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Epidermal growth factor receptors (EGFR) of tyrosine kinase (TK) have shown high expression levels in most cancers and are considered a promising target for cancer diagnosis and therapy. Expanding the investigation for novel targeted radiopharmaceuticals, an EGFR inhibitor such as 4-aminoquinazoline derivatives along with a radionuclide such as technetium-99m (99mTc) could be ideal. Thus, we report herein the synthesis, characterization, and biological evaluation of new “4 + 1” mixed-ligand ReIII- and 99mTcIII-complexes of the general formula [99mTc][Tc(NS3)(CN-R)] bearing tris(2-mercaptoethyl)-amine (NS3) as the tetradentate tripodal ligand and a series of isocyanide derivatives (CN-R) of tyrosine kinase inhibitor (3-bromophenyl)quinazoline-4,6-diamine as the monodentate ligand. The quinazoline isocyanide derivatives 4a-d were prepared in two steps and reacted with the [Re(NS3)PMe2Ph] precursor leading to the final complexes 5a-d in high yield. All compounds were characterized by elemental analysis, IR, and NMR spectroscopies. In vitro studies, for their potency to inhibit the cell growth, using intact A431 cells indicate that the quinazoline derivatives 4a-d and the Re complexes 5a-d significantly inhibit the A431 cell growth. In addition, the EGFR autophosphorylation study of complex 5b shows an IC50 value in the nanomolar range. The corresponding “4 + 1” 99mTc-complexes 6a-d were prepared by employing the [99mTc]TcEDTA intermediate and the appropriate monodentate 4a-d in a two-step synthetic procedure with a radiochemical yield (RCY) from 63 to 77 % and a radiochemical purity (RCP) > 99 % after HPLC purification. Their structures have been established by HPLC comparative studies using the well-characterized Re-complexes 5a-d as reference. All 99mTc-complexes remain stable for at least 6 h, and their logD7.4 values confirmed their anticipated lipophilic character. Biodistribution studies in healthy Swiss albino mice of 99mTc-complexes showed hepatobiliary excretion and initial fast blood clearance. Complex 6b was also tested in Albino SCID mice bearing A431 tumors and showed rapid tumor uptake at 5 min (2.80 % ID/g) with a moderate tumor/muscle ratio (2.06) at 4 h p.i. The results encourage further investigation for this type of 99mTc-complexes as single-photon emission computed tomography (SPECT) radio agents for imaging tumors overexpressing EGFR. © 2022 Elsevier Ltd

The synthesis and biological evaluation of 5-arylidene-N-acetyl-tetramic acids cadmium(II) complexes are reported. Eleven novel compounds were prepared, characterized by nuclear magnetic resonance experiments and screened for their antimicrobial activity against five bacterial species (Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus [MRSA]) and two fungi (Candida albicans and Cryptococcus neoformans). The complexes showed similar or enhanced activities against MRSA in comparison to the corresponding ligands and, additionally, promising antifungal activities against C. neoformans. The most active compounds 3c and 3h showed remarkable activities against MRSA (minimum inhibitory activity [MIC] values of 32 and 4 μg/ml, respectively) and C. neoformans (MIC values of 8 and 16 μg/ml, respectively), accompanied by no human cell toxicity and hemolytic activity within the tested concentration range. The results demonstrate that appropriately functionalized tetramic acids attached with lipophilic alkanoyl chain and after complexation with cadmium(II) ions may act as valuable lead compounds for further investigations toward the development of novel antibacterial and/or antifungal agents.

Light state transitions (STs) is a reversible physiological process that oxygenic photosynthetic organisms use in order to minimize imbalances in the electronic excitation delivery to the reaction centers of Photosystems I and II, and thus to optimize photosynthesis. STs have been studied extensively in plants, green algae, red algae and cyanobacteria, but sparsely in algae with secondary red algal plastids, such as diatoms and haptophytes, despite their immense ecological significance. In the present work, we examine whether the haptophyte alga Phaeocystis antarctica, and dinoflagellate cells that host kleptoplasts derived from P. antarctica, both endemic in the Ross Sea, Antarctica, are capable of light adaptive STs. In these organisms, Chl a fluorescence can be excited either by direct light absorption, or indirectly by electronic excitation (EE) transfer from ultraviolet light absorbing mycosporine-like amino acids (MAAs) to Chl a (Stamatakis et al., Biochim. Biophys. Acta 1858 [2017] 189-195). Here we show that, on adaptation to PS II-selective light, dark-adapted P. antarctica cells shift from light state 1 (ST1; more EE ending up in PS II) to light state 2 (ST2; more EE ending up in PS I), as revealed by the spectral distribution of directly-excited Chl a fluorescence and by changes in the macro-organization of pigment-protein complexes evidenced by circular dichroism (CD) spectroscopy. In contrast, no STs are clearly detected in the case of the kleptoplast-hosting dinoflagellate cells, and in the case of indirectly excited Chls a, via MAAs, in P. antarctica cells.

The synthesis and characterization of the dinuclear Cu(II) complex [Cu(μ2-OH){Ph2P(O)NP(O)Ph2-κ1O,O′}(1,10-phen-κ2N,N′)]2·2H2O (1), 1,10-phen = 1,10-phenanthroline, is described. X-ray crystallographic studies reveal that the Cu(II) centers of 1 are bridged by two OH− groups and are coordinated by the (O,O) = Ph2P(O)NP(O)Ph2− ligand in a monodentate fashion, unprecedented for Cu(II). The crystal lattice of 1 also contains H2O molecules, which are involved in the formation of a hydrogen bonding network with bridging OH− groups and noncoordinated O atoms of the (O,O) ligand. These H2O molecules are arranged in the crystal lattice of 1 as tetrameric clusters. The packing of molecules in the structure of 1 was investigated by Hirshfeld Surface analysis.

(E)-1-(4-Ethoxycarbonylphenyl)-5-(3,4-dimethoxyphenyl)-3-(3,4-dimethoxystyryl)-2-pyrazoline was synthesized via the cyclization reaction between the monocarbonyl curcuminoid (2E,6E)-2,6-bis(3,4-dimethoxybenzylidene)acetone and ethyl hydrazinobenzoate in high yield and purity (>95% by High-performance liquid chromatography (HPLC)). The compound has been fully characterized by 1H, 13C NMR, FTIR, UV-Vis and HRMS and its activity was evaluated in terms of its potential interaction with DNA as well as its cytotoxicity against resistant and non-resistant tumor cells. Both DNA thermal denaturation and DNA viscosity measurements revealed that a significant intercalation binding takes place upon treatment of the DNA with the synthesized pyrazoline, causing an increase in melting temperature by 3.53 ± 0.11 °C and considerable DNA lengthening and viscosity increase. However, neither re-sensitisation of Doxorubicin (DO X)-resistant breast cancer and multidrug resistance (MDR) reversal nor synergistic activity with DOX by potentially increasing the DOX cell killing ability was observed.

This study aims at the further expansion of knowledge on the antimicrobial activities of the tetramic acid moiety and the effect of metal complexation. Complexes of the N-acetyl-3-acetyl-5-benzylidenetetramic acid with Mn, Co, Ni, Cu, Zn and Cd were synthesized and screened against 5 key ESKAPE pathogens (Escherichia coli, methicillin-resistant Staphylococcus aureus (MRSA), Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa) and 2 fungi (Cryptococcus neoformans and Candida albicans). The cadmium complex was found to effectively inhibit the fungus Cryptococcus neoformans with minimum inhibitory concentration (MIC) of 8 μg/mL, with no human cell toxicity and hemolytic activity within the tested concentration range. The biologically active tetramic acid‑cadmium complex was structurally characterized by single-crystal X-ray analysis. Furthermore, the thermal stability of the ligand and the complexes was investigated along with NMR and EPR studies of the Cd(II) and Co(II) complexes respectively.

The data presented here were derived by 1H NMR metabolic profiling of stamnagathi (Cichorium spinosum L.) plants following treatments with different isosmotic salt solutions; eight saline nutrient solutions with two different levels of total molar concentrations, which were obtained by adding different amounts of NaCl, KCl, Na2SO4 or CaCl2 to the replenishment nutrient solution, were applied. The 1H NMR metabolite profiles of stamnagathi plants’, which are included in this article, were recorded 56 days after transplanting. Since stamnagathi is a niche product combining unique taste and superior phytonutrient content (e.g. vitamins C and K1, lutein, β-carotene, tocopherols, phenolic acids, fatty acids, minerals, and glutathione), the dataset could serve as a reference for future metabolomics studies related to the investigation of the effects of the four salinity sources on the plant's metabolism. Also, the dataset could be a valuable resource for the discovery of validated biomarkers of the plant's tolerance to salinity stress and responses to new plant protection products (e.g. bioelicitors). The dataset support the research article “Salinity source alters mineral composition and metabolism of Cichorium spinosum” authored by Ntatsi et al., (2017) [1].

The steady rise of the antimicrobial resistance is a major global threat to human health that requires the urgent need for novel antibiotics. In this work we report the synthesis of a small library of 3-subsituted-5-arylidene tetramic acids in order to investigate the scope of our previously established methodology via an intermediate oxazolone and their antimicrobial activity. From this series of 14 tetramic acids, 11 derivatives are novel and one of them is a Schiff base, which was structurally characterized with single-crystal X-ray analysis and NMR spectroscopy. The compounds incorporating a lipophilic acyl group at carbon-3 of the ring showed moderate to high activity with minimum inhibitory activity of 4–32 μg/mL against methicillin-resistant Staphylococcus aureus (MRSA), accompanied by no human cell toxicity and hemolytic activity within the tested concentration range. The substituent at para position of the aryl ring seemed to have no or little effect on the antimicrobial activity of these compounds.

In this study, bauxite residue was directly leached using the Br&oslash, nsted acidic ionic liquid 1-ethyl-3-methylimidazolium hydrogensulfate. Stirring rate, retention time, temperature, and pulp density have been studied in detail as the parameters that affect the leaching process. Their optimized combination has shown high recovery yields of Sc, nearly 80%, and Ti (90%), almost total dissolution of Fe, while Al and Na were partially extracted in the range of 30&ndash, 40%. Si and rare earth element (REEs) dissolutions were found to be negligible, whereas Ca was dissolved and reprecipitated as CaSO4. The solid residue after leaching was fully characterized, providing explanations for the destiny of REEs that remain undissolved during the leaching process. The solid residue produced after dissolution can be further treated to extract REEs, while the leachate can be subjected to metal recovery processes (i.e., liquid&ndash, liquid extraction) to extract metals and regenerate ionic liquid.

Objectives To evaluate the stability and reactivity of γ-methacryloxypropyl trimethoxysilane (MPTMS) in commercially available primers and adhesives. Methods Four representative primer formulations [Calibra Silane Coupling Agent/Dentsply (CLB), G-Multi Primer/GC (GMP), Kerr Silane Primer/Kerr (KSP), Monobond Plus/Ivoclar Vivadent (MBP)] and a universal adhesive [Scotchbond Universal/3M ESPE (SBU)] containing MPTMS were analyzed spectroscopically. For the stability study, the silanol content was evaluated in bulk solutions as received (reference-RE) and after aging (AG, 48 °C/1 month) by 1H, 13C, 31P NMR and in fresh films by transmission FTIR analysis (TIR, films applied on Ge windows after solvent evaporation). The reactivity, as expressed by the siloxane formation capacity of the RE products, was evaluated by micro-multiple internal reflectance FTIR analysis (MIR, films applied on Ge crystals) after drying and ethanol rinsing (t0) and following 1 (t1) and 24 h (t24) storage (air/37 °C). Results NMR and TIR showed ∼60% MPTMS silanol groups in RE-CLB, with the other (∼40%) groups being methylated or ethoxylated. In AG-CLB, the silanol peaks further decreased, while ethoxylation and siloxane derivatization increased. In all other products and aging conditions no silanols were traced and formation of small- and large-size MPTMS derivatives was evident. Apart from the 10-MDP molecule, phosphorous impurities were identified in all RE specimens (2–5%), which after AG reached a maximum value of 15% (MBP). MIR analysis showed siloxane formation in all products, regardless the presence of free silanols (t1), which further increased at t24 especially in CLB, GMP and MBP. Significance MPTMS silanols are very sensitive to mild thermal aging. Incorporation of MPTMS in the same vials with adhesive and conventional methacrylate monomers, results in derivatization with no detectable silanols, even in fresh materials. The condensates formed may induce additional siloxane formation due to residual activity, which greatly varies among the materials tested. These may have a detrimental effect on MPTMS silanol chemisorption and bonding capacity.

Glycogen phosphorylase (GP), a validated target for the development of anti-hyperglycaemic agents, has been targeted for the design of novel glycopyranosylamine inhibitors. Exploiting the two most potent inhibitors from our previous study of N-acyl-β-D-glucopyranosylamines (Parmenopoulou et al., Bioorg. Med. Chem. 2014, 22, 4810), we have extended the linking group to -NHCONHCO- between the glucose moiety and the aliphatic/aromatic substituent in the GP catalytic site β-cavity. The N-acyl-N´-(β-D-glucopyranosyl) urea inhibitors were synthesized and their efficiency assessed by biochemical methods, revealing inhibition constant values of 4.95 µM and 2.53 µM. Crystal structures of GP in complex with these inhibitors were determined and analyzed, providing data for further structure based design efforts. A novel Linear Response - Molecular Mechanics Coulomb Surface Area (LR-MM-CBSA) method has been developed which relates predicted and experimental binding free energies for a training set of N-acyl-N´-(β-D-glucopyranosyl) urea ligands with a correlation coefficient R(2) of 0.89 and leave-one-out cross-validation (LOO-cv) Q(2) statistic of 0.79. The method has significant applications to direct future lead optimization studies, where ligand entropy loss on binding is revealed as a key factor to be considered. ADMET property predictions revealed that apart from potential permeability issues, the synthesized N-acyl-N´-(β-D-glucopyranosyl) urea inhibitors have drug-like potential without any toxicity warnings.

The synthesis and characterization of the new NSN tridentate bifunctional chelating agent 3-[2-(2′-pyridin-2-yl-ethylsulfanyl)ethylamino] propionic acid (as its hydrochloric salt, 1 ) and of its corresponding rhenium complex fac -[Re(NSN)(CO) 3 ] + , 2 , is described. Both compounds were characterized by elemental analysis, IR and NMR spectroscopies and X-ray crystallography. In complex 2 the coordination geometry around rhenium is distorted octahedral with the NSN atoms participating in the coordination sphere while the carboxylate group remains free. At tracer level, the analogous complex fac -[ 99m Tc(NSN)(CO) 3 ] + , 3 , was obtained in high yield by reacting ligand 1 with the fac -[ 99m Tc(H 2 O) 3 (CO) 3 ] + precursor at pH 6.5. The structure of 3 was established by HPLC comparison to the prototype rhenium complex 2. Complex 3 is stable in solution as well as in the presence of strongly coordinating agents like histidine or cysteine. Our data indicate that ligand 1 can be used as a bifunctional NSN chelating agent in the design of potential 99m Tc-radiopharmaceuticals.

The reactions of the NSO ligands 2-[2-(pyridin-2-yl)ethylthio]acetic acid (HL1), 3-[2-(pyridin-2-yl)ethylthio]propanoic acid (HL2), 2-(carboxymethylthio)-3-(1H-imidazol-4-yl)propanoic acid (H2L3), and 2-(carboxyethylthio)-3-(1H-imidazol-4-yl)propanoic acid (H2L4) with [NEt4]2[ReBr3(CO)3] are presented. Ligands HL1, H2L3, and H2L4 act as tridentate NSO chelators and readily generate the fac-[Re(NSO)(CO)3]complexes Re-L1, Re-HL3, and Re-HL4. Ligand HL2 acts as NSO tridentate chelator only in the presence of base to give complex Re-L2, while without base it coordinates as a NS bidentate chelator to generate complex fac-[ReBr(NS)(CO)3], Re-HL2. All complexes were isolated and characterized by elemental analysis, IR and 1H, 13C NMR spectroscopy. Complex Re-L1, Re-HL2, and Re-HL3 were characterized also by X-ray crystallography. Furthermore, the analogous technetium complexes fac-[99mTc(NSO)(CO)3]+, 99mTc-L1, 99mTc-L2, 99mTc-HL3, and 99mTc-HL4 were synthesized by reacting ligands HL1–H2L4 with the fac-[99mTc(OH2)3(CO)3]+ precursor for 30 min at 75 °C. The tracer complexes 99mTc-L1–99mTc-HL4 were found to be stable in L-cysteine and L-histidine challenge experiments. The bifunctional chelating agents that bear a second carboxylate group are promising for the development of targeted 99mTc radiopharmaceuticals.

Two rhenium(I) tricarbonyl complexes with the tridentate monoanionic NSO ligands, 4-(benzimidazol-2-yl)-3-thiabutanoic acid (complex 3) and [1-(11-carboxyundecanyl)-4-(benzimidazol-2-yl)]-3-thiabutanoic acid (complex 4) were synthesized and characterized by spectroscopic methods and elemental analysis. X-ray crystallographic analysis of complex 3 revealed a distorted octahedral geometry around rhenium defined by the three facially bound CO groups and the NSO donor atom set of the tridentate ligand. The analogous technetium-99m complexes (complexes 5 and 6) were also prepared quantitatively by reaction of the NSO ligands with the fac-[Tc-99m(H2O)(3)(CO)(3)](+) synthon and their identity was established by chromatographic comparison to their rhenium congeners. Biodistribution in mice of complex 6 bearing the fatty acid chain showed significant heart uptake (6.26 +/- 0.79% ID/g p.i.) at 1 min accompanied, however, with a heart: blood ratio below 1. (C) 2011 Elsevier B. V. All rights reserved.

The reaction of [NEt4]2[Re(CO)3Br3] with equimolar amount of a tridentate NSO ligand in methanol leads to the formation of neutral tricarbonyl rhenium(I) complexes of the general formula Re(CO)3(NSO), where the NSO ligand is o-C5H4N-CH2CH2-S-CH2CH(NHCOCH3)COOH (L1H), complex 1 or o-C5H4N-CH2CH2-S-C(CH3)2CH(NHCOCH3)COOH (L2H), complex 2. Both complexes have been characterized by elemental analysis and spectroscopic methods, while complex 2 has also been characterized by X-rays analysis. At technetium-99m level, the corresponding fac-[99mTc(CO)3(NSO)] complexes 3 and 4, were obtained in high yield by reacting ligands L1H or L2H with the fac-[99mTc(CO)3(H2O)3]+ precursor in water. Their structure was established by chromatographic comparison to the prototype rhenium complex using high-performance liquid chromatographic techniques.

Glycogen phosphorylase (GP), a validated target for the development of anti-hyperglycaemic agents, has been targeted for the design of novel glycopyranosylamine inhibitors. Exploiting the two most potent inhibitors from our previous study of N-acyl-β-D-glucopyranosylamines (Parmenopoulou et al., Bioorg. Med. Chem. 2014, 22, 4810), we have extended the linking group to -NHCONHCO- between the glucose moiety and the aliphatic/aromatic substituent in the GP catalytic site β-cavity. The N-acyl-N´-(β-D-glucopyranosyl) urea inhibitors were synthesized and their efficiency assessed by biochemical methods, revealing inhibition constant values of 4.95 µM and 2.53 µM. Crystal structures of GP in complex with these inhibitors were determined and analyzed, providing data for further structure based design efforts. A novel Linear Response - Molecular Mechanics Coulomb Surface Area (LR-MM-CBSA) method has been developed which relates predicted and experimental binding free energies for a training set of N-acyl-N´-(β-D-glucopyranosyl) urea ligands with a correlation coefficient R(2) of 0.89 and leave-one-out cross-validation (LOO-cv) Q(2) statistic of 0.79. The method has significant applications to direct future lead optimization studies, where ligand entropy loss on binding is revealed as a key factor to be considered. ADMET property predictions revealed that apart from potential permeability issues, the synthesized N-acyl-N´-(β-D-glucopyranosyl) urea inhibitors have drug-like potential without any toxicity warnings.

Novel hybrid drugs, [Pt(NH 3 ) 2 (Ftorafur–H) 2 ] ( 1 ) and [Pt(NH 3 ) 2 (Furavir) 2 ](NO 3 ) 2 ( 2 ), have been prepared by reaction of Ftorafur (Ft) and Furavir (Fr) with cisplatin . Ftorafur, a prodrug of 5-fluorouracil containing a 2-tetrahydrofuranyl radical linked to N(1), is stable when coordinated to platinum through N(3) but the N(1)furanyl bond is hydrolysed by platinum substrates (such as [Pt(NH 3 ) 2 (H 2 O) 2 ] 2+ and [Pt(dien)(H 2 O)] 2+ ) in the free state. In contrast, Furavir, a derivative of N(2)-acetyl-acyclovir carrying a 2-tetrahydrofuranyl radical linked to the terminal part of the (2-oxy)-ethoxymethyl chain bound to N(9), when coordinated to platinum through N(7), readily undergoes hydrolysis of the Ofuranyl bond releasing 2-hydroxytetrahydrofuran and leaving N(2)-acetyl-acyclovir coordinated to platinum. It is suggested that the hydrolysis of the Xfuranyl bond (X=N or O for Ftorafur and Furavir, respectively), which is catalysed by Lewis acids, is favoured in the latter case by the long and flexible (2-oxy)-ethoxymethyl chain which allows the metal centre to reach over the furanyl moiety. This is not possible in the case of the Ftorafur derivative. This investigation has demonstrated the possibility of controlling the hydrolysis of a coordinated substrate in a multifunctional platinum drug by a suitable choice of the position of the breakable bond with respect to the metal centre.

(NO)(H2O)(CO)3] which reacts readily at room temperature with equimolar quantity of cyclohexyl isocyanide to produce the “2 + 1” mixed ligand complex fac-[Re(NO)(isc)(CO)3]. When the reaction takes place with excess of the isocyanide in refluxing toluene for prolonged time, the complexes trans-cis-[Re(NO)(isc)2(CO)2] and [Re(NO)(isc)3(CO)] are isolated by gradual replacement of the carbonyl ligands by isocyanide. All complexes were fully characterized by elemental analysis, spectroscopic methods and X-ray crystallography. These model compounds may prove useful for the development of multimodal complexes bearing more than one pharmacophore for nuclear medicine applications.