for upcoming post modifications to enable targeted cancer therapy.
Subject(s)
Antineoplastic Agents/pharmacology , Coordination Complexes/pharmacology , Gold/pharmacology , Heterocyclic Compounds/pharmacology , Histidine/pharmacology , Methane/analogs & derivatives , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line , Cell Proliferation/drug effects , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Gold/chemistry , Heterocyclic Compounds/chemistry , Histidine/chemistry , Humans , Methane/chemistry , Methane/pharmacology , Molecular Structure , Optical Imaging , Structure-Activity RelationshipABSTRACT
A novel N,N'-allyl-bridged bisimidazolium salt and a novel dinuclear Ag(I) and a Au(I) NHC complex are reported. Both metallacyclic complexes have a twisted structural shape due to the rigid allylic system and form two different isomers relating to the position of the double bonds. The allyl-group shows photoisomerisation, but no reactivity towards bases for the additional coordination of Pd(II).
ABSTRACT
A straightforward modification route to obtain mono- and di-substituted anthroyl ester bridge functionalized dinuclear Au(I) bis-N-heterocyclic carbene complexes is presented. The functionalization can be achieved starting from a hydroxyl-functionalized ligand precursor followed by transmetallation of the corresponding Ag complex or via esterification of the hydroxyl-functionalized gold complex. The compounds are characterized by NMR-spectroscopy, ESI-MS, elemental analysis and SC-XRD. The mono-ester Au complex shows quantum yields around 18%. In contrast, the corresponding syn-di-ester Au complex, exhibits significantly lower quantum yields of around 8%. Due to insufficient water solubility of the di-ester, only the mono-ester complex has been tested regarding its antiproliferative activity against HeLa- (cervix) and MCF-7- (breast) cancer cell lines and a healthy fibroblast cell line (V79). IC50 values of 7.26â µM in the HeLa cell line and 7.92â µM in the MCF-7â cell line along with selectivity indices of 8.8 (HeLa) and 8.0 (MCF-7) are obtained. These selectivity indices are significantly higher than those obtained for the reference drugs cisplatin or auranofin.
