📚 BiometalDB

Title: Re(I)[2-aryl-1 Abstract: Recently, achieving selective cancer therapy with trifling side effects has been a great challenge in the eradication of cancer. Thus, to amplify the cytoselective approach of complexes, herein, we developed a series of Re(I)[2-aryl-1H-imidazo[4,5-f][1,10]phenanthroline] tricarbonyl chloride complexes and screened their potency against HeLa and MCF-7 cell lines together with the evaluation of their toxicity towards a normal kidney cell line (HEK-293). On meticulous investigation, complex [ReI(CO)3Cl(K2-N,N-(2c))] (3c) was found to be the most potent anticancer entity among other complexes. Complex 3c also showed competency to induce apoptosis in MCF-7 cells through G2/M phase cell-cycle arrest in association with the generation of ample reactive oxygen species (ROS), eventually leading to DNA intercalation and internucleosomal cleavage. The order of the cytotoxicity of these complexes depended on their lipophilic character and the electron-withdrawing halogen substitution at the para-position of the phenyl ring in the imidazophenanthroline ligand. Show less

We report the synthesis, characterization, and in vivo evaluation of the anticancer activity of a series of 5- and 6-(halomethyl)-2,2'-bipyridine rhenium tricarbonyl complexes. The study was promoted in order to understand if the presence and position of a reactive halomethyl substituent on the diimine ligand system of fac-[Re(CO)₃]⁺ species may be a key molecular feature for the design of active and non-toxic anticancer agents. Only compounds potentially able to undergo ligand-based alkylating reactions show significant antiproliferative activity against colorectal and pancreatic cell lines. Of the new species presented in this study, one compound (5-(chloromethyl)-2,2'-bipyridine derivative) shows significant inhibition of pancreatic tumour growth in vivo in zebrafish-Panc-1 xenografts. The complex is noticeably effective at 8 μM concentration, lower than its in vitro IC₅₀ values, being also capable of inhibiting in vivo cancer cells dissemination. Show less

Title: Comparative Study of Sonodynamic and Photoactivated Cancer Therapies with Re(I)-Tricarbonyl Complexes Comprising Phenanthroline Ligands. Abstract: Herein, we have compared the effectivity of light-based photoactivated cancer therapy and ultrasound-based sonodynamic therapy with Re(I)-tricarbonyl complexes (Re1-Re3) against cancer cells. The observed photophysical and TD-DFT calculations indicated the potential of Re1-Re3 to act as good anticancer agents under visible light/ultrasound exposure. Re1 did not display any dark- or light- or ultrasound-triggered anticancer activity. However, Re2 and Re3 displayed concentration-dependent anticancer activity upon light and ultrasound exposure. Interestingly, Re3 produced 1O2 and OH• on light/ultrasound exposure. Moreover, Re3 induced NADH photo-oxidation in PBS and produced H2O2. To the best of our knowledge, NADH photo-oxidation has been achieved here with the Re(I) complex for the first time in PBS. Additionally, Re3 released CO upon light/ultrasound exposure. The cell death mechanism revealed that Re3 produced an apoptotic cell death response in HeLa cells via ROS generation. Interestingly, Re3 showed slightly better anticancer activity under light exposure compared to ultrasound exposure. Show less

Title: Cancer phototherapy by CO releasing terpyridine-based Re(I) tricarbonyl complexes Abstract: Here, we have synthesized and characterized three visible light responsive terpyridine based-Re(I)-tricarbonyl complexes; [Re(CO)3(ph-tpy)Cl] (Retp1), [Re(CO)3(an-tpy)Cl] (Retp2), and [Re(CO)3(py-tpy)Cl] (Retp3) where ph-tpy = 4'-phenyl-2,2':6',2″-terpyridine; an-tpy = 4'-anthracenyl-2,2':6',2″-terpyridine, py-tpy = 4'-pyrenyl-2,2':6',2″-terpyridine. The structures of Retp1 and Retp2 were confirmed from the SC-XRD data, indicating distorted octahedral structures. Unlike traditional PDT agents, these complexes generated reactive oxygen species (ROS) via type I and type II pathways and oxidized redox crucial NADH (reduced nicotinamide adenine dinucleotide) upon visible light exposure. Retp3 showed significant mitochondrial localization and demonstrated photoactivated anticancer activity (IC50 ∼ 2 µM) by inducing ROS-mediated cell death in cancer cells selectively (photocytotoxicity Index, PI > 28) upon compromising mitochondrial function in A549 cells. Their diagnostic capabilities were ultimately assessed using clinically relevant 3D multicellular tumor spheroids (MCTs). Show less

A series of N,N-disubstituted salicylaldehyde semicarbazones (SSCs), HOC(6)H(4)CHN-NHCONR(2), and their rhenium(I) tricarbonyl complexes, [ReBr(CO)(3)(SSC)], have been synthesised and characterised by IR and (1)H NMR spectroscopy. Crystallographic analysis of the complex [ReBr(CO)(3)(H(2)Bu(2))] (H(2)Bu(2)=SSC where R=Bu(n)) showed that the SSC acts as a bidentate ligand via its imino nitrogen and carbonyl oxygen atoms. The [ReBr(CO)(3)(SSC)] complexes exhibit moderate to high cytotoxicities towards MOLT-4 cells (IC(50)=1-24μM, cf. 18μM for cisplatin), and the majority of them are virtually non-toxic against non-cancerous human fibroblasts. Apoptotic assays of [ReBr(CO)(3)(H(2)Bnz(2))] (Bnz=benzyl) revealed that it mediates cytotoxicity in MOLT-4 cells via apoptosis. The complex [ReBr(CO)(3)(H(2)Bnz(2))] reacts with guanosine by proton transfer from the phenolic OH group to N(7) of guanosine. In (CD(3))(2)SO, [ReBr(CO)(3)(H(2)Bnz(2))] undergoes facile conversion to the dimeric complex, [Re(CO)(3)(HBnz(2))](2), via bromide dissociation. Show less

We report here the design of the first class of luminescent biotinylation reagents derived from rhenium(I) polypyridine complexes. These complexes [Re(N-N)(CO)(3)(py-biotin-NCS)](PF(6)) (py-biotin-NCS = 3-isothiocyanato-5-(N-((2-biotinamido)ethyl)aminocarbonyl)pyridine; N-N = 1,10-phenanthroline (phen) (1a), 3,4,7,8-tetramethyl-1,10-phenanthroline (Me(4)-phen) (2a), 4,7-diphenyl-1,10-phenanthroline (Ph(2)-phen) (3a)), containing a biotin unit and an isothiocyanate moiety, have been synthesized from the precursor amine complexes [Re(N-N)(CO)(3)(py-biotin-NH(2))](PF(6)) (py-biotin-NH(2) = 3-amino-5-(N-((2-biotinamido)ethyl)aminocarbonyl)pyridine; N-N = phen (1c), Me(4)-phen (2c), Ph(2)-phen (3c)). To investigate the amine-specific reactivity of the isothiocyanate complexes 1a-3a, they have been reacted with a model substrate ethylamine, resulting in the formation of the thiourea complexes [Re(N-N)(CO)(3)(py-biotin-TU-Et)](PF(6)) (py-biotin-TU-Et = 3-ethylthioureidyl-5-(N-((2-biotinamido)ethyl)aminocarbonyl)pyridine; N-N = phen (1b), Me(4)-phen (2b), Ph(2)-phen (3b)). All the rhenium(I) complexes have been characterized, and their photophysical properties have been studied. The avidin-binding properties of the thiourea complexes 1b-3b have been examined by the 4'-hydroxyazobenzene-2-carboxylic acid (HABA) assay. Titration results indicated that the complexes exhibited emission enhancement by ca. 1.4-1.5-fold upon binding to avidin, and the lifetimes were elongated to ca. 0.8-2.0 micros. Additionally, we have biotinylated bovine serum albumin (BSA) with the isothiocyanate complexes. All the resultant rhenium-BSA bioconjugates displayed intense and long-lived orange-yellow to greenish-yellow emission upon irradiation in aqueous buffer under ambient conditions. The avidin-binding properties of the bioconjugates have been investigated using the HABA assay. Furthermore, the cytotoxicity of the thiourea complexes 1b-3b toward the HeLa cells has been examined by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay. The IC50 values were determined to be ca. 17.5-28.5 microM, which are comparable to that of cisplatin (26.7 microM) under the same conditions. The cellular uptake of complex 3b has been investigated by fluorescence microscopy, and the results showed that the complex was localized in the perinuclear region after interiorization. Show less

Title: The impact of biomolecule interactions on the cytotoxic effects of rhenium(I) tricarbonyl complexes. Abstract: Rhenium complexes show great promise as anticancer drug candidates. Specifically, compounds with a Re(CO)3(NN)(py)+ core in their architecture have shown cytotoxicity equal to or greater than that of well-established anticancer drugs based on platinum or organic molecules. This study aimed to evaluate how the strength of the interaction between rhenium(I) tricarbonyl complexes fac-[Re(CO)3(NN)(py)]+, NN = 1,10-phenanthroline (phen), dipyrido[3,2-f:2',3'-h]quinoxaline (dpq) or dipyrido[3,2-a:2'3'-c]phenazine (dppz) and biomolecules (protein, lipid and DNA) impacted the corresponding cytotoxic effect in cells. Results showed that fac-[Re(CO)3(dppz)(py)]+ has higher Log Po/w and binding constant (Kb) with biomolecules (protein, lipid and DNA) compared to complexes of fac-[Re(CO)3(phen)(py)]+ and fac-[Re(CO)3(dpq)(py)]+. As consequence, fac-[Re(CO)3(dppz)(py)]+ exhibited the highest cytotoxicity (IC50 = 8.5 μM for HeLa cells) for fac-[Re(CO)3(dppz)(py)]+ among the studied compounds (IC50 > 15 μM). This highest cytotoxicity of fac-[Re(CO)3(dppz)(py)]+ are probably related to its lipophilicity, higher permeation of the lipid bilayers of cells, and a more potent interaction of the dppz ligand with biomolecules (protein and DNA). Our findings open novel avenues for rational drug design and highlight the importance of considering the chemical structures of rhenium complexes that strongly interact with biomolecules (proteins, lipids, and DNA). Show less

Lysosomes play a critical role in the autophagy process. The impairment of lysosomes can affect the degradation of autophagic cargo, leading to the blockage of autophagy at the lysosomal stage and subsequent cell death. Herein, two phosphorescent Re(i) tricarbonyl complexes (Re1 and Re2) bearing β-carboline derivatives have been synthesized and characterized. Both complexes show pH-dependent phosphorescence, which can be used to specifically image the lysosomes. Cytotoxicity assay shows that they exhibit high anticancer activity and are able to overcome cross-resistance to cisplatin. Re2 can induce autophagy, which is blocked at the lysosomal stage due to lysosomal dysfunction, such as the decrease of cathepsin B activity, subsequently leading to both autophagy and apoptosis dependent cell death. In vivo studies revealed that it could significantly inhibit tumor growth. Show less

In this article, we report on the development of new metal-based anticancer agents with imaging, chemotherapeutic and photosensitizing properties. Hence, a new heterobimetallic complex (Pt-LQ-Re) was prepared by connecting a non-conventional trans-chlorido Pt(ii) complex to a photoactive Re tricarbonyl unit (LQ-Re), which can be replaced by ^99mTc to allow for in vivo imaging. We describe the photophysical and biological properties of the new complexes, in the dark and upon light irradiation (DNA interaction, cellular localization and uptake, and cytotoxicity). Furthermore, planar scintigraphic images of mice injected with Pt-LQ-Tc clearly showed that the radioactive compound is taken up by the excretory system organs, namely liver and kidneys, without significant retention in other tissues. All in all, the strategy of conjugating a chemotherapeutic compound with a PDT photosensitizer endows the resulting complexes with an intrinsic cytotoxic activity in the dark, driven by the non-classical platinum core, and a selective activity upon light irradiation. Most importantly, the possibility of integrating a SPECT imaging radiometal (^99mTc) in the structure of these new heterobimetallic complexes might allow for in vivo non-invasive visualization of their tumoral accumulation, a crucial issue to predict therapeutic outcomes. Show less

We report here a new class of biological reagents derived from luminescent rhenium(I) polypyridine complexes modified with a poly(ethylene glycol) (PEG) pendant. The PEG-amine complexes [Re(N(⁾N)(CO)(3)(py-PEG-NH(2))](PF(6)) (py-PEG-NH(2) = 3-amino-5-(N-(2-(ω-methoxypoly(1-oxapropyl))ethyl)aminocarbonyl)pyridine, MW(PEG) = 5000 Da, PDI(PEG) < 1.08; N(⁾N = 1,10-phenanthroline (phen) (1-PEG-NH(2)), 3,4,7,8-tetramethyl-1,10-phenanthroline (Me(4)-phen) (2-PEG-NH(2)), 4,7-diphenyl-1,10-phenanthroline (Ph(2)-phen) (3-PEG-NH(2))) and [Re(bpy-PEG)(CO)(3)(py-NH(2))](PF(6)) (bpy-PEG = 4-(N-(2-(ω-methoxypoly(1-oxapropyl))ethyl)aminocarbonyl)-4'-methyl-2,2'-bipyridine; py-NH(2) = 3-aminopyridine) (4-PEG-NH(2)) have been synthesized and characterized. The photophysical properties, lipophilicity, water solubility, cytotoxic activity, and cellular uptake properties of these complexes have been compared to those of their PEG-free counterparts [Re(N(⁾N)(CO)(3)(py-Et-NH(2))](PF(6)) (py-Et-NH(2) = 3-amino-5-(N-(ethyl)aminocarbonyl)pyridine; N(⁾N = phen (1-Et-NH(2)), Me(4)-phen (2-Et-NH(2)), Ph(2)-phen (3-Et-NH(2))) and [Re(bpy-Et)(CO)(3)(py-NH(2))](PF(6)) (bpy-Et = 4-(N-(ethyl)aminocarbonyl)-4'-methyl-2,2'-bipyridine) (4-Et-NH(2)). The PEG complexes exhibited significantly higher water solubility and lower cytotoxicity (IC(50) = 6.6 to 1152 μM) than their PEG-free counterparts (IC(50) = 3.6 to 159 μM), indicating that the covalent attachment of a PEG pendant to rhenium(I) polypyridine complexes is an effective way to increase their biocompatibility. The amine complexes 1-PEG-NH(2)-4-PEG-NH(2) have been activated with thiophosgene to yield the isothiocyanate complexes [Re(N(⁾N)(CO)(3)(py-PEG-NCS)](PF(6)) (py-PEG-NCS = 3-isothiocyanato-5-(N-(2-(ω-methoxypoly(1-oxapropyl))ethyl)aminocarbonyl)pyridine; N(⁾N = phen (1-PEG-NCS), Me(4)-phen (2-PEG-NCS), Ph(2)-phen (3-PEG-NCS)), and [Re(bpy-PEG)(CO)(3)(py-NCS)](PF(6)) (py-NCS = 3-isothiocyanatopyridine) (4-PEG-NCS) as a new class of luminescent PEGylation reagents. To examine their PEGylation properties, these isothiocyanate complexes have been reacted with a model substrate n-butylamine, resulting in the formation of the thiourea complexes [Re(N(⁾N)(CO)(3)(py-PEG-Bu)](PF(6)) (py-PEG-Bu = 3-n-butylthioureidyl-5-(N-(2-(ω-methoxypoly(1-oxapropyl))ethyl)aminocarbonyl)pyridine; N(⁾N = phen (1-PEG-Bu), Me(4)-phen (2-PEG-Bu), Ph(2)-phen (3-PEG-Bu)), and [Re(bpy-PEG)(CO)(3)(py-Bu)](PF(6)) (py-Bu = 3-n-butylthioureidylpyridine) (4-PEG-Bu). Additionally, bovine serum albumin (BSA) and poly(ethyleneimine) (PEI) have been PEGylated with the isothiocyanate complexes to yield bioconjugates 1-PEG-BSA-4-PEG-BSA and 1-PEG-PEI-4-PEG-PEI, respectively. Upon irradiation, all the PEGylated BSA and PEI conjugates exhibited intense and long-lived emission in aqueous buffer under ambient conditions. The DNA-binding and polyplex-formation properties of conjugate 3-PEG-PEI have been studied and compared with those of unmodified PEI. Furthermore, the in vivo toxicity of complex 3-PEG-NH(2) and its PEG-free counterpart 3-Et-NH(2) has been investigated using zebrafish embryos as an animal model. Embryos treated with the PEG complex at high concentrations revealed delayed hatching, which has been ascribed to hypoxia as a result of adhering of the complex to the external surface of the chorion. Show less

Rhenium and ruthenium complexes containing N-heterocylic carbene (NHC) ligands and conjugated to indomethacin were prepared. The anticancer properties were probed against pancreatic cell lines, revealing a remarkable activity of the rhenium fragment as anticancer agent. The ruthenium complexes were found to be inactive against the same pancreatic cancer cell lines, either alone or in conjugation with indomethacin. An in-depth biological study revealed the origin of the anticancer properties of the rhenium tricarbonyl fragment, of which a complete elucidation had yet to be achieved. It was found that the rhenium complexes induce cell cycle arrest at the G2/M phase by inhibiting the phosphorylation of Aurora-A kinase. A preliminary study on the structure-activity relationship on a large family of these complexes revealed that the anticancer properties are mainly associated with the lability of the ancillary ligand, with inert complexes showing limited to no anticancer properties. Show less

Mitochondrial metabolism is essential for tumorigenesis, and the development of cancer is usually accompanied by alternations of mitochondrial function. Emerging studies have demonstrated that targeting mitochondria and mitochondrial metabolism is an effective strategy for cancer therapy. In this work, eight phosphorescent organometallic rhenium(I) complexes have been synthesized and explored as mitochondria-targeted theranostic agents, capable of inducing and tracking the therapeutic effect simultaneously. Complexes 1b-4b can quickly and efficiently penetrate into A549 cells, specifically localizing within mitochondria, and their cytotoxicity is superior to cisplatin against the cancer cells screened. Notably, complex 3b [Re(CO)₃(DIP) (py-3-CH₂Cl)]⁺ containing thiol-reactive chloromethylpyridyl moiety for mitochondria immobilization shows higher cytotoxicity and selectivity against cancer cells than other Re(I) complexes without mitochondria-immobilization properties. Mechanistic studies show that complexes 1b-4b induce a cascade of mitochondria-dependent events including mitochondrial damage, mitochondrial respiration inhibition, cellular ATP depletion, reactive oxygen species (ROS) elevation, and caspase-dependent apoptosis. By comparison, mitochondria-immobilized 3b causes more effective repression of mitochondrial metabolism than mitochondrial-nonimmobilized complexes. The excellent phosphorescence and O₂-sensitive lifetimes of mitochondria-immobilized 3b can be utilized for real-time tracking of the morphological changes of mitochondria and mitochondrial respiration repression during therapy process, accordingly providing reliable information for understanding anticancer mechanisms. Show less

Complexes of the element Re have recently been shown to possess promising anticancer activity through mechanisms of action that are distinct from the conventional metal-based drug cisplatin. In this study, we report our investigations on the anticancer activity of the complex [Re(CO)₃ (dmphen)(p-tol-ICN)]⁺ (TRIP) in which dmphen=2,9-dimethyl-1,10-phenanthroline and p-tol-ICN=para-tolyl isonitrile. TRIP was synthesized by literature methods and exhaustively characterized. This compound exhibited potent in vitro anticancer activity in a wide variety of cell lines. Flow cytometry and immunostaining experiments indicated that TRIP induces intrinsic apoptosis. Comprehensive biological mechanistic studies demonstrated that this compound triggers the accumulation of misfolded proteins, which causes endoplasmic reticulum (ER) stress, the unfolded protein response, and apoptotic cell death. Furthermore, TRIP induced hyperphosphorylation of eIF2α, translation inhibition, mitochondrial fission, and expression of proapoptotic ATF4 and CHOP. These results establish TRIP as a promising anticancer agent based on its potent cytotoxic activity and ability to induce ER stress. Show less

Title: Synthesis, characterisation and biological evaluation of monometallic Re(I) and heterobimetallic Re(I)/Fe(II) complexes with a 1,2,3-triazolyl pyridine chelating moiety. Abstract: Bioorganometallic complexes have attracted considerable interest and have shown promise for potential application in the treatment and diagnosis of cancer, as well as bioimaging agents, some acting as theranostic agents. The series of novel ferrocene, benzimidazo[1,2-a]quinoline and fluorescein derivatives with bidentate pyridyl-1,2,3-triazole and 2,2'-dipyridylamine and their tricarbonylrhenium(I) complexes was prepared and fully characterised by NMR, single-crystal X-ray diffraction, UV-Vis and fluorescence spectroscopy in biorelevant conditions. The fluorescein and benzimidazo[1,2-a]quinoline ligands and their complexes with Re(I) showed interactions with ds-DNA/RNA and HSA, characterised by thermal denaturation measurements, fluorimetric and circular dichroism titrations. The binding constants revealed that addition of Re(I) increases the affinity of fluorescein but decreases the affinity of benzimidazo[1,2-a]quinoline. The complexation of Re(I) had the opposite effect on fluorescein and benzimidazo[1,2-a]quinoline ligands' fluorimetric sensitivity upon biomacromolecule binding, Re(I) fluorescein complex emission being strongly quenched by DNA/RNA or HSA, while emission of Re(I) benzimidazo[1,2-a]quinolone complex was enhanced, particularly for HSA, making it a promising fluorescent probe. Some mono- and heterobimetallic complexes showed considerable antiproliferative activity on colon cancer cells (CT26 and HT29), with ferrocene dipyridylamine complexes exhibiting the best inhibitory activity, comparable to cisplatin. The correlation of the cytotoxicity data with the linker type between the ferrocene and the 1,2,3-triazole ring suggests that direct binding of the metallocene to the 1,2,3-triazole is favourable for antitumor activity. The Re(I) benzimidazo[1,2-a]quinolone complex showed moderate antiproliferative activity, in contrast to the Re(I) fluorescein complex, which exhibited weak activity on CT26 cells and no activity on HT29 cells. The accumulation of the Re(I) benzimidazo[1,2-a]quinolone complex in the lysosomes of CT26 cells indicates the site of its bioactivity, thus making this complex a potential theranostic agent. Show less

Title: Rhenium-guanidine complex as photosensitizer: trigger HeLa cell apoptosis through death receptor-mediated, mitochondria-mediated, and cell cycle arrest pathways. Abstract: The growing evidence over the past few decades has indicated that the photodynamic antitumor activity of transition metal complexes, and Re(I) compounds are potential candidates for photodynamic therapy. This study reports the synthesis, characterization, and anti-tumor activity of three new Re(I)-guadinium complexes. Cytotoxicity tests reveal that complex Re1 increased cytotoxicity by 145-fold from IC50 > 180 μM in the dark to 1.3 ± 0.7 μM following 10 min of light irradiation (425 nm) in HeLa cells. Further, the mechanism by which Re1 induces apoptosis in the presence or absence of light irradiation was investigated, and results indicate that cell death was caused through different pathways. Upon irradiation, Re1 first accumulates on the cell membrane and interacts with death receptors to activate the extrinsic death receptor-mediated signaling pathway, and then is transported into the cell cytoplasm. Most of the intracellular Re1 locates within mitochondria, improving the reactive oxygen species level, and decreasing mitochondrial membrane potential and ATP levels, and inducing the activation of caspase-9 and, thus, apoptosis. Subsequently, the residual Re1 can translocate into the cell nucleus, and activates the p53 pathway, causing cell cycle arrest and eventually cell death. Show less

Title: Cytotoxic properties of rhenium(I) tricarbonyl complexes of N-heterocyclic carbene ligands. Abstract: A family of eight rhenium(I) tricarbonyl complexes bearing pyridyl-imidazolylidene or bis-imidazolylidene ligands in combination with a series of N-acetyl amino acids ligands (glycine, isoleucine, and proline) and an acetate have been synthesised and characterised. These complexes are of interest as potential anticancer agents, where the oxygen bound carboxylate ligand can exchange with water giving rise to cytotoxic cationic complexes. The pseudo-first-order aquation rate constants for the complexes were evaluated using 1H NMR time-course experiments and for the complexes of the bis-imidazolylidene ligand the average k1 value was 6.22 × 10-5 s-1 while for the pyridyl-imidazolylidene ligand the aquation rate was slower with the average k1 value being 3.00 × 10-5 s-1. Cytotoxicity studies in three cancer cell lines (MDA-MB-231, PC3 and HEPG2) showed that the Re(I) complexes of the bis-imidazolylidene ligand were significantly more toxic than those of the pyridyl-imidazolylidene ligand. Show less

Reaction of [ReOCl₃(PPh₃)₂] or [ReO₂I(PPh₃)₂] with 2,2'-diphenylglycine (dpgH₂) in refluxing ethanol afforded the air-stable complex [ReO(dpgH)(dpg)(PPh₃)] (1). Treatment of [ReO(OEt)I₂(PPh₃)₂] with 1,2,3-triaza-7-phosphaadamantane (PTA) afforded the complex [ReO(OEt)I₂(PTA)₂] (2). Reaction of [ReOI₂(PTA)₃] with dpgH₂ led to the isolation of the complex [Re(NCPh₂)I₂(PTA)₃]·0.5EtOH (3·0.5EtOH). A similar reaction but using [ReOX₂(PTA)₃] (X = Cl, Br) resulted in the analogous halide complexes [Re(NCPh₂)Cl₂(PTA)₃]·2EtOH (4·2EtOH) and [Re(NCPh₂)(PTA)₃Br₂]·1.6EtOH (5·1.6EtOH). Using benzilic acid (2,2'-diphenylglycolic acid, benzH) with 2 afforded the complex [ReO(benz)₂(PTA)][PTAH]·EtOH (6·EtOH). The potential for the formation of complexes using radioisotopes with relatively short half-lives suitable for nuclear medicine applications by developing conditions for [Re(NCPh₂)(dpg)I(PTA)₃] (7)[ReO₄]^- in a 4 h time scale was investigated. A procedure for the technetium analog of complex [Re(NCPh₂)I₂(PTA)₃] (3) from ^99mTc[TcO₄]^- was then investigated. The molecular structures of 1-7 are reported; complexes 3-7 have been studied using in vitro cell assays (HeLa, HCT116, HT-29, and HEK 293) and were found to have IC₅₀ values in the range of 29-1858 μM. Show less

The synthesis, structural characterization and biological activity of eight ortho-quinone(N-aryl)-oximine rhenium(I) complexes are described. The reaction of the halogenido complexes (CO)(5)ReX (X = Cl (4), Br (5)) with 2-nitroso-N-arylanilines {(C(6)H(3)ClNO)NH(C(6)H(4)R)} (R = p-Cl, p-Me, o-Cl, H) (3a-d) in tetrahydrofurane (THF) yields the complexes fac-(CO)(3)XRe{(C(6)H(3)ClNO)NH(C(6)H(4)R)} (6a-d, 7a-d) with the tautomerized ligand acting as a N,N'-chelate. The substitution of two carbonyl ligands leads to the formation of a nearly planar 5-membered metallacycle. During coordination the amino-proton is shifted to the oxygen of the nitroso group which can be observed in solution for 6 and 7 by (1)H NMR spectroscopy and in solid state by crystal structure analysis. After purification, all compounds have been fully characterized by their (1)H and (13)C NMR, IR, UV/visible (UV/Vis) and mass spectra. The X-ray structure analyses revealed a distorted octahedral coordination of the CO, X and N,N'-chelating ligands for all Re(I) complexes. Biological activity of four oximine rhenium(I) complexes was assessed in vitro in two highly aggressive cancer cell lines: human metastatic melanoma A375 and human chronic myelogenous leukemia K562. Chlorido complexes (6a and 6c) were more efficient than bromido compounds (7d and 7b) in inducing apoptotic cell death of both types of cancer cells. Melanoma cells were more susceptible to tested rhenium(I) complexes than leukemia cells. None of the ligands (3a-d) showed any significant anticancer activity. Show less

Rhenium(i) di- and tri-carbonyl complexes of the form fac-[Re(CO)₃(L,L'-Bid)X] and [Re(CO)₂(L,L'-Bid)X₂], where X = aqua (H₂O), methanol (CH₃OH), triphenylphosphine (PPh₃), 1,3,5-triaza-7-phosphaadamantane (PTA), tricyclohexylphosphine (PCy₃) and L,L'-Bid = O,O' bidentate ligands (tropolone = TropH and 3-hydroxyflavone = FlavH) and N,O bidentate ligands (8-hydroxyquinoline = QuinH, 5,7-chloro-8-hydroxyquinoline = diCl-QuinH and quinoline-2,4-dicarboxylic acid = QuinH₂), were synthesized and unambiguously characterized by ¹H-, ¹³C-and ³¹P-NMR, IR, UV/Vis and micro-analysis. The crystal structures of four complexes, namely fac-[Re(CO)₃(QuinH)(H₂O)]·H₂O (5), fac-[Re(CO)₃(Quin)(PPh₃)] (11), fac-[Re(CO)₃(diCl-Quin)(PPh₃)] (12) and [Re(CO)₂(Trop)(PPh₃)₂]·2C₆H₅CH₃ (20) were obtained. Re-P bonding distances for 11 and 12 are 2.4948(8) and 2.4908(8) Å, respectively, indicating the effect of the electron-withdrawing substituents of the diCl-Quin^- ligand. The second-order rate constants for the substitutions of methanol at 25.1 °C in fac-[Re(CO)₃(L,L'-Bid)(CH₃OH)] (L,L'-Bid = Trop, Flav and QuinH) type complexes by different entering phosphine ligands (PPh₃, PCy₃, and PTA) varied between 7.23(7) × 10^-5 and 1.32(3) × 10^-3 M^-1 s^-1 and were found to depend on the coordinated bidentate ligand (in general k₁ (QuinH) < k₁ (Trop) < k₁ (Flav)). The toxicity of fac-[Re(CO)₃(QuinH)(PTA)], fac-[Re(CO)₃(Trop)(PTA)], fac-[Re(CO)₃(Trop)(PPh₃)] and fac-[Re(CO)₃(Flav)(PPh₃)] on the cervical cancer HeLa and epithelial RPE-1 cell lines was then evaluated. Complex fac-[Re(CO)₃(Flav)(PPh₃)] (16) and fac-[Re(CO)₃(Trop)(PPh₃)] (13) displayed the highest cytotoxicity with IC₅₀ values of 12.21 ± 0.17 μM and 13.35 ± 0.94 μM, respectively in HeLa cells. Interestingly, a small selectivity towards cancer over non-cancerous cells was observed for these compounds (IC₅₀ = 18.41 ± 3.16 μM and >25 μM in RPE-1 cells). Show less

The potential chemotherapeutic properties coupled to photochemical transitions make the family of fac-[Re(CO)₃(N,N)X]^0/+ (N,N = a bidentate diimine such as 2,2'-bipyridine (bpy); X = halide, H₂O, pyridine derivatives, PR₃, etc.) complexes of special interest. We have investigated reactions of the aqua complex fac-[Re(CO)₃(bpy)(H₂O)](CF₃SO₃) (1) with potential anticancer activity with the amino acid L-cysteine (H₂Cys), and its derivative N-acetyl-L-cysteine (H₂NAC), as well as the tripeptide glutathione (H₃A), under physiological conditions (pH 7.4, 37 °C), to model the interaction of 1 with thiol-containing proteins and enzymes, and the impact of such coordination on its photophysical properties and cytotoxicity. We report the syntheses and characterization of fac-[Re(CO)₃(bpy)(HCys)]·0.5H₂O (2), Na(fac-[Re(CO)₃(bpy)(NAC)]) (3), and Na(fac-[Re(CO)₃(bpy)(HA)])·H₂O (4) using extended X-ray absorption spectroscopy, IR and NMR spectroscopy, electrospray ionization spectrometry, as well as the crystal structure of {fac-[Re(CO)₃(bpy)(HCys)]}₄·9H₂O (2 + 1.75 H₂O). The emission spectrum of 1 displays a variance in Stokes shift upon coordination of L-cysteine and N-acetyl-L-cysteine. Laser excitation at λ = 355 nm of methanol solutions of 1-3 was followed by measuring their ability to produce singlet oxygen (¹O₂) using direct detection methods. The cytotoxicity of 1 and its cysteine-bound complex 2 was assessed using the MDA-MB-231 breast cancer cell line, showing that the replacement of the aqua ligand on 1 with L-cysteine significantly reduced the cytotoxicity of the Re(I) tricarbonyl complex. Probing the cellular localization of 1 and 2 using X-ray fluorescence microscopy revealed an accumulation of 1 in the nuclear and/or perinuclear region, whereas the accumulation of 2 was considerably reduced, potentially explaining its reduced cytotoxicity. Replacing the aqua ligand with cysteine in the antitumor active fac-[Re(CO)₃(bpy)(H₂O)](CF₃SO₃) complex significantly reduced its cellular accumulation and cytotoxicity against the MDA-MB-213 breast cancer cell line, shifted its maximum emission to considerably higher energies, and decreased its fluorescence quantum yield. Show less

As the "powerhouse" of a cell, mitochondria maintain energy homeostasis, synthesize ATP via oxidative phosphorylation, generate ROS signaling molecules, and modulate cell apoptosis. Herein, three Re(I) complexes bearing guanidinium derivatives have been synthesized and characterized. All of these complexes exhibit moderate anticancer activity in HepG2, HeLa, MCF-7, and A549 cancer cells. Mechanism studies indicate that complex 3, [Re(CO)3(L)(Im)](PF₆)₂, can selectively localize in the mitochondria and induce cancer cell death through mitochondria-associated pathways. In addition, complex 3 can effectively depress the ability of cell migration, cell invasion, and colony formation. Show less