Morpholine motif is an important pharmacophore and, depending on the molecular design, may localize in cellular acidic vesicles. To understand the importance of the presence of pendant morpholine in a Show more
Morpholine motif is an important pharmacophore and, depending on the molecular design, may localize in cellular acidic vesicles. To understand the importance of the presence of pendant morpholine in a metal complex, six bidentate N,O-donor ligands with or without a pendant morpholine unit and their corresponding ruthenium(II) p-cymene complexes (1-6) are synthesized, purified, and structurally characterized by various analytical methods including X-ray diffraction. Complexes 2-4 crystallized in the P21/c space group, whereas 5 and 6 crystallized in the P1̅ space group. The solution stability studies using 1H NMR support instantaneous hydrolysis of the native complexes to form monoaquated species in a solution of 3:7 (v/v) dimethyl sulfoxide-d6 and 20 mM phosphate buffer (pH* 7.4, containing 4 mM NaCl). The monoaquated complexes are stable for at least up to 24 h. The complexes display excellent in vitro antiproliferative activity (IC50 ca. 1-14 μM) in various cancer cell lines, viz., MDA-MB-231, MiaPaCa2, and Hep-G2. The presence of the pendant morpholine does not improve the dose efficacy, but rather, with 2-[[(2,6-dimethylphenyl)imino]methyl]phenol (HL1) and its pendant morpholine analogue (HL3) giving complexes 1 and 3, respectively, the antiproliferative activity was poorer with 3. MDA-MB-231 cells treated with the complexes show that the acidic vesicles remain acidic, but the population of acidic vesicles increases or decreases with time of exposure, as observed from the dispersed red puncta, depending on the complex used. The presence of the 2,6-disubstituted aniline and the naphthyl group seems to improve the antiproliferative dose. The complex treated MDA-MB-231 cells show that cathepsin D, which is otherwise present in the cytosolic lysosomes, translocates to the nucleus as a result of exposure to the complexes. Irrespective of the presence of a morpholine motif, the complexes do not activate caspase-3 to induce apoptosis and seem to favor the necrotic pathway of cell killing. Show less
A set of five gold complexes with the general formula Au(PR3)(C≡C-C6H4-4-R′) (R = PPh3, R′ = –CHO (1), R = PCy3, R′ = –CHO (2), R = PPh3, R′ = –N=CH-C6H4-2-OH (3), R = PPh3, R′ = –N=CH-C6H4-4-OH (4), Show more
A set of five gold complexes with the general formula Au(PR3)(C≡C-C6H4-4-R′) (R = PPh3, R′ = –CHO (1), R = PCy3, R′ = –CHO (2), R = PPh3, R′ = –N=CH-C6H4-2-OH (3), R = PPh3, R′ = –N=CH-C6H4-4-OH (4), R = PCy3, R′ = –N=CH-C6H4-2-OH (5)) were synthesized and characterized by elemental analysis, 1H-NMR spectroscopy, 31P-NMR spectroscopy, and mass spectrometry. The structures of complexes 2 and 5 were determined by X-ray crystallography. The effects of the structural modifications on the protein binding affinities and anticancer activities of the five gold complexes were assessed. Fluorescence quenching experiments to assess binding to human serum albumin (HSA) revealed that the Schiff base complexes (3, 4, and 5) had binding constants that were superior to their parent aldehyde complexes and highlighted the position of the hydroxy group because complex 4 (4-hydroxy) had a binding constant 6400 times higher than complex 3 (2-hydroxy). The anticancer activities of the complexes against the OVCAR-3 (ovarian carcinoma) and HOP-62 (non-small-cell lung) cancer cell lines showed that the Schiff bases (3–5) were more cytotoxic than the aldehyde-containing complexes (1 and 2). Notably, compound 4 had cytotoxic activity comparable to that of cisplatin against OVCAR-3, demonstrating the significance of the para position for the hydroxy group. Molecular docking studies against the enzyme thioredoxin reductase (TrxR) and human serum albumin were conducted, with docking scores in good agreement with the experimental data. The current study highlights how small structural modifications can alter physiochemical and anticancer properties. Moreover, this simple design strategy using the aldehyde group can generate extensive opportunities to explore new gold(I)-based anticancer drugs via condensation, cyclization, or nucleophilic addition reactions of the aldehyde. Show less
2021 · Frontiers in Chemistry · Frontiers · added 2026-05-21
A class of phosphane gold(I) compounds, made of azoles and phosphane ligands, was evaluated for a screening on the regards of Breast Cancer cell panels (BC). The compounds possess N-Au-P or Cl-Au-P bo Show more
A class of phosphane gold(I) compounds, made of azoles and phosphane ligands, was evaluated for a screening on the regards of Breast Cancer cell panels (BC). The compounds possess N-Au-P or Cl-Au-P bonds around the central metal, and they differ for the presence of aprotic or protic polar groups in the azoles and/or the phosphane moieties to tune their hydrophilicity. Among the six candidates, only the compounds having the P-Au-N environment and not displaying neither the hydroxyl nor carboxyl groups in the ligands were found active. The compounds were screened by MTT tests in SKBR3, A17, and MDA-MB231 cancer cells, and two compounds (namely the 4,5-dicyano-imidazolate-1yl-gold(I)-(triphenylphosphane, 5, and 4,5-dichloro-imidazolate-1yl-gold(I)-triphenylphosphane, 6) were found very cytotoxic, with the most active with an IC50 value of 3.46 μM in MDA-MB231 cells. By performing enzymatic assays in the treated cells lysates, the residual enzymatic activity of dihydrofolate reductase (DHFR) has been measured after cell treatment for 4 or 12 h in comparison with control cells. Upon 12 h of treatment, the activity of DHFR was significantly reduced in both SKBR3 and A17 cells by compounds 5 and 6, but not in human MDA-MB231 cells; interestingly, it was found remarkably high after 4 h of treatment, revealing a time dependence for the DHFR enzymatic assays. The DHFR inhibition data have been compared to those for the thioredoxin reductase (TrxR), the most recognized molecular target for gold compounds. For this latter, similar residual activities (i.e., 37 and 49% for the match of SKBR3 cells and compound 5 or 6, respectively) were found. Binding studies on the regards of ct-DNA (calf-thymus-DNA) and of plasma transporters proteins, such as BSA (bovine serum albumin) and ATF (apo transferrin), were performed. As expected for gold compounds, the data support strong binding to proteins (Ksv values range: 1.51 ÷ 2.46 × 104 M−1) and a weaker interaction with ct-DNA's minor groove (Ksv values range: 1.55 ÷ 6.12 × 103 M−1). Show less
Significance: The nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (NRF2/KEAP1) pathway is a crucial and highly conserved defensive system that is required to maintain o Show more
Significance: The nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (NRF2/KEAP1) pathway is a crucial and highly conserved defensive system that is required to maintain or restore the intracellular homeostasis in response to oxidative, electrophilic, and other types of stress conditions. The tight control of NRF2 function is maintained by a complex network of biological interactions between positive and negative regulators that ultimately ensure context-specific activation, culminating in the NRF2-driven transcription of cytoprotective genes. Recent Advances: Recent studies indicate that deregulated NRF2 activation is a frequent event in malignant tumors, wherein it is associated with metabolic reprogramming, increased antioxidant capacity, chemoresistance, and poor clinical outcome. On the other hand, the growing interest in the modulation of the cancer cells' redox balance identified NRF2 as an ideal therapeutic target. Critical Issues: For this reason, many efforts have been made to identify potent and selective NRF2 inhibitors that might be used as single agents or adjuvants of anticancer drugs with redox disrupting properties. Despite the lack of specific NRF2 inhibitors still represents a major clinical hurdle, the researchers have exploited alternative strategies to disrupt NRF2 signaling at different levels of its biological activation. Future Directions: Given its dualistic role in tumor initiation and progression, the identification of the appropriate biological context of NRF2 activation and the specific clinicopathological features of patients cohorts wherein its inactivation is expected to have clinical benefits, will represent a major goal in the field of cancer research. In this review, we will briefly describe the structure and function of the NRF2/ KEAP1 system and some of the most promising NRF2 inhibitors, with a particular emphasis on natural compounds and drug repurposing. Antioxid. Redox Signal. 34, 1428-1483. Show less
Pd(II)-compounds are presently regarded as promising anticancer drugs, as an alternative to
Pt(II)-based drugs (e.g., cisplatin), which typically trigger severe side-effects and acquired resistance.
D Show more
Pd(II)-compounds are presently regarded as promising anticancer drugs, as an alternative to
Pt(II)-based drugs (e.g., cisplatin), which typically trigger severe side-effects and acquired resistance.
Dinuclear Pd(II) complexes with biogenic polyamines such as spermine (Pd2 Spm) have exhibited
particularly beneficial cytotoxic properties, hence unveiling the importance of understanding their
impact on organism metabolism. The present study reports the first nuclear magnetic resonance
(NMR)-based metabolomics study to assess the in vivo impact of Pd2 Spm on the metabolism of
healthy mice, to identify metabolic markers with possible relation to biotoxicity/side-effects and
their dynamics. The changes in the metabolic profiles of both aqueous and lipophilic extracts of mice
kidney, liver, and breast tissues were evaluated, as a function of drug-exposure time, using cisplatin
as a reference drug. A putative interpretation was advanced for the metabolic deviations specifically
triggered by Pd2 Spm, this compound generally inducing faster metabolic response and recovery to
control levels for all organs tested, compared to cisplatin (except for kidney lipid metabolism). These
results constitute encouraging preliminary metabolic data suggestive of potential lower negative
effects of Pd2 Spm administration.
Academic Editor: Ian D Wilson Show less
Three half-sandwich organometallic ruthenium(ii) complexes containing purine analogs such as triazolopyrimidines of general formula [(η6-p-cym)Ru(L)Cl2], where p-cym represents p Show more
Three half-sandwich organometallic ruthenium(ii) complexes containing purine analogs such as triazolopyrimidines of general formula [(η6-p-cym)Ru(L)Cl2], where p-cym represents p-cymene and L is 5,6,7-trimethyl-1,2,4-triazolo[1,5-a]pyrimidine (tmtp for 1), 5,7-diethyl-1,2,4-triazolo[1,5-a]pyrimidine (detp for 2) and 5-methyl-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-one (HmtpO for 3), have been synthesized and characterized by elemental analysis, infrared, multinuclear magnetic resonance spectroscopic techniques (1H, 13C, 15N), and single-crystal X-ray diffraction (for 1 and 2). All these complexes have been thoroughly screened for their in vitro cytotoxicity against MCF-7 and HeLa cell lines as well as L929 murine fibroblast cells, indicating [(η6-p-cym)Ru(HmtpO)Cl2] (3) as the most active representative against the HeLa cell line and simultaneously being 64-fold less toxic to normal L929 murine fibroblast cells than cisplatin. At the same time, 3 has shown antimetastatic activity comparable to NAMI-A against HeLa cells both after 24 and 48 h of treatment in a wound healing assay. In order to better understand the mechanism of anticancer action and differences in the cytotoxic activity of 1-3, the studies were expanded to determining their lipophilicity, the kinetic stability at pH 6.5-8, the effect on reactive oxygen species (ROS) production in HeLa cells and interactions with significant biomolecules (DNA and albumin) by using molecular docking and circular dichroism (CD) experiments. Furthermore, antiparasitic studies against L. braziliensis, L. infantum and T. cruzi reveal that the newly synthesized complexes 1-3 are very promising candidates which can compete with commercial antiparasitic drugs. Complex 3 in particular, on top of exhibiting a high antiparasitic effect (IC50 < 1 μM against two strains), reaches a selectivity index >1000. Show less
The vascular endothelial glycocalyx is a dense, bush-like structure that is synthesized and secreted by endothelial cells and evenly distributed on the surface of vascular endothelial cells. The blood Show more
The vascular endothelial glycocalyx is a dense, bush-like structure that is synthesized and secreted by endothelial cells and evenly distributed on the surface of vascular endothelial cells. The blood-brain barrier (BBB) is mainly composed of pericytes endothelial cells, glycocalyx, basement membranes, and astrocytes. The glycocalyx in the BBB plays an indispensable role in many important physiological functions, including vascular permeability, inflammation, blood coagulation, and the synthesis of nitric oxide. Damage to the fragile glycocalyx can lead to increased permeability of the BBB, tissue edema, glial cell activation, up-regulation of inflammatory chemokines expression, and ultimately brain tissue damage, leading to increased mortality. This article reviews the important role that glycocalyx plays in the physiological function of the BBB. The review may provide some basis for the research direction of neurological diseases and a theoretical basis for the diagnosis and treatment of neurological diseases. Show less
Mitochondria are vital subcellular organelles that generate most cellular chemical energy, regulate cell metabolism and maintain cell function. Mitochondrial dysfunction is directly linked to numerous Show more
Mitochondria are vital subcellular organelles that generate most cellular chemical energy, regulate cell metabolism and maintain cell function. Mitochondrial dysfunction is directly linked to numerous diseases including neurodegenerative disorders, diabetes, thyroid squamous disease, cancer and septicemia. Thus, the design of specific mitochondria-targeting molecules and the realization of real-time acquisition of mitochondrial activity are powerful tools in the study and treatment of mitochondria dysfunction in related diseases. Recent advances in mitochondria-targeting agents have led to several important mitochondria chemical probes that offer the opportunity for selective targeting molecules, novel biological applications and therapeutic strategies. This review details the structural and physiological functional characteristics of mitochondria, and comprehensively summarizes and classifies mitochondria-targeting agents. In addition, their pros and cons and their related chemical biological applications are discussed. Finally, the potential biomedical applications of these agents are briefly prospected. Show less
The photophysical and biological properties of two new phenanthroline-based ligand ruthenium complexes were investigated in detail. Their DNA interaction modes were determined to be the intercalation Show more
The photophysical and biological properties of two new phenanthroline-based ligand ruthenium complexes were investigated in detail. Their DNA interaction modes were determined to be the intercalation mode using spectra titration and viscosity measurements. Under irradiation, obvious photo-reduced DNA cleavages were observed in the two complexes via singlet oxygen generation. Furthermore, complex 2 showed higher DNA affinity, photocleavage activity, and singlet oxygen quantum yields than complex 1. The two complexes showed no toxicity towards tumor cells (HeLa, A549, and A375) in the dark. However, obvious photocytotoxicities were observed in the two complexes. Complex 2 exhibited large PIs (phototherapeutic indices) (ca. 400) towards HeLa cells. The study suggests that these complexes may act as DNA intercalators, DNA photocleavers, and photocytotoxic agents. Show less
Phase separation of DNA is involved in chromatin packing for the regulation of gene transcription. Visualization and manipulation of DNA phase separation in living cells present great challenges. Here Show more
Phase separation of DNA is involved in chromatin packing for the regulation of gene transcription. Visualization and manipulation of DNA phase separation in living cells present great challenges. Herein, we present a Ru(II) complex (Ru1) with high DNA binding affinity and DNA "light-switch" behavior that can induce and monitor DNA phase separation both in vitro and in living cells. Molecular dynamics simulations indicate that the two phen-PPh3 ligands with positively charged lipophilic triphenylphosphine substituents and flexible long alkyl chains in Ru1 play essential roles in the formation of multivalent binding forces between DNA molecules to induce DNA phase separation. Importantly, the unique environmental sensitive emission property of Ru1 enables direct visualization of the dynamic process of DNA phase separation in living cells by two-photon phosphorescent lifetime imaging. Moreover, Ru1 can change the gene expression pattern by modulating chromatin accessibility as demonstrated by integrating RNA-sequencing and transposase-accessible chromatin with high-throughput sequencing. In all, we present here the first small-molecule-based tracer and modulator of DNA phase separation in living cells and elucidate its impact on the chromatin state and transcriptome. Show less
Ruthenium(II) complexes (Ru1-Ru5), with the general formula [Ru(N-S)(dppe)2]PF6, bearing two 1,2-bis(diphenylphosphino)ethane (dppe) ligands and a series of Show more
Ruthenium(II) complexes (Ru1-Ru5), with the general formula [Ru(N-S)(dppe)2]PF6, bearing two 1,2-bis(diphenylphosphino)ethane (dppe) ligands and a series of mercapto ligands (N-S), have been developed. The combination of these ligands in the complexes endowed hydrophobic species with high cytotoxic activity against five cancer cell lines. For the A549 (lung) and MDA-MB-231 (breast) cancer cell lines, the IC50 values of the complexes were 288- to 14-fold lower when compared to cisplatin. Furthermore, the complexes were selective for the A549 and MDA-MB-231 cancer cell lines compared to the MRC-5 nontumor cell line. The multitarget character of the complexes was investigated by using calf thymus DNA (CT DNA), human serum albumin, and human topoisomerase IB (hTopIB). The complexes potently inhibited hTopIB. In particular, complex [Ru(dmp)(dppe)2]PF6 (Ru3), bearing the 4,6-diamino-2-mercaptopyrimidine (dmp) ligand, effectively inhibited hTopIB by acting on both the cleavage and religation steps of the catalytic cycle of this enzyme. Molecular docking showed that the Ru1-Ru5 complexes have binding affinity by active sites on the hTopI and hTopI-DNA, mainly via π-alkyl and alkyl hydrophobic interactions, as well as through hydrogen bonds. Complex Ru3 displayed significant antitumor activity against murine melanoma in mouse xenograph models, but this complex did not damage DNA, as revealed by Ames and micronucleus tests. Show less
Mitochondrial structure and organization is integral to maintaining mitochondrial homeostasis and an emerging biological target in aging, inflammation, neurodegeneration, and cancer. The study of mito Show more
Mitochondrial structure and organization is integral to maintaining mitochondrial homeostasis and an emerging biological target in aging, inflammation, neurodegeneration, and cancer. The study of mitochondrial structure and its functional implications remains challenging in part because of the lack of available tools for direct engagement, particularly in a disease setting. Here, we report a gold-based approach to perturb mitochondrial structure in cancer cells. Specifically, the design and synthesis of a series of tricoordinate Au(I) complexes with systematic modifications to group 15 nonmetallic ligands establish structure-activity relationships (SAR) to identify physiologically relevant tools for mitochondrial perturbation. The optimized compound, AuTri-9 selectively disrupts breast cancer mitochondrial structure rapidly as observed by transmission electron microscopy with attendant effects on fusion and fission proteins. This phenomenon triggers severe depolarization of the mitochondrial membrane in cancer cells. The high in vivo tolerability of AuTri-9 in mice demonstrates its preclinical utility. This work provides a basis for rational design of gold-based agents to control mitochondrial structure and dynamics. Show less
The mitochondrial uniporter is a Ca2+-selective ion-conducting channel in the inner mitochondrial membrane that is involved in various cellular processes. The components of this uniporter, including t Show more
The mitochondrial uniporter is a Ca2+-selective ion-conducting channel in the inner mitochondrial membrane that is involved in various cellular processes. The components of this uniporter, including the pore-forming membrane subunit MCU and the modulatory subunits MCUb, EMRE, MICU1, and MICU2, have been identified in recent years. Previously, extensive studies revealed various aspects of uniporter activities and proposed multiple regulatory models of mitochondrial Ca2+ uptake. Recently, the individual auxiliary components of the uniporter and its holocomplex have been structurally characterized, providing the first insight into the component structures and their spatial relationship within the context of the uniporter. Here, we review recent uniporter structural studies in an attempt to establish an architectural framework, elucidating the mechanism that governs mitochondrial Ca2+ uptake and regulation, and to address some apparent controversies. This information could facilitate further characterization of mitochondrial Ca2+ permeation and a better understanding of uniporter-related disease conditions. Show less
Eight new ruthenium(II) complexes of N,N-chelating pyrazolylbenzimidazole ligands of the general formula [RuII(p-cym)(L)X]+ [where the ligand L is 2-(1HShow more
Eight new ruthenium(II) complexes of N,N-chelating pyrazolylbenzimidazole ligands of the general formula [RuII(p-cym)(L)X]+ [where the ligand L is 2-(1H-pyrazol-1-yl)-1H-benzo[d]imidazole (L1) substituted at the 4 position of the pyrazole ring by Cl (L2), Br (L3), or I (L4) and X = Cl- and I-] were synthesized and characterized using various analytical techniques. Complexes 1 and 3 were also characterized by single-crystal X-ray crystallography, and they crystallized as a monoclinic crystal system in space groups P21/n and P21/c, respectively. The complexes display good solution stability at physiological pH 7.4. The iodido-coordinated pyrazolylbenzimidazole ruthenium(II) p-cymene complexes (2, 4, 6, and 8) are more resistant toward hydrolysis and have less tendency to form monoaquated complexes in comparison to their chlorido analogues (1, 3, 5, and 7). The halido-substituted 2-(1H-pyrazol-1-yl)-1H-benzo[d]imidazole ligands, designed as organic-directing molecules, inhibit vascular endothelial growth factor receptor 2 (VEGFR2) phosphorylation. In addition, the ruthenium(II) complexes display a potential to bind to DNA bases. The cytotoxicity profile of the complexes (IC50 ca. 9-12 μM for 4-8) against the triple-negative breast cancer cells (MDA-MB-231) show that most of the complexes are efficient. The lipophilicity and cellular accumulation data of the complexes show a good correlation with the cytotoxicity profile of 1-8. The representative complexes 3 and 7 demonstrate the capability of arresting the cell cycle in the G2/M phase and induce apoptosis. The inhibition of VEGFR2 phosphorylation with the representative ligands L2 and L4 and the corresponding metal complexes 3 and 7in vitro shows that the organic-directing ligands and their complexes inhibit VEGFR2 phosphorylation. Besides, L2, L4, 3, and 7 inhibit the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and proto-oncogene tyrosine-protein kinase (Src), capable of acting downstream of VEGFR2 as well as independently. Compounds L2, L4, 3, and 7 have a lesser effect on ERK1/2 and more prominently affect Src phosphorylation. We extended the study for L2 and 3 in the Tg(fli1:gfp) zebrafish model and found that L2 is more effective in vivo compared to 3 in inhibiting angiogenesis. Show less
Solution chemical properties of two novel 8-hydroxyquinoline-D-proline and homo-proline hybrids were investigated along with their complex formation with [Rh(η5-C5Me5) Show more
Solution chemical properties of two novel 8-hydroxyquinoline-D-proline and homo-proline hybrids were investigated along with their complex formation with [Rh(η5-C5Me5)(H2O)3]2+ and [Ru(η6-p-cymene)(H2O)3]2+ ions by pH-potentiometry, UV-visible spectrophotometry and 1H NMR spectroscopy. Due to the zwitterionic structure of the ligands, they possess excellent water solubility as well as their complexes. The complexes exhibit high solution stability in a wide pH range; no significant dissociation occurs at physiological pH. The hybrids and their Rh(η5-C5Me5) complexes displayed enhanced cytotoxicity in human colon adenocarcinoma cell lines and exhibited multidrug resistance selectivity. In addition, the Rh(η5-C5Me5) complexes showed increased selectivity to the chemosensitive cancer cells over the normal cells; meanwhile, the Ru(η6-p-cymene) complexes were inactive, most likely due to arene loss. Interaction of the complexes with human serum albumin (HSA) and calf-thymus DNA (ct-DNA) was investigated by capillary electrophoresis, fluorometry and circular dichroism. The complexes are able to bind strongly to HSA and ct-DNA, but DNA cleavage was not observed. Changing the five-membered proline ring to the six-membered homoproline resulted in increased lipophilicity and cytotoxicity of the Rh(η5-C5Me5) complexes while changing the configuration (L vs. D) rather has an impact on HSA or ct-DNA binding. Show less
Title: Cytotoxicity evaluation and DNA interaction of Ru
Abstract: Although there are various treatment options for cancer, this disease still has caused an increasing number of deaths, demanding mor Show more
Title: Cytotoxicity evaluation and DNA interaction of Ru
Abstract: Although there are various treatment options for cancer, this disease still has caused an increasing number of deaths, demanding more efficient, selective and less harmful drugs. Several classes of ruthenium compounds have been investigated as metallodrugs for cancer, mainly after the entry of imidazolH [trans-RuCl4-(DMSO-S)(imidazole)] (NAMI-A) and indazolH [trans-RuCl4-(Indazol)2] (KP1019) in clinical trials. In this sense, RuII complexes with general formula [Ru(L1-3)(bipy)2]PF6 (1-3) (L1 = ethyl 3-(6-methyl-2-oxo-2H-chromen-3-yl)-3-oxopropanoate, L2 = ethyl 3-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)-3-oxopropanoate, L3 = ethyl 3-(8-methoxy-2-oxo-2H-chromen-3-yl)-3-oxopropanoate and bipy = bipyridine) have been synthesized. The crystal structure of 2 revealed that the RuII atom lies on a distorted octahedral geometry with the deprotonated ligand (L2-) coordinated through β-ketoester group oxygen atoms. In vitro cytotoxic activity of the compounds was evaluated against 4T1 (murine mammary carcinoma) and B16-F10 (murine metastatic melanoma) tumor cells, and the non-tumor cell line BHK-21 (baby hamster kidney). Coordination with RuII resulted in expressive enhancement of cytotoxic activity. The precursors were inactive below 100 μM and the final RuII complexes (1-3) showed IC50 ranging from 2.0 to 12.8 μM; 2 being the most potent compound. DNA interaction studies revealed a greater capacity of the complexes to interact with DNA than the ligands, where, 2 exhibited the highest Kb constant of 2.2 × 104 M-1. Fluorescence investigation demonstrated that 1-3 are capable of quenching the fluorescence emission of the EtdBr-DNA complex up to 40%. Molecular docking showed that the interaction of 1-3 between the DNA base pairs from the coumarin portion was with scores of 67.28, 68.62 and 64.88, respectively, and 75.45 for ellipticine, suggesting an intercalative mode of binding. Our findings show that the RuII complexes are eligible for continuing to be investigated as potential antitumor compounds. Show less
The antiproliferative activity of three cyclometalated Ru(II) complexes with the formula [Ru(bpy)2L]PF6, where bpy = 2,2'-bipyridine, Ru1: L1 = phenanthro[4,5-fgh]quinoxaline; Ru Show more
The antiproliferative activity of three cyclometalated Ru(II) complexes with the formula [Ru(bpy)2L]PF6, where bpy = 2,2'-bipyridine, Ru1: L1 = phenanthro[4,5-fgh]quinoxaline; Ru2: L2 = benzo[f]naphtho[2,1-h]quinoxaline; and Ru3: L3 = phenanthro[9,10-b]pyrazine, have been synthesized and characterized. The lipophilicity of the three Ru(II) complexes was modulated by the alteration of the planarity in the ligands of the complexes. With appropriate lipophilicity, Ru1-Ru3 exhibited mitochondrial accumulating property and cytotoxic activity against a spectrum of cancer cell lines. The underlying mechanism study indicated that these Ru(II) complexes can selectively accumulate in mitochondria and disrupt physiological processes, including the redox balance and energy generation in cancer cells. Elevation of iron content in triple-negative breast cancer (MDA-MB-231 cells) was observed after treatment with Ru(II) complexes, which may contribute to the production of reactive oxygen species (ROS) via Fenton reaction chemistry. Besides, the Ru(II) complexes decreased the intracellular glutathione (GSH) in cancer cells, leading to the failure in the cells to combat oxidative damage. Both of the mentioned processes contribute to the high oxidative stress and eventually lead to cancer cell death. On the other hand, Ru1-Ru3 significantly induced the depletion of adenosine triphosphate (ATP), causing disturbance of energy generation. Moreover, the results of wound-healing assay and transwell invasion assay, as well as the tube formation assay indicated the anti-migration and anti-angiogenesis properties of Ru1-Ru3. Our study demonstrated that these Ru(II) complexes are promising chemotherapeutic agents with oxidative stress induction and energy generation disturbance. Show less
Title: Luminescent naphthalimide-tagged ruthenium(ii)-arene complexes: cellular imaging, photocytotoxicity and transferrin binding.
Abstract: Two water-soluble piano-stool shaped ruthenium(ii)-arene Show more
Title: Luminescent naphthalimide-tagged ruthenium(ii)-arene complexes: cellular imaging, photocytotoxicity and transferrin binding.
Abstract: Two water-soluble piano-stool shaped ruthenium(ii)-arene complexes, [RuII(η6-p-cymene)(L)Cl2] [RuLCl] and [RuII(η6-p-cymene)(L)(PTA)Cl] [RuLPTA], were designed as emissive photocytotoxic agents tagged with morpholine as the lysosome targeting moiety. Here, L = N-(2-morpholinoethyl)-4-(2-aminoethyl)amino-naphthalimide, and PTA = 1,3,5-triaza-7-phosphatricyclo-[3.3.1.1]decane. The crystal structure of [RuLCl] exhibits the pseudooctahedral 'three-legged piano-stool' geometry, wherein Ru(ii) is bound to the η6-p-cymene moiety as a base and two chlorides and the amine-N of the ligand L occupies the three legs of the stool. The complexes exhibited both the possibility of covalent adduct formation via the hydrolyzed Ru-Cl bond and non-covalent intercalation binding through planar naphthalimide moieties. The complexes showed enhanced photo-cytotoxicity under low-power blue LED light irradiation (λmax = 448 nm) mediated by 1O2, thereby acting as potential PDT agents. Fluorescence microscopy studies revealed that luminescent complexes preferentially localized in both the lysosomes and nucleus for effectively targeting and damaging the nuclear DNA for PDT effects. Due to enhanced lipophilicity of [RuLCl], it showed higher internalization into MCF-7 cell, measured in terms of the ruthenium content using ICP-MS. The interaction of the complexes with human transferrin (hTf) proteins was studied through molecular docking calculations, suggesting favorable binding through histidine residues and possible internalization into cancer cells via TfR-mediated endocytosis. The luminescence properties of the complexes were well-utilized to study their cellular uptake mechanism via endocytosis using fluorescence microscopy. Show less
The number of cancer cases continues to increase worldwide, and unfortunately the main systemic treatments available have numerous of side effects. Ruthenium complexes have shown to be promising chemo Show more
The number of cancer cases continues to increase worldwide, and unfortunately the main systemic treatments available have numerous of side effects. Ruthenium complexes have shown to be promising chemotherapeutic agents, since they present low toxicity and are more selective for tumor tissues. We report the synthesis, characterization and biological properties of two new ruthenium (II) complexes containing Lapachol and Lawsone as ligands: (1) [Ru(Law)(dppb)(phen)]PF6 and (2) [Ru(Lap)(dppb)(phen)]PF6, where Law = Lawsone, Lap = Lapachol, dppb = 1,4-bis(diphenylphosphine)butane and phen = 1,10-phenanthroline. The ability of the complexes (1) and (2) to interact with CT-DNA (Calf Thymus) was investigated, and the results indicate that the complexes have shown a weak interaction with this macromolecule. Complexes (1) and (2) showed a moderate interaction with BSA, via a spontaneous process with the involvement of van der Waals and hydrogen bond interactions. Both complexes were tested against human lung cancer cell lines, chronic human myeloid leukemia, murine melanoma and human cervical and non-tumoral murine fibroblast adenocarcinoma, human lung fibroblasts and monkey kidney epithelia. The potential for cytotoxicity was tested out using the MTT assay and the neutral red test, to calculate inhibitory concentrations (IC50) and selectivity indices (IS). Both complexes showed a higher selectivity index of 1.17 and 10.91, respectively, for the HeLa tumor line. Studies of toxicological evaluation, using the micronucleus test and the comet assay against non-tumor cells, as well as an assessment of the potential for acute toxicity and neurotoxicity in zebrafish (Danio rerio). In the in vitro micronucleus test, complex (1) showed the least genotoxic potential, and in the in vitro comet assay both compounds had revealed a genotoxic potential at 0.5 and 1.0 mg L-1, with no difference between 24 h and 48 h exposure times. In the acute toxicity tests on zebrafish embryos, complex (1) showed sublethal effects such as decreased blood circulation and heartbeat rate, which were less pronounced than with complex (2). In contrast to complex 2, which caused lethality even before 48h, complex (1) did not cause the death of the embryos at concentrations up to (2.0 mg L-1). Complex (2) also lead to a delay in the embryo. Cell based in vitro methods thus proved able to provide specific toxicological data, allowing a significant reduction in ∖animal experimentation. Given that in vitro tests cannot completely replace animal tests, the use of less advanced developmental stages such as zebrafish embryos, which - at least in the European Union - are not regarded protected, could be shown to be an excellent alternative for testing with, e.g., mammals. Show less
The ability to detect oxygen availability is a ubiquitous attribute of aerobic organisms. However, the mechanism(s) that transduce oxygen concentration or availability into appropriate physiological r Show more
The ability to detect oxygen availability is a ubiquitous attribute of aerobic organisms. However, the mechanism(s) that transduce oxygen concentration or availability into appropriate physiological responses is less clear and often controversial. This review will make the case for oxygen-dependent metabolism of hydrogen sulfide (H2S) and polysulfides, collectively referred to as reactive sulfur species (RSS) as a physiologically relevant O2 sensing mechanism. This hypothesis is based on observations that H2S and RSS metabolism is inversely correlated with O2 tension, exogenous H2S elicits physiological responses identical to those produced by hypoxia, factors that affect H2S production or catabolism also affect tissue responses to hypoxia, and that RSS efficiently regulate downstream effectors of the hypoxic response in a manner consistent with a decrease in O2. H2S-mediated O2 sensing is then compared to the more generally accepted reactive oxygen species (ROS) mediated O2 sensing mechanism and a number of reasons are offered to resolve some of the confusion between the two. Show less
To unearth suitable complexes that are capable of inhibiting the growth of MDA-MB-468 and Caco-2 cells, 2,2'-bipyrimidine-based luminescent Ru(ii)/Ir(iii)-arene monometallic and homo- and hetero-bimet Show more
To unearth suitable complexes that are capable of inhibiting the growth of MDA-MB-468 and Caco-2 cells, 2,2'-bipyrimidine-based luminescent Ru(ii)/Ir(iii)-arene monometallic and homo- and hetero-bimetallic complexes were synthesized. The complex [(η6-p-cymene)(η5-Cp*)RuIIIrIIICl2(K2-N,N-bipyrimidine)](PF6)2 [LRuIr] exhibited the best potency in both cells along with good GSH stability and strong binding efficacy with the biomolecules. The apoptotic event occurred in MDA-MB-468 cancer cells via cell cycle arrest. Show less
Background/Aim. The use of cisplatin as a chemotherapeutic opened the door to the new metal-based drug research. New complexes containing metals such as platinum, palladium, ruthenium and gold have re Show more
Background/Aim. The use of cisplatin as a chemotherapeutic opened the door to the new metal-based drug research. New complexes containing metals such as platinum, palladium, ruthenium and gold have recently been analyzed as potential antitumor agents. The aim of the study was to investigate the cytotoxicity of Au(III) complexes with pincer-type ligands against cervical carcinoma cells (HeLa), breast cancer cells (MDA-MB-231 and 4T1) and colon carcinoma cells (HCT116 and CT26), as well as to examine the type and mechanism of cell death that these complexes induced in cancer cells. Methods. The cytotoxicity of Au(III) complexes was investigated by MTT assay. The apoptosis of the treated cancer cells was measured by flow cytometry and applying Annexin V/7AAD staining. The expressions of active proapoptotic protein Bax, antiapoptotic protein Bcl-2 and the percentage of cells containing cleaved caspase-3 in the treated cancer cells were determined by flow cytometry. Results. Complex 1 showed the most potent antitumor effect on HeLa cells, both compared to other two examined gold complexes and compared to cisplatin. The IC50 values on HeLa cells after 72 hours were 1.3 ? 0.4 ?M, 3.4 ? 1.3 ?M, 5.7 ? 0.6 ?M, 26.7 ? 6.5 ?M for complexes 1, 2, 3 and cisplatin, respectively. Complex 1 also exhibited the highest cytotoxicity against MDA-MB-231 and HCT116 cells compared to other tested compounds. The results of Annexin V/7AAD staining showed that all three gold complexes induced apoptosis in the treated cells. Our Au(III) complexes induced apoptosis by caspase-dependent mechanism, but we did not observe that the activation of an internal pathway of apoptosis occurred in the treated cancer cells. Conclusion. According to the results of our in vitro study, all three gold compounds, and especially complex 1, are promising candidates for a new generation of anticancer drugs. Show less
Au2phen ((2,9-dimethyl-1,10-phenanthroline)2Au2(µ-O)2)(PF6)2 and Auoxo6 ((6,6′-dimethyl-2,2′-bipyridine)2Au2(µ-O)2)(PF6)2 are two structurally related gold(III) complexes that were previously reported Show more
Au2phen ((2,9-dimethyl-1,10-phenanthroline)2Au2(µ-O)2)(PF6)2 and Auoxo6 ((6,6′-dimethyl-2,2′-bipyridine)2Au2(µ-O)2)(PF6)2 are two structurally related gold(III) complexes that were previously reported to display relevant and promising anticancer properties in vitro toward a large number of human cancer cell lines. To expand the knowledge on the molecular mechanisms through which these gold(III) complexes trigger apoptosis in cancer cells, further studies have been performed using A2780 ovarian cancer cells as reference models. For comparative purposes, parallel studies were carried out on the gold(III) complex AuL12 (dibromo(ethylsarcosinedithiocarbamate)gold(III)), whose proapoptotic profile had been earlier characterized in several cancer cell lines. Our results pointed out that all these gold(III) compounds manifest a significant degree of similarity in their cellular and proapoptotic effects; the main observed perturbations consist of potent thioredoxin reductase inhibition, disruption of the cell redox balance, impairment of the mitochondrial membrane potential, and induction of associated metabolic changes. In addition, evidence was gained of the remarkable contribution of ASK1 (apoptosis-signal-regulating kinase-1) and AKT pathways to gold(III)-induced apoptotic signaling. Overall, the observed effects may be traced back to gold(III) reduction and subsequent formation and release of gold(I) species that are able to bind and inhibit several enzymes responsible for the intracellular redox homeostasis, in particular the selenoenzyme thioredoxin reductase. Show less
Fourteen new RuII -arene (p-cymene/benzene) complexes (C1-C14) have been synthesized by varying the N-terminal substituent in the furoylthiourea ligand and satisfactorily characterized by u Show more
Fourteen new RuII -arene (p-cymene/benzene) complexes (C1-C14) have been synthesized by varying the N-terminal substituent in the furoylthiourea ligand and satisfactorily characterized by using analytical and spectroscopic techniques. Electrostatic potential maps predicted that the electronic effect of the substituents was mostly localized, with some influence seen on the labile chloride ligands. The structure-activity relationships of the Ru-p-cymene and Ru-benzene complexes showed opposite trends. All the complexes were found to be highly toxic towards IMR-32 cancer cells, with C5 (Ru-p-cymene complex containing C6 H2 (CH3 )3 as N-terminal substituent) and C13 (Ru-benzene complex containing C6 H4 (CF3 ) as N-terminal substituent) showing the highest activity among each set of complexes, and hence they were chosen for further study. These complexes showed different behavior in aqueous solutions, and were also found to catalytically oxidize glutathione. They also promoted cell death by apoptosis and cell cycle arrest. Furthermore, the complexes showed good binding ability with the receptors Pim-1 kinase and vascular endothelial growth factor receptor 2, commonly overexpressed in cancer cells. Show less
Developing the cell-impermeable Ru(II) polypyridyl cationic complexes as effective photosensitizers (PS) which have high cellular uptake and photo-toxicity, but low dark toxicity, is quite challenging Show more
Developing the cell-impermeable Ru(II) polypyridyl cationic complexes as effective photosensitizers (PS) which have high cellular uptake and photo-toxicity, but low dark toxicity, is quite challenging. Here we found that the highly reactive singlet oxygen (1O2) can be generated by the irradiation of a typical Ru(II) polypyridyl complex Ru(II)tris(tetramethylphenanthroline) ([Ru(TMP)3]2+) under visible light irradiation by ESR with TEMPO (2,2,6,6-tetramethyl-4-piperidone-N-oxyl) as 1O2 probe. Effective cellular and nuclear delivery of cationic [Ru(TMP)3]2+ was achieved through our recently developed ion-pairing method, and 2,3,4,5-tetrachlorophenol (2,3,4,5-TeCP) was found to be the most effective among all chlorophenols tested. The accelerated cellular, especially nuclear uptake of [Ru(TMP)3]2+ results in the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and DNA strand breaks, caspase 3/7 activation and cell apoptosis in HeLa cells upon light irradiation. More importantly, compared with other traditional photosensitizers, [Ru(TMP)3]2+ showed significant photo-toxicity but low dark toxicity. Similar effects were observed when 2,3,4,5-TeCP was substituted by the currently clinically used anti-inflammatory drug flufenamic acid. This represents the first report that the cell-impermeable Ru(II) polypyridyl complex ion-paired with suitable lipophilic counter-anions functions as potent intracellular photosensitizer under visible light irradiation mainly via a 1O2-mediated mechanism. These findings should provide new perspectives for future investigations on other metal complexes with similar characteristics as promising photosensitizers for potential photodynamic therapy. Show less
2021 · Chemistry – A European Journal · Wiley · added 2026-05-21
AbstractCyclic (Alkyl)(Amino)Carbenes (CAACs) have become forceful ligands for gold due to their ability to form very strong ligand‐metal bonds. Inspired by the success of Auranofin and other gold com Show more
AbstractCyclic (Alkyl)(Amino)Carbenes (CAACs) have become forceful ligands for gold due to their ability to form very strong ligand‐metal bonds. Inspired by the success of Auranofin and other gold complexes as antitumor agents, we have studied the cytotoxicity of bis‐ and mono‐CAAC‐gold complexes on different cancer cell lines: HeLa (cervical cancer), A549 (lung cancer), HT1080 (fibrosarcoma) and Caov‐3 (ovarian cancer). Further investigations aimed at elucidating their mechanism of action are described. This includes quantification of affinities for TrxR, evaluation of their bioavailability and determination of associated cell death process. Moreover, Transmission Electron Microscopy (TEM) was used to study morphological changes upon exposure. Noticeably, a significant reduction in non‐specific binding to serum proteins was observed with CAAC complexes when compared to Auranofin. These results confirm the potential of CAAC‐gold complexes in biological environments, which may result in more specific drug‐target interactions and decreased side effects.
TLDR: The results confirm the potential of CAAC-gold complexes in biological environments, which may result in more specific drug-target interactions and decreased side effects, and further investigations aimed at elucidating their mechanism of action are described. Show less
Cisplatin is one of the most commonly used drugs for the treatment of various solid neoplasms, including testicular, lung, ovarian, head and neck, and bladder cancers. Unfortunately, the therapeutic e Show more
Cisplatin is one of the most commonly used drugs for the treatment of various solid neoplasms, including testicular, lung, ovarian, head and neck, and bladder cancers. Unfortunately, the therapeutic efficacy of cisplatin against colorectal cancer is poor. Various mechanisms appear to contribute to cisplatin resistance in cancer cells, including reduced drug accumulation, enhanced drug detoxification, modulation of DNA repair mechanisms, and finally alterations in cisplatin DNA damage signaling preventing apoptosis in cancer cells. Regarding colorectal cancer, defects in mismatch repair and altered p53-mediated DNA damage signaling are the main factors controlling the resistance phenotype. In particular, p53 inactivation appears to be associated with chemoresistance and poor prognosis. To overcome resistance in cancers, several strategies can be envisaged. Improved cisplatin analogues, which retain activity in resistant cancer, might be applied. Targeting p53-mediated DNA damage signaling provides another therapeutic strategy to circumvent cisplatin resistance. This review provides an overview on the DNA repair pathways involved in the processing of cisplatin damage and will describe signal transduction from cisplatin DNA lesions, with special attention given to colorectal cancer cells. Furthermore, examples for improved platinum compounds and biochemical modulators of cisplatin DNA damage signaling will be presented in the context of colon cancer therapy. Show less