Structural and tribological studies on the interaction of porcine gastric mucin with non- and cationic-modified ß-lactoglobulins.

ß-lactoglobulin (BLG) is the major whey protein with negative charges at neutral pH in aqueous media. Thus, the interaction with mucins, the major polyanionic component of mucus, is very weak due to the electrostatic repulsion between them. The present study postulates that cationization of BLG molecules may reverse the interaction characteristics between BLG and mucin from repulsive to associative. To this end, cationic-modified BLGs were prepared by grafting positively charged ethylenediamine (EDA) moieties into the negatively charged carboxyl groups on the aspartic and glutamic acid residues and compared with non-modified BLG upon mixing with porcine gastric mucin (PGM). To characterize the structural and conformational features of PGM, non/cationized BLGs, and their mixtures, various spectroscopic approaches, including zeta potential, dynamic light scattering (DLS), and circular dichroism (CD) spectroscopy were employed. Importantly, we have taken surface adsorption with optical waveguide lightmode spectroscopy (OWLS), and tribological properties with pin-on-disk tribometry at the sliding interface as the key approaches to determine the interaction nature between them as mixing PGM with polycations can lead to synergistic lubrication at the nonpolar substrate in neutral aqueous media as a result of an electrostatic association. All the spectroscopic studies and a substantial improvement in lubricity collectively supported a tenacious and associative interaction between PGM and cationized BLGs, but not between PGM and non-modified BLG. This study demonstrates a unique and successful approach to intensify the interaction between BLG and mucins, which is meaningful for a broad range of disciplines, including food science, macromolecular interactions, and biolubrication etc.

Design, Synthesis, Electrochemical, and Biological Evaluation of Fluorescent Chlorido[N,N'-bis(methoxy/hydroxy)salicylidene-1,2-bis(4-methoxyphenyl)ethylenediamine]iron(III) Complexes as Anticancer Agents.

The impact of methoxy and hydroxyl groups at the salicylidene moiety of chlorido[N,N'-bis(methoxy/hydroxy)salicylidene-1,2-bis(4-methoxyphenyl)ethylenediamine]iron(III) complexes was evaluated on human MDA-MB 231 breast cancer and HL-60 leukemia cells. Methoxylated complexes (C1-C3) inhibited proliferation, migration, and metabolic activity in a concentration-dependent manner following the rank order: C2 > C3 > C1. In particular, C2 was highly cytotoxic with an IC50 of 4.2 µM which was 6.6-fold lower than that of cisplatin (IC50 of 27.9 µM). In contrast, hydroxylated complexes C4-C6 were almost inactive up to the highest concentration tested due to lack of cellular uptake. C2 caused a dual mode of cell death, ferroptosis, and necroptosis, whereby at higher concentrations, ferroptosis was the preferred form. Ferroptotic morphology and the presence of ferrous iron and lipid reactive oxygen species proved the involvement of ferroptosis. C2 was identified as a promising lead compound for the design of drug candidates inducing ferroptosis.

Comparative assessment of two biodegradable chelants, S,S-ethylenediamine disuccinic acid and nitrilotriacetic acid, in facilitating Cd remediation by lesser swine cress (Coronopus didymus, Brassicaceae).

Chemically assisted phytoremediation is suggested as an effective approach to amplify the metal-remediating potential of hyperaccumulators. The current study assessed the efficiency of two biodegradable chelants (S,S-ethylenediamine disuccinic acid, EDDS; nitrilotriacetic acid, NTA) in enhancing the remediation of Cd by Coronopus didymus (Brassicaceae). C. didymus growing in Cd-contaminated soil (35-175 mg kg-1 soil) showed increased growth and biomass due to the hormesis effect, and chelant supplementation further increased growth, biomass, and Cd accumulation. A significant interaction with chelants and different Cd concentrations was observed, except for Cd content in roots and Cd content in leaves, which exhibited a non-significant interaction with chelant addition. The effect of the NTA amendment on the root dry biomass and shoot dry biomass was more pronounced than EDDS at all the Cd treatments. Upon addition of EDDS and NTA, bio-concentration factor values were enhanced by ~184-205 and ~ 199-208, respectively. The tolerance index of root and shoot increased over the control upon the addition of chelants, with NTA being better than EDDS. With chelant supplementation, bio-accumulation coefficient values were in the order Cd35 + NTA (~163%) > Cd105 + NTA (~137%) > Cd35 + EDDS (~89%) > Cd175 + NTA (~85%) > Cd105 + EDDS (~62%) > Cd175 + EDDS (~40%). The translocation factor correlated positively (r ≥ 0.8) with tolerance index and Cd accumulation in different plant parts. The study demonstrated that chelant supplementation enhanced Cd-remediation efficiency in C. didymus as depicted by improved plant growth and metal accumulation, and NTA was more effective than EDDS in reclaiming Cd.

A Comparative XPS, UV PES, NEXAFS, and DFT Study of the Electronic Structure of the Salen Ligand in the H2(Salen) Molecule and the [Ni(Salen)] Complex.

A comparative study of the electronic structure of the salen ligand in the H2(Salen) molecule and the [Ni(Salen)] complex was performed using the experimental methods of XPS, UV PES, and NEXAFS spectroscopy along with DFT calculations. Significant chemical shifts of +1.0 eV (carbon), +1.9 eV (nitrogen), and -0.4 eV (oxygen) were observed in the 1s PE spectra of the salen ligand atoms when passing from a molecule to a complex, unambiguously indicating a substantial redistribution of the valence electron density between these atoms. It is proposed that the electron density transfer to the O atoms in [Ni(Salen)] occurred not only from the Ni atom, but also from the N and C atoms. This process seemed to be realized through the delocalized conjugated π-system of the phenol C 2p electronic states of the ligand molecule. The DFT calculations (total and partial DOS) for the valence band H2(Salen) and [Ni(Salen)] described well the spectral shape of the UV PE spectra of both compounds and confirmed their experimental identification. An analysis of the N and O 1s NEXAFS spectra clearly indicated that the atomic structure of the ethylenediamine and phenol fragments was retained upon passing from the free salen ligand to the nickel complex.

Cd2+-selective fluorescence response of TQEN (N,N,N',N'-tetrakis(2-quinolylmethyl)ethylenediamine) derivatives bearing ether oxygen-binding sites.

Moderate Zn2+ selectivity over Cd2+ (IZn/ICd = 1.6) in the fluorescence enhancement of TQEN (N,N,N',N'-tetrakis(2-quinolylmethyl)ethylenediamine) was changed to Cd2+ preference via the introduction of a methoxymethyloxy (MOMO) substituent at the 8-position of one of the four quinoline rings (IZn/ICd = 0.2). Thus, 8-MOMOTQEN (N-(8-methoxymethyloxy-2-quinolylmethyl)-N,N',N'-tris(2-quinolylmethyl)ethylenediamine) showed not only high Cd2+-selectivity but also an enhanced fluorescence quantum yield upon Cd2+ binding and high sensitivity for Cd2+ detection as shown by ϕCd = 0.065 and LOD (limit of detection) = 19 nM. The two oxygen atoms of the MOMO group in 8-MOMOTQEN play a crucial role in the fluorescent metal-ion selectivity because the corresponding hydroxy (8-OHTQEN) and methoxy (8-MeOTQEN) derivatives resulted in a poor fluorescent response and metal selectivity, respectively. Another N6O2 ligand, N,N'-bis(8-methoxy-2-quinolylethyl)-N,N'-bis(2-quinolylmethyl)ethylenediamine ((8-MeO)2TQEN) exhibited a Zn2+-selective fluorescence enhancement (IZn/ICd = 2.2), indicating the superiority of the MOMO group for the selective sensing of Cd2+.

Post-Modification of Copolymers Obtained by ATRP for an Application in Heterogeneous Asymmetric Salen Catalysis.

Copolymers are valuable supports for obtaining heterogeneous catalysts that allow their recycling and therefore substantial savings, particularly in the field of asymmetric catalysis. This contribution reports the use of two comonomers: Azido-3-propylmethacrylate (AZMA) bearing a reactive azide function was associated with 2-methoxyethyl methacrylate (MEMA), used as a spacer, for the ATRP synthesis of copolymers, and then post-functionalized with a propargyl chromium salen complex. The controlled homopolymerization of MEMA by ATRP was firstly described and proved to be more controlled in molar mass than that of AZMA for conversions up to 63%. The ATRP copolymerization of both monomers made it possible to control the molar masses and the composition, with nevertheless a slight increase in the dispersity (from 1.05 to 1.3) when the incorporation ratio of AZMA increased from 10 to 50 mol%. These copolymers were post-functionalized with chromium salen units by click chemistry and their activity was evaluated in the asymmetric ring opening of cyclohexene oxide with trimethylsilyl azide. At an equal catalytic ratio, a significant increase in enantioselectivity was obtained by using the copolymer containing the largest part of salen units, probably allowing, in this case, the more favorable bimetallic activation of both the engaged nucleophile and electrophile. Moreover, the catalytic polymer was recovered by simple filtration and re-engaged in subsequent catalytic runs, up to seven times, without loss of activity or selectivity.

Consequences of zinc deficiency on zinc localization, taurine transport, and zinc transporters in rat retina.

The colocalization of taurine and zinc transporters (TAUT, ZnTs) has not been explored in retina. Our objective is to evaluate the effect of the intracellular zinc chelator N,N,N,N-tetrakis-(2-pyridylmethyl) ethylenediamine (TPEN) on zinc localization and colocalization TAUT and ZnT-1 (of plasma membrane), 3 (vesicular), and 7 (vesicular and golgi apparatus) in layers of retina by immunohistochemistry. To mark zinc, it was used cell-permeable fluorescent Zinquin ethyl ester. Specific first and secondary antibodies, conjugated with rhodamine or fluorescein-isothiocyanate were used to mark TAUT and ZnTs. The fluorescence results were reported as integrated optical density (IOD). Zinc was detected in all layers of the retina. The treatment with TPEN produced changes in the distribution of zinc in layers of retina less in the outer nuclear layer compared with the control. TAUT was detected in all layers of retina and TPEN chelator produced decrease of IOD in all layers of retina except in the photoreceptor compared with the control. ZnT 1, 3, and 7 were distributed in all retina layers, with more intensity in ganglion cell layer (GCL) and in the layers where there is synaptic connection. For all transporters, the treatment with TPEN produced significant decrease of IOD in layers of retina least in the inner nuclear layer for ZnT1, in the photoreceptor for ZnT3 and in the GCL and outer plexiform layer for ZnT7. The distribution of zinc, TAUT, and ZnTs in the layers of retina is indicative of the interaction of taurine and zinc for the function of the retina and normal operation of said layers. HIGHLIGHTS: Taurine and zinc are two molecules highly concentrated in the retina and with relevant functions in this structure. Maintaining zinc homeostasis in this tissue is necessary for the normal function of the taurine system in the retina. The study of the taurine transporter and the different zinc transporters in the retina (responsible for maintaining adequate levels of taurine and zinc) is relevant and novel, since it is indicative of the interactions between both molecules in this structure.

Electronic Tuning in Reaction-Based Fluorescent Sensing for Instantaneous and Ultrasensitive Visualization of Ethylenediamine.

Manipulation of a multi-physical quantity to steer a molecular photophysical property is of great significance in improving sensing performance. Here, an investigation on how a physical quantity rooted in the molecular structure induces an optical behavior change to facilitate ultrasensitive detection of ethylenediamine (EDA) is performed by varying a set of thiols. The model molecule consisting of a thiol with dual-carboxyl exhibits the strongest fluorescence, which is ascribed to the electron-donating ability and prompted larger orbital overlap and oscillator strength. The elevated fluorescence positively corelated to the increased EDA, endowing an ultrasensitive response to the nanomolar-liquid/ppm-vapor. A gas detector with superior performance fulfills a contactless and real-time management of EDA. We envisage this electron-tuning strategy-enabled fluorescence enhancement can offer in-depth insight in advancing molecule-customized design, further paving the way to widening applications.

Biodegradable chelant-metal complexes enhance cadmium phytoextraction efficiency of Solanum americanum.

Toxic contaminants (metals and metal-containing compounds) are accumulating in the environment at an astonishing rate and jeopardize human health. Remarkable industrial revolution and the spectacular economic growth are the prime causes for the release of such toxic contaminants in the environment. Cadmium (Cd) is ranked the 7th most toxic compound by the Agency for Toxic Substances and Disease Registry (USA), owing to its high carcinogenicity and non-biodegradability even at miniscule concentration. The present study assessed the efficiency of four biodegradable chelants [nitrilotriacetic acid (NTA), ethylenediamine disuccinate (EDDS), ethylene glycol tetraacetic acid (EGTA), and citric acid (CA)] and their dose (5 mM and 10 mM) in enhancing metal accumulation in Solanum americanum Mill. (grown under 24 mg Cd kg-1 soil) through morpho-physiological and metal extraction parameters. Significant variations were observed for most of the studied parameters in response to chelants and their doses. However, ratio of root and shoot length, and plant height stress tolerance index differed non-significantly. The potential of chelants to enhance Cd removal efficiency was in the order - EGTA (7.44%) > EDDS (6.05%) > NTA (4.12%) > CA (2.75%). EGTA and EDDS exhibited dose-dependent behavior for Cd extraction with 10 mM dose being more efficient than 5 mM dose. Structural equation model (SEM) depicted strong positive interaction of metal extraction parameters with chelants (Z-value = 11.61, p = 0.001). This study provides insights into the importance of selecting appropriate dose of biodegradable chelants for Cd extraction, as high chelant concentration might also result in phytotoxicity. In the future, phytoextraction potential of these chelants needs to be examined through field studies under natural environmental conditions.

Making Chiral Salen Complexes Work with Organocatalysts.

Bisimine derivatives of salicylaldehyde with chiral diamines (salens) are privileged ligands in asymmetric organometallic catalysis, which can be used in cooperation with organocatalysts as additives. The latter can be a modifier of the metal reactivity by liganding or a true co-catalyst working in tandem or in a dual system. All scenarios encountered in the literature are reviewed and classified according to the organocatalyst. In each case, mechanistic and physical-organic chemistry considerations are discussed to better understand the gears of these complex catalytic settings.

Short divalent ethacrynic amides as pro-inhibitors of glutathione S-transferase isozyme Mu and potent sensitisers of cisplatin-resistant ovarian cancers.

The linking of ethacrynic acid with ethylenediamine and 1,4-butanediamine gave EDEA and BDEA, respectively, as membrane-permeable divalent pro-inhibitors of glutathione S-transferase (GST). Their divalent glutathione conjugates showed subnanomolar inhibition and divalence-binding to GSTmu (GSTM) (PDB: 5HWL) at ∼0.35 min-1. In cisplatin-resistant SK-OV-3, COC1, SGC7901 and A549 cells, GSTM activities probed by 15 nM BDEA or EDEA revealed 5-fold and 1.0-fold increases in cisplatin-resistant SK-OV-3 and COC1 cells, respectively, in comparison with the susceptible parental cells. Being tolerable by HEK293 and LO2 cells, BDEA at 0.2 µM sensitised resistant SK-OV-3 and COC1 cells by ∼3- and ∼5-folds, respectively, released cytochrome c and increased apoptosis; EDEA at 1.0 µM sensitised resistant SK-OV-3 and A549 cells by ∼5- and ∼7-fold, respectively. EDEA at 1.7 µg/g sensitised resistant SK-OV-3 cells to cisplatin at 3.3 µg/g in nude mouse xenograft model. BDEA and EDEA are promising leads for probing cellular GSTM and sensitising cisplatin-resistant ovarian cancers.

Polyaminated pullulan, a new biodegradable and cationic pullulan derivative for mucosal drug delivery.

AIM: To prepare new polycationic pullulan derivatives exhibiting highly mucoadhesive and sustained drug release properties. METHODS: Hydroxy groups of pullulan were activated with mesyl chloride followed by conjugation with low-molecular weight polyamines. Pullulan-tris(2-aminoethyl)amine (Pul-TAEA) and pullulan-polyethyleneimine (Pul-PEI) were evaluated regarding swelling behaviour, mucoadhesive properties and potential to control drug release. RESULTS: Pul-TAEA and Pul-PEI exhibited excellent swelling properties at pH 6.8 showing 240- and 370-fold increase in weight. Compared to unmodified pullulan, Pul-TAEA and Pul-PEI displayed 5- and 13.3-fold increased dynamic viscosity in mucus. Mucoadhesion studies of Pul-TAEA and Pul-PEI on intestinal mucosa showed a 6- and 37.8-fold increase in tensile strength, and a 72- and 120-fold increase in mucoadhesion time compared to unmodified pullulan, respectively. Due to additional ionic interactions between cationic groups on polyaminated pullulans and an anionic model drug, a sustained drug release was achieved. CONCLUSIONS: Polyaminated pullulans are promising novel mucoadhesive excipients for mucosal drug delivery.

Effect of cysteine thiols on the catalytic and anticancer activity of Ru(II) sulfonyl-ethylenediamine complexes.

We have synthesized a series of novel substituted sulfonyl ethylenediamine (en) RuII arene complexes 1-8 of [(η6-arene)Ru(R1-SO2-EnBz)X], where the arene is benzene, HO(CH2)2O-phenyl or biphenyl (biph), X = Cl or I, and R1 is phenyl, 4-Me-phenyl, 4-NO2-phenyl or dansyl. The 'piano-stool' structure of complex 3, [(η6-biph)Ru(4-Me-phenyl-SO2-EnBz)I], was confirmed by X-ray crystallography. The values of their aqua adducts were determined to be high (9.1 to 9.7). Complexes 1-8 have antiproliferative activity against human A2780 ovarian, and A549 lung cancer cells with IC50 values ranging from 4.1 to >50 µM, although, remarkably, complex 7 [(η6-biph)Ru(phenyl-SO2-EnBz)Cl] was inactive towards A2780 cells, but as potent as the clinical drug cisplatin towards A549 cells. All these complexes also showed catalytic activity in transfer hydrogenation (TH) of NAD+ to NADH with sodium formate as hydride donor, with TOFs in the range of 2.5-9.7 h-1. The complexes reacted rapidly with the thiols glutathione (GSH) and N-acetyl-L-cysteine (NAC), forming dinuclear bridged complexes [(η6-biph)2Ru2(GS)3]2- or [(η6-biph)2Ru2(NAC-H)3]2-, with the liberation of the diamine ligand which was detected by LC-MS. In addition, the switching on of fluorescence for complex 8 in aqueous solution confirmed release of the chelated DsEnBz ligand in reactions with these thiols. Reactions with GSH hampered the catalytic TH of NAD+ to NADH due to the decomposition of the complexes. Co-administration to cells of complex 2 [(η6-biph)Ru(4-Me-phenyl-SO2-EnBz)Cl] with L-buthionine sulfoximine (L-BSO), an inhibitor of GSH synthesis, partially restored the anticancer activity towards A2780 ovarian cancer cells. Complex 2 caused a concentration-dependent G1 phase cell cycle arrest, and induced a significant level of reactive oxygen species (ROS) in A2780 human ovarian cancer cells. The amount of induced ROS decreased with increase in GSH concentration, perhaps due to the formation of the dinuclear Ru-SG complex.

Cationic Effects on the Net Hydrogen Atom Bond Dissociation Free Energy of High-Valent Manganese Imido Complexes.

Local electric fields can alter energy landscapes to impart enhanced reactivity in enzymes and at surfaces. Similar fields can be generated in molecular systems using charged functionalities. Manganese(V) salen nitrido complexes (salen = N,N'-ethylenebis(salicylideneaminato)) appended with a crown ether unit containing Na+ (1-Na), K+, (1-K), Ba2+ (1-Ba), Sr2+ (1-Sr), La3+ (1-La), or Eu3+ (1-Eu) cation were investigated to determine the effect of charge on pKa, E1/2, and the net bond dissociation free energy (BDFE) of N-H bonds. The series, which includes the manganese(V) salen nitrido without an appended crown, spans 4 units of charge. Bounds for the pKa values of the transient imido complexes were used with the Mn(VI/V) reduction potentials to calculate the N-H BDFEs of the imidos in acetonitrile. Despite a span of >700 mV and >9 pKa units across the series, the hydrogen atom BDFE only spans ∼6 kcal/mol (between 73 and 79 kcal/mol). These results suggest that the incorporation of cationic functionalities is an effective strategy for accessing wide ranges of reduction potentials and pKa values while minimally affecting the BDFE, which is essential to modulating electron, proton, or hydrogen atom transfer pathways.

Analysis of the oligomeric state of mycobacterial membrane protein large 3 and its interaction with SQ109 with native cell membrane nanoparticles system.

Mycobacterial membrane protein large 3 (Mmpl3) as a trehalose monomycolate lipid transporter contributes to cell wall biosynthesis. Inhibition of Mmpl3 can suppress cell growth and lead to mycobacterial death. SQ109 is a hydrophobic inhibitor of Mmpl3. We have devised a detergent-free strategy to characterize the SQ109/Mmpl3 interaction using the Native Cell Membrane Nanoparticles (NCMN) system, a new method for extracting membrane proteins that better retains native lipids. The homogeneity of the Mmpl3 NCMN particles was confirmed with electron microscopy. The hydrophobic protein-ligand interaction analysis shown for Mmpl3 using the NCMN system may broadly apply to other membrane proteins.

B- and N-doped carbon dots by one-step microwave hydrothermal synthesis: tracking yeast status and imaging mechanism.

BACKGROUND: Carbon dots (CDs) are widely used in cell imaging due to their excellent optical properties, biocompatibility and low toxicity. At present, most of the research on CDs focuses on biomedical application, while there are few studies on the application of microbial imaging. RESULTS: In this study, B- and N-doped carbon dots (BN-CDs) were prepared from citric acid, ethylenediamine, and boric acid by microwave hydrothermal method. Based on BN-CDs labeling yeast, the dead or living of yeast cell could be quickly identified, and their growth status could also be clearly observed. In order to further observe the morphology of yeast cell under different lethal methods, six methods were used to kill the cells and then used BN-CDs to label the cells for imaging. More remarkably, imaging of yeast cell with ultrasound and antibiotics was significantly different from other imaging due to the overflow of cell contents. In addition, the endocytosis mechanism of BN-CDs was investigated. The cellular uptake of BN-CDs is dose, time and partially energy-dependent along with the involvement of passive diffusion. The main mechanism of endocytosis is caveolae-mediated. CONCLUSION: BN-CDs can be used for long-term stable imaging of yeast, and the study provides basic research for applying CDs to microbiol imaging.

Asymmetric Silica Nanoparticles with Tailored Spiky Coverage Derived from Silica-Polymer Cooperative Assembly for Enhanced Hemocompatibility and Gene Delivery.

Asymmetric mesoporous silica nanoparticles (AMSNs) with one side featuring a spiky nanotopography, while the other side is smooth and solid, were synthesized via an ethylenediamine (EDA)-directed silica-polymer cooperative assembly approach. By simply varying the EDA amount (x), AMSNs-x samples with adjustable spiky surface coverage were obtained. It is demonstrated that a spiky coverage higher than 50% improved the hemocompatibility of AMSN-x, possibly due to the reduced contact area of the smooth side exposed to the red blood cell (RBC) membrane. Moreover, AMSNs-175 and AMSNs-200 with high spiky coverage enhanced their plasmid DNA (pDNA) loading and binding capability, as well as cellular uptake into HEK-293T cells, thus resulting in high transfection performance. The good hemocompatibility and high performance in pDNA delivery of AMSNs-x with high spiky coverage allow them to serve as promising nonviral vectors for potential applications in gene therapies and DNA vaccines.

Enzyme-support interactions and inactivation conditions determine Thermomyces lanuginosus lipase inactivation pathways: Functional and florescence studies.

Lipase from Thermomyces lanuginosus (TLL) has been covalently immobilized on heterofunctional octyl-vinyl agarose. That way, the covalently immobilized enzymes will have identical orientation. Then, it has blocked using hexyl amine (HEX), ethylenediamine (EDA), Gly and Asp. The initial activity/stability of the different biocatalysts was very different, being the most stable the biocatalyst blocked with Gly. These biocatalysts had been utilized to analyze if the enzyme activity could decrease differently along thermal inactivation courses depending on the utilized substrate (that is, if the enzyme specificity was altered during its inactivation using 4 different substrates to determine the activity), and if this can be altered by the nature of the blocking agent and the inactivation conditions (we use pH 5, 7 and 9). Results show great changes in the enzyme specificity during inactivation (e.g., activity versus triacetin was much more quickly lost than versus the other substrates), and how this was modulated by the immobilization protocol and inactivation conditions. The difference in the changes induced by immobilization and inactivation were confirmed by fluorescence studies. That is, the functional and structural analysis of partially inactivated immobilized enzyme showed that their inactivation pathway is strongly depended on the support features and inactivation conditions.

Clinically Applicable Cyclotron-Produced Gallium-68 Gives High-Yield Radiolabeling of DOTA-Based Tracers.

By using solid targets in medical cyclotrons, it is possible to produce large amounts of 68GaCl3. Purification of Ga3+ from metal ion impurities is a critical step, as these metals compete with Ga3+ in the complexation with different chelators, which negatively affects the radiolabeling yields. In this work, we significantly lowered the level of iron (Fe) impurities by adding ascorbate in the purification, and the resulting 68GaCl3could be utilized for high-yield radiolabeling of clinically relevant DOTA-based tracers. 68GaCl3 was cyclotron-produced and purified with ascorbate added in the wash solutions through the UTEVA resins. The 68Ga eluate was analyzed for radionuclidic purity (RNP) by gamma spectroscopy, metal content by ICP-MS, and by titrations with the chelators DOTA, NOTA, and HBED. The 68GaCl3eluate was utilized for GMP-radiolabeling of the DOTA-based tracers DOTATOC and FAPI-46 using an automated synthesis module. DOTA chelator titrations gave an apparent molar activity (AMA) of 491 ± 204 GBq/µmol. GMP-compliant syntheses yielded up to 7 GBq/batch [68Ga]Ga-DOTATOC and [68Ga]Ga-FAPI-46 (radiochemical yield, RCY ~ 60%, corresponding to ten times higher compared to generator-based productions). Full quality control (QC) of 68Ga-labelled tracers showed radiochemically pure and stable products at least four hours from end-of-synthesis.

Synthesis, DFT Calculations, Antiproliferative, Bactericidal Activity and Molecular Docking of Novel Mixed-Ligand Salen/8-Hydroxyquinoline Metal Complexes.

Despite the common use of salens and hydroxyquinolines as therapeutic and bioactive agents, their metal complexes are still under development. Here, we report the synthesis of novel mixed-ligand metal complexes (MSQ) comprising salen (S), derived from (2,2'-{1,2-ethanediylbis[nitrilo(E) methylylidene]}diphenol, and 8-hydroxyquinoline (Q) with Co(II), Ni(II), Cd(II), Al(III), and La(III). The structures and properties of these MSQ metal complexes were investigated using molar conductivity, melting point, FTIR, 1H NMR, 13C NMR, UV-VIS, mass spectra, and thermal analysis. Quantum calculation, analytical, and experimental measurements seem to suggest the proposed structure of the compounds and its uncommon monobasic tridentate binding mode of salen via phenolic oxygen, azomethine group, and the NH group. The general molecular formula of MSQ metal complexes is [M(S)(Q)(H2O)] for M (II) = Co, Ni, and Cd or [M(S)(Q)(Cl)] and [M(S)(Q)(H2O)]Cl for M(III) = La and Al, respectively. Importantly, all prepared metal complexes were evaluated for their antimicrobial and anticancer activities. The metal complexes exhibited high cytotoxic potency against human breast cancer (MDA-MB231) and liver cancer (Hep-G2) cell lines. Among all MSQ metal complexes, CoSQ and LaSQ produced IC50 values (1.49 and 1.95 µM, respectively) that were comparable to that of cisplatin (1.55 µM) against Hep-G2 cells, whereas CdSQ and LaSQ had best potency against MDA-MB231 with IC50 values of 1.95 and 1.43 µM, respectively. Furthermore, the metal complexes exhibited significant antimicrobial activities against a wide spectrum of both Gram-positive and -negative bacterial and fungal strains. The antibacterial and antifungal efficacies for the MSQ metal complexes, the free S and Q ligands, and the standard drugs gentamycin and ketoconazole decreased in the order AlSQ > LaSQ > CdSQ > gentamycin > NiSQ > CoSQ > Q > S for antibacterial activity, and for antifungal activity followed the trend of LaSQ > AlSQ > CdSQ > ketoconazole > NiSQ > CoSQ > Q > S. Molecular docking studies were performed to investigate the binding of the synthesized compounds with breast cancer oxidoreductase (PDB ID: 3HB5). According to the data obtained, the most probable coordination geometry is octahedral for all the metal complexes. The molecular and electronic structures of the metal complexes were optimized theoretically, and their quantum chemical parameters were calculated. PXRD results for the Cd(II) and La(III) metal complexes indicated that they were crystalline in nature.