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Present study aimed to establish the stimulatory effects of bee drone larvae (BDL) on the androgenic effects and growth performance of goat male kids (GMK). The effects of BDL on growth and testosterone hormone levels were investigated in Saanen male kids. A total of 26 Saanen male kids (13 heads control, 13 heads treatment groups) were used for determining the effects of BDL 60 days after the weaning period. BDL was obtained from good beekeeping practices hives. Hormone levels, growth trials, testes characteristics, and body measurements were determined every 14 days on the days 75, 90, 105, 120, and 135 of the trial. The increasing level of testosterone hormone in the treatment group on 135 days strengthened the hypothesis that the BDL could have greater effects in the case of more application that is expensive and considering the time of maturity of Saanen GMK. The lipid composition of BDL was identified by GC/MS. Oleic acid (64.75 %) and palmitic acid (26.08 %) were the dominant lipid compounds of BDL. Additionally, the phenolic/organic acid profile investigated by HPLC-DAD revealed that trans-aconitic acid (11.20 +/- 0.32 mu g/g) and fumaric acid (5.03 +/- 0.41 mu g/g) were found as major compounds in BDL., Ege University Scientific Research Projects Directorate [2017 ZRF 036], This study was supported by Ege University Scientific Research Projects Directorate under Grant 2017 ZRF 036: Effects of bee drone larvae (apilarnil) on development, sexual maturity and testis characteristics in pure Saanen goat male kids, 2017-2019.

A new dicoumarin, jusan coumarin, (1), has been isolated from Artemisia glauca aerial parts. The chemical structure of jusan coumarin was estimated, by 1D, 2D NMR as well as HR-Ms spectroscopic methods, to be 7-hydroxy-6-methoxy-3-[(2-oxo-2H-chromen-6-yl)oxy]-2H-chromen-2-one. As the first time to be introduced in nature, its potential against SARS-CoV-2 has been estimated using various in silico methods. Molecular similarity and fingerprints experiments have been utilized for 1 against nine co-crystallized ligands of COVID-19 vital proteins. The results declared a great similarity between Jusan Coumarin and X77, the ligand of COVID-19 main protease (PDB ID: 6W63), Mpro. To authenticate the obtained outputs, a DFT experiment was achieved to confirm the similarity of X77 and 1. Consequently, 1 was docked against Mpro. The results clarified that 1 bonded in a correct way inside Mpro active site, with a binding energy of -18.45 kcal/mol. Furthermore, the ADMET and toxicity profiles of 1 were evaluated and showed the safety of 1 and its likeness to be a drug. Finally, to confirm the binding and understand the thermodynamic characters between 1 and Mpro, several molecular dynamics (MD) simulations studies have been administered. Additionally, the known coumarin derivative, 7-isopentenyloxycoumarin (2), has been isolated as well as β-sitosterol (3). ispartof: MOLECULES vol:27 issue:7 ispartof: location:Switzerland status: published

We report the efficient and selective Cu(ii)-catalysed β-silylation of naturally occurring dehydroalanine (Dha) residues in various ribosomally synthesized and post-translationally modified peptides (RiPPs). The method is also applicable to proteins, as was shown by the modification of a Dha residue that was chemically introduced into Small Ubiquitin-like Modifier (SUMO).

A new flavonoid, Jusanin, (1) has been isolated from the aerial parts of Artemisia commutata. The chemical structure of Jusanin has been elucidated using 1D, 2D NMR, and HR-Ms spectroscopic methods to be 5,2',4'-trihydroxy-6,7,5'-trimethoxyflavone. Being new in nature, the inhibition potential of 1 has been estimated against SARS-CoV-2 using different in silico techniques. Firstly, molecular similarity and fingerprint studies have been conducted for Jusanin against co-crystallized ligands of eight different SARS-CoV-2 essential proteins. The studies indicated the similarity between 1 and X77, the co-crystallized ligand SARS-CoV-2 main protease (PDB ID: 6W63). To confirm the obtained results, a DFT study was carried out and indicated the similarity of (total energy, HOMO, LUMO, gap energy, and dipole moment) between 1 and X77. Accordingly, molecular docking studies of 1 against the target enzyme have been achieved and showed that 1 bonded correctly in the protein's active site with a binding energy of -19.54 Kcal/mol. Additionally, in silico ADMET in addition to the toxicity evaluation of Jusanin against seven models have been preceded and indicated the general safety and the likeness of Jusanin to be a drug. Finally, molecular dynamics simulation studies were applied to investigate the dynamic behavior of the Mpro-Jusanin complex and confirmed the correct binding at 100 ns. In addition to 1, three other metabolites have been isolated and identified to be сapillartemisin A (2), methyl-3-[S-hydroxyprenyl]-cumarate (3), and β-sitosterol (4). ispartof: MOLECULES vol:27 issue:5 ispartof: location:Switzerland status: published

Two rare 2-phenoxychromone derivatives, 6-demethoxy-4`-O-capillarsine (1) and tenuflorin C (2), were isolated from the areal parts of Artemisia commutata and A. glauca, respectively, for the first time. Being rare in nature, the inhibition potentialities of 1 and 2 against SARS-CoV-2 was investigated using multistage in silico techniques. At first, molecular similarity and fingerprint studies were conducted for 1 and 2 against co-crystallized ligands of eight different COVID-19 enzymes. The carried-out studies indicated the similarity of 1 and 2 with TTT, the co-crystallized ligand of COVID-19 Papain-Like Protease (PLP), (PDB ID: 3E9S). Therefore, molecular docking studies of 1 and 2 against the PLP were carried out and revealed correct binding inside the active site exhibiting binding energies of -18.86 and -18.37 Kcal/mol, respectively. Further, in silico ADMET in addition to toxicity evaluation of 1 and 2 against seven models indicated the general safety and the likeness of 1 and 2 to be drugs. Lastly, to authenticate the binding and to investigate the thermodynamic characters, molecular dynamics (MD) simulation studies were conducted on 1 and PLP. ispartof: MOLECULES vol:27 issue:4 ispartof: location:Switzerland status: published

Allium species belong to the Amaryllidaceae family and are represented with approximately 900 species, with 220 taxa found in Turkey. The aim of the present study is to analyze the chemical structure and to investigate the enzyme inhibitory activities linked to Alzheimer's Disease, skin disorders, and type 2 Diabetes Mellitus of essential oil obtained from Allium proponticum subsp. proponticum, which is an endemic species. The essential oil was obtained with hydrodistillation using a Clevenger-type apparatus from flower parts of the plant and the analysis was carried out by Gas Chromatography Mass Spectrometry. Inhibitory activities of samples against acetylcholinesterase, butyrylcholinesterase, tyrosinase, a-amylase, and a-glucosidase were realized in a 96-well microplate using an ELISA microplate reader. The yield of essential oils was 0.0095 %. A total of 17 components, 11 of sulfur-containing compounds (73.83 %), were identified, constituting 86.72 % of the total essential oil. IC50 values of enzymes inhibitory activities were 258.47 +/- 3.28 for acetylcholinesterase, 522.81 +/- 1.29 for butyrylcholinesterase, 38.22 +/- 1.87 for tyrosinase, 28.50 +/- 1.12 for a-glucosidase and 14.68 +/- 0.78 for a-amylase. To conclude, the essential oil of Allium proponticum subsp. proponticum with its sulfur-containing compounds may be a promising natural product due to its activity in inhibition of tyrosinase, a-amylase, a-glucosidase., Ege University Scientific Research Projects Coordination Unit [20257], Present study was financially supported by Ege University Scientific Research Projects Coordination Unit. Project Number: 20257. Special thanks are extended to Dr. Zinar Pinar Gumus for performing the GC/MS analysis and Dr. Hasan Yildirim for plant identification.

Lead optimization represents the tedious process of fine-tuning lead compounds from biologically active hits to suitable drug candidates for clinical trials. By chemically modifying a hit structure, an improved compound can be obtained in terms of activity, selectivity, and pharmacokinetic ADME (absorption, distribution, metabolism, and excretion) properties. The carboxylic acid moiety is known to be a crucial functionality in many pharmaceutically active compounds. Despite its common use as a key functionality in drugs, its presence in a lead molecule is often associated with poor pharmacokinetic properties and toxicity. In this literature overview, we discuss how the shortcomings of a carboxylic acid can be circumvented by replacing this functionality with bioisosteres. In this way, the positive aspects of this moiety, such as its activity, for example, by virtue of its capacity to form hydrogen bonds, can be maintained or even improved. To that end, we provide an overview of the most promising carboxylic acid bioisosteres and discuss a selection of synthetic routes towards the main functionalities.

Human Interleukin-18 (IL-18) is an omnipresent proinflammatory cytokine of the IL-1 family with central roles in autoimmune and inflammatory diseases and serves as a staple biomarker in the evaluation of inflammation in physiology and disease, including the inflammatory phase of COVID-19. The sequestration of IL-18 by its soluble decoy receptor IL-18-Binding Protein (IL-18BP) is critical to the regulation of IL-18 activity. Since an imbalance in expression and circulating levels of IL-18 is associated with disease, structural insights into how IL-18BP outcompetes binding of IL-18 by its cognate cell-surface receptors are highly desirable; however, the structure of human IL-18BP in complex with IL-18 has been elusive. Here, we elucidate the sequestration mechanism of human IL-18 mediated by IL-18BP based on the crystal structure of the IL-18:IL-18BP complex. These detailed structural snapshots reveal the interaction landscape leading to the ultra-high affinity of IL-18BP toward IL-18 and identify substantial differences with respect to previously characterized complexes of IL-18 with IL-18BP of viral origin. Furthermore, our structure captured a fortuitous higher-order assembly between IL-18 and IL-18BP coordinated by a disulfide-bond distal to the binding surface connecting IL-18 and IL-18BP molecules from different complexes, resulting in a novel tetramer with 2:2 stoichiometry. This tetrapartite assembly was found to restrain IL-18 activity more effectively than the canonical 1:1 complex. Collectively, our findings provide a framework for innovative, structure-driven therapeutic strategies and further functional interrogation of IL-18 in physiology and disease.

In the study, by using 5-amino-4-arylazo-3-methyl-1H-pyrazole derivatives and 2-hydroxy-5(phenyldiazenyl) benzaldehyde; eight novel heterocyclic disperse disazo-azomethine dyes were synthesized, their chemical structures were characterized via FT-IR and 1 H NMR studies. Synthesized compounds were also investigated computationally by performing various techniques. In the computational part of the study, geometry optimizations, frequency analyses, frontier molecular orbital (FMO) calculations, molecular electrostatic potential (MEP) map calculations, FT-IR and NMR spectral analyses were performed on the compounds. Additionally, to reveal their potentials against SARS-CoV-2 main protease (SARS-CoV-2 M-pro), acetylcholine esterase (AChE), heat shock protein (HSP90 alpha) and nicotinamide N-methyl transferase (NNMT), molecular docking calculations were also performed on the synthesized compounds. Molecular dynamics (MD) simulations were carried out on the top-scoring ligand-receptor complexes to evaluate the stability of the complexes and the interactions between ligands and receptors in more detail. Results showed that synthesized compounds can interact with all these four receptors effectively and can be promising structures for further studies. (C) 2021 Elsevier B.V. All rights reserved.

Metastasis or the progression of malignancy poses a major challenge in cancer therapy and is the principal reason for increased mortality. The epithelial-mesenchymal transition (EMT) of the basement membrane (BM) allows cells of epithelial phenotype to transform into a mesenchymal-like (quasi-mesenchymal) phenotype and metastasize via the lymphovascular system through a metastatic cascade by intravasation and extravasation. This helps in the progression of carcinoma from the primary site to distant organs. Collagen, laminin, and integrin are the prime components of BM and help in tumor cell metastasis, which makes them ideal cancer drug targets. Further, recent studies have shown that collagen, laminin, and integrin can be used as a biomarker for metastatic cells. In this review, we have summarized the current knowledge of such therapeutics, which are either currently in preclinical or clinical stages and could be promising cancer therapeutics.Data availability: Not applicable Scientific Research at Majmaah University [R-2022-117] Dr. Niraj Kumar Jha is thankful to Sharda University for the infra-structure and facility. The author would like to thank Deanship of Sci-entific Research at Majmaah University for supporting this work under project number No. R-2022-117. The authors would like to acknowledge the support from their respective institutes throughout the review writing process.

Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver an opinion on the safety of calcidiol monohydrate as a novel food (NF) pursuant to Regulation (EU) 2015/2283, including its bioavailability as a metabolite of vitamin D3 when added for nutritional purposes to food supplements. The NF is produced chemically. It is proposed in food supplements up to 10 lg/day for individuals > 11 years of age, including pregnant and lactating women and up to 5 lg/day in 3- to 10-year-old children. The production process, composition, specifications and stability of the NF do not raise safety concerns. Animal and human data indicate efficient absorption. The NF contains a fraction of nanoparticles, which are fat soluble and unlikely to reach systemic distribution. There are no concerns regarding genotoxicity. Human adult studies do not raise safety concerns. Combined intake estimates of calcidiol from the NF and calcidiol and vitamin D from the diet were below the tolerable upper intake level (UL) for vitamin D for subjects above 11 years of age. The achieved mean serum 25(OH)D concentration in adults supplemented with 10 lg NF per day remained below 200 nmol/L. The Panel concludes that the NF is safe under the proposed conditions of use and use levels for individuals > 11 years old, including pregnant and lactating women. The applicant did not provide data on the bioavailability and safety of the NF in children. The combined intake estimation in children (3-10 years) is close to the UL for vitamin D. Therefore, the Panel could not conclude on the safety of consumption of the NF in children (3-10 years) at the proposed daily intake. The NF is a bioavailable source of the biologically active metabolite of vitamin D, i.e. 1,25-dihydroxyvitamin D. (C) 2021 European Food Safety Authority. EFSA Journal published by John Wiley and Sons Ltd on behalf of European Food Safety Authority.

The application of Peptide Nucleic Acids (PNAs), mimics of DNA lacking the sugar-phosphate backbone, for antisense/anti-gene therapy and gene editing is limited by their low uptake by cells. Currently, no simple and efficient delivery systems and methods are available to solve this open issue. One of the most promising approach is the modification of the PNA structure through the covalent linkage of poliarginine tails, but this means that every PNA intended to be internalized must be modified. Herein we report the results relative to the delivery ability of a macrocyclic multivalent tetraargininocalix[4]arene (1) used as non-covalent vector for anti-miR-221-3p PNAs. High delivery efficiency, low cytotoxicity, maintenance of the PNA biological activity and ease preparation of the transfection formulation, simply attained by mixing PNA and calixarene, candidate this vector as universal delivery system for this class of nucleic acid analogues.

In this study, five new pyrazolyazo pyrazole dyestuff syntheses are reported. For this purpose, 5-amino-4-arylazo-3-methyl-1H-pyrazoles were diazotised and coupled with 3-amino-5-hydroxy-1H-pyrazole. Fourier Transform-infrared, ultraviolet-visible and proton nuclear magnetic resonance spectroscopy were used to investigate the properties of aminopyrazole-based dyes obtained in this study. The maximum absorption wavelengths of these dyes in various solvents were determined. The theoretical calculations of the molecules in the ground state were performed with the density functional theory/Becke 3-parameter and Lee-Yang-Parr/6-311G(d,p) method by using the Gaussian 0.9 W program. The results were compared with the corresponding experimental data. Acid-base and substituent effects on the absorption spectra of dyes were also examined and reported.

The control of ovulation helps guarantee the success of reproduction and as such, contributes to the fitness of a species. In mammals, two types of ovulation are observed: induced and spontaneous ovulation. Recent work on camelids, that are induced ovulators, highlighted the role of a factor present in seminal plasma, beta Nerve Growth Factor (β-NGF), as the factor that triggers ovulation in a GnRH dependent manner. In the present work, we characterized alpaca β-NGF (aβ-NGF) and its 3D structure and compared it with human recombinant β-NGF (hβ-NGF). We showed that the β-NGF enriched fraction of alpaca semen and the human recombinant protein, both stimulated spontaneous electrical activity of primary GnRH neurons derived from mouse embryonic olfactory placodes. This effect was dose-dependent and mediated by p75 receptor signaling. P75 receptors were found expressed in vitro by olfactory ensheathing cells (OEC) in close association with GnRH neurons and in vivo by tanycytes in close vicinity to GnRH fibers in adult mouse. Altogether, these results suggested that β-NGF induced ovulation through an increase in GnRH secretion provoked by a glial dependent P75 mediated mechanism.

From the organic extract of Lavandula stoechas, a Mediterranean native plant species, two new phytotoxic copaane sesquiterpenoids were isolated and named stoechanones A and B (1 and 2). They were obtained together with the methyl esters of caffeic and p-coumaric acids and the flavonoid apigenin (3-5, respectively). The structures of stoechanones A and B were determined by spectroscopic (essentially 1D and 2D 1H and 13C NMR and HRESIMS) and chemical methods, and they were characterized as 9,10-dihydroxy-8-isopropyl-1,5-dimethyltricyclo[4.4.0.02.7]dec-4-en-3-one and its 9-O-acetyl derivative. Their relative configurations were assigned by NOESY experiments, and the absolute configurations by comparison of the experimental and DFT-computed ECD spectra. When assayed through Petri dish bioassays, both stoechanones A and B showed phytotoxic effects against seed germination and seedling growth of Amaranthus retroflexus, strongly inhibiting seed germination percentage and radicle and hypocotyl lengths of seedlings. Owing to the herbicidal activity toward A. retroflexus, these two new tricyclic sesquiterpenoids could be proposed and developed as natural bioherbicides in order to increase the control of this problematic weed in the future.

African trypanosomiasis, a deadly infectious disease caused by the protozoan Trypanosoma brucei spp., is spread to new hosts by bites of infected tsetse flies. Currently approved therapies all have their specific drawbacks, prompting a search for novel therapeutic agents. T. brucei lacks the enzymes necessary to forge the purine ring from amino acid precursors, rendering them dependent on the uptake and interconversion of host purines. This dependency renders analogues of purines and corresponding nucleosides an interesting source of potential anti-T. brucei agents. In this study, we synthesized and evaluated a series of 7-substituted 7-deazainosine derivatives and found that 6-O-alkylated analogues in particular showed highly promising in vitro activity with EC50 values in the mid-nanomolar range. SAR investigation of the O-alkyl chain showed that antitrypanosomal activity increased, and also cytotoxicity, with alkyl chain length, at least in the linear alkyl chain series. However, this could be attenuated by introducing a terminal branch point, resulting in the highly potent and selective analogues, 36, 37 and 38. No resistance related to transporter-mediated uptake could be identified, earmarking several of these analogues for further in vivo follow-up studies. (C) 2020 Elsevier Masson SAS. All rights reserved.

The implications of lysine-specific demethylase-1 (LSD1) in tumorigenesis have urged scientists to develop diagnostic tools in order to explore the function of this enzyme. In this work, we present our efforts on the development of tranylcypromine (TCP)-based functionalized probes for activity-based protein profiling (ABPP) of LSD1 activity. Biotinylated forms of selected compounds enabled dose-dependent enzyme labeling of recombinant LSD1. However, treatment with LSD1 inhibitors did not clearly reduce the LSD1 labeling efficiency thus indicating that labeling using these probes is not activity dependent. This calls for alternative strategies to develop probes for ABPP of the enzyme LSD1.

Hydrogels are three-dimensional polymeric networks capable of absorbing large amounts of water or biological fluids with the properties resembling natural living tissues. Herein, polyvinyl alcohol (PVA)/N-succinyl chitosan (NSCS)/lincomycin hydrogels for wound dressing were prepared by the freezing/thawing method, then characterized by FTIR, SEM, and TGA. The compression strength, swelling behavior, water retention capacity, antibacterial activity, drug release and cytotoxicity were systematically investigated. The results showed that the introduction of NSCS remarkably enhanced the swelling capacity, leading to the maximum swelling ratio of 19.68 g/g in deionized water. The optimal compression strength of 0.75 MPa was achieved with 30 % NSCS content.Additionally, the incorporation of lincomycin brought a remarkable antibacterial activity against both Escherichia coli and Staphylococcus aureus. Specifically, 77.71 % of Staphylococcus aureus was inhibited with 75 μg/mL lincomycin, while the MTT assay demonstrated the nontoxic nature of the composite hydrogels. In summary, this PVA/NSCS/lincomycin hydrogel showed promising potential for wound dressing. ispartof: CARBOHYDRATE POLYMERS vol:261 ispartof: location:England status: published

The present study investigated the effects of the combined treatment of two peptide nucleic acids (PNAs), directed against microRNAs involved in caspase‑3 mRNA regulation (miR‑155‑5p and miR‑221‑3p) in the temozolomide (TMZ)‑resistant T98G glioma cell line. These PNAs were conjugated with an octaarginine tail in order to obtain an efficient delivery to treated cells. The effects of singularly administered PNAs or a combined treatment with both PNAs were examined on apoptosis, with the aim to determine whether reversion of the drug‑resistance phenotype was obtained. Specificity of the PNA‑mediated effects was analyzed by reverse transcription‑quantitative polymerase‑chain reaction, which demonstrated that the effects of R8‑PNA‑a155 and R8-PNA-a221 anti‑miR PNAs were specific. Furthermore, the results obtained confirmed that both PNAs induced apoptosis when used on the temozolomide‑resistant T98G glioma cell line. Notably, co‑administration of both anti‑miR‑155 and anti‑miR‑221 PNAs was associated with an increased proapoptotic activity. In addition, TMZ further increased the induction of apoptosis in T98G cells co‑treated with anti‑miR‑155 and anti‑miR‑221 PNAs.

A series of cationic chlorido arene-iridium(III) and arene-osmium(II) complexes with bidentate pyridyl functionalized mesoionic carbenes (MIC) of the 1,2,3-triazol-5-ylidene type have been prepared. The variations in the ligand structures include the position of the pyridyl substituent relative to the triazolylidene ring (N-wingtip vs C-wingtip), phenyl versus ethyl substituents, and incorporation of several functional groups at the phenyl substituents. Five complexes have been characterized by X-ray structural analysis. All complexes, including osmium(II) and ruthenium(II) analogues having a pyrimidyl in place of the pyridyl group, have been studied for their cytotoxic activity on a human cervical carcinoma HeLa cell line. Two of the compounds, Ir5 and Ir9, were the most cytotoxic with IC50 values of 7.33 μM and 2.01 μM, respectively. Examination of their cytotoxic effect on different cell lines revealed that they preferentially kill cancer over normal cells. The Ir5 and Ir9 compounds arrested cells in G2 and induced a dose-dependent increase in SubG0/G1 cell population. Apoptosis, as the primary mode of cell death, was confirmed by Annexin V/PI staining, detection of cleaved PARP, and caspases 3 and 7 activity upon treatment of HeLa cells with both compounds. The higher toxicity of Ir9 is probably due to its increased accumulation in the cells compared to Ir5. The role of glutathione (GSH) in the protection of cells against Ir5 and Ir9 cytotoxicity was confirmed by pretreatment of cells either with buthionine sulfoximine (inhibitor of GSH synthesis) or N-acetyl-cysteine (precursor in GSH synthesis).

Sen, Ali/0000-0002-2144-5741, WOS: 000503393100009, In this study, we report anti-inflammatory and antioxidant activities of two acylated isoscutellarein glucosides isolated from ethyl acetate extract of Stachys subnuda aerial part. 4'-O-methylisoscutellarein-7-O-2 ''-O-(6 ''' acetyl-beta-D-allopyranosyl)-beta-D-glucopyranoside (SS1) and isoscutellarein-7-O-2 ''-O-(6 '''-O-acetyl-beta-D allopyranosyl)-beta-D -glucopyranoside (SS2) were isolated as major compounds from ethyl acetate extract (SSEA). Also, 2 hydroxycinnamic acid derivatives, and 5 isoscutellarein glucoside derivatives in the SSEA were identified using LC-MS/MS. SS1 with IC50 values of 2.35 and 1.98 mu g/mL and SS2 with IC50 values 13.94 and 12.76 mu g/mL showed fairly strong antioxidant activity against DPPH (1,1-diphenyl-2-picrylhydrazyl) and ABTS (2,2'-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid) radicals, respectively. SS1 and SS2 inhibited 5-lipoxygenase (5-LOX) activity with IC(50 )values of 47.23 and 41.60 mu g/mL, respectively. the results demonstrated that SS1 and SS2 have significant anti-inflammatory and antioxidant potential. Acylated flavonoid glycosides have been first reported for Stachys subnuda. Also, the activities of SS1 and SS2 have been investigated for the first time in this study., Scientific and Technological Research Council of Turkey (TUBITAK)Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [1919B011603877, 2209-A], This work was supported by a grant from the Scientific and Technological Research Council of Turkey (TUBITAK), under the project 1919B011603877 (Code: 2209-A).

The field of photopharmacology uses molecular photoswitches to establish control over the action of bioactive molecules. It aims to reduce systemic drug toxicity and the emergence of resistance, while achieving unprecedented precision in treatment. By using small molecules, photopharmacology provides a viable alternative to optogenetics. We present here a critical overview of the different pharmacological targets in various organs and a survey of organ systems in the human body that can be addressed in a non-invasive manner. We discuss the prospects for the selective delivery of light to these organs and the specific requirements for light-activatable drugs. We also aim to illustrate the druggability of medicinal targets with recent findings and emphasize where conceptually new approaches have to be explored to provide photopharmacology with future opportunities to bring smart molecular design ultimately to the realm of clinical use.

Benzothiadiazine type compounds (BTDs) have gained great attention for their potential therapeutic activity as nootropic and neuroprotective agents. BTDs, acting as AMPA positive allosteric modulators, potentiate the glutamatergic neurotransmission without the side effects typically associated with direct agonists. Studies regarding the binding mode of racemic BTDs into the receptor binding pocket demonstrated that one enantiomer establishes a more favourable interaction and possesses a higher biological activity with respect to the other one. The S enantiomer was proved to be the eutomer for both IDRA21 and S18986, two of the most studied BTD AMPA positive allosteric modulators. However, recent data highlighted an opposite stereoselectivity for some substituted BTDs (7-chloro-9-(furan-3-yl)-2,3,3a,4-tetrahydro-1H-benzo[e]pyrrolo[2,1-c][1,2,4]thiadiazine 5,5-dioxide and 7-chloro-2,3,4-trimethyl-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide) showing unexpected structure–activity relationships. In this work, the synthesis and configuration assignment of the stereoisomers of 7-chloro-5-(3-furanyl)-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide, one of the most active BTDs, are reported. Electrophysiological tests demonstrated that the R form is the eutomer. Docking and molecular dynamics simulations on the AMPA GluA2 binding site revealed new insights into the stereodiscrimination process. Lastly, metabolic studies disclosed a stereoselective hepatic metabolization of this chiral BTD.

Five copper(II) complexes 1-5 with aromatic nitrogen-containing heterocycles, pyrimidine (pm, 1), pyrazine (pz, 2), quinazoline (qz, 3 and 4) and phthalazine (phtz, 5) have been synthesized and structurally characterized by spectroscopic and single-crystal X-ray diffraction techniques. The crystallographic results show that, dependent on the ligand structure, complexes 1-5 are of different nuclearity. The antimicrobial efficiency of complexes 1-5 has been evaluated against three clinically relevant microorganisms and none of the complexes showed significant growth inhibiting activity, with values of minimum inhibitory concentrations (MIC) in the mM range. Since in many bacteria, pathogenicity and virulence are regulated by intercellular communication processes, quorum sensing (QS), the effect of the copper(II) complexes on bacterial QS has also been examined. The results indicate that the investigated complexes inhibit violacein production in Chromobacterium violaceum CV026, suggesting an anti-QS activity. In order to differentiate, which of the QS pathways was affected by the copper(II) complexes, three biosensor strains were used: the PAO1 Delta rhlIpKD-rhlA and the PA14-R3 Delta lasIPrsaI lux strain to directly measure the levels of C4-HSL (N-butanoyl-homoserine lactone) and 3OC12-HSL (N-3-oxo-dodecanoyl- homoserine lactone), respectively, and PAO1 Delta pqsA mini-CTX luxPpqsA for the detection of AHQs (2-alkyl-4-quinolones). Complexes 1-5 were shown to be efficient inhibitors of biofilm formation of the human opportunistic pathogen Pseudomonas aeruginosa PAO1, with the qz-containing complex 3 being the most active. Finally, the most anti-QS-active complexes 1 and 3 showed synergistic activity against a multi-drug resistant clinical isolate of P. aeruginosa, when supplied in combination with the known antibiotics piperacillin and ceftazidime.

The structure-activity relationship was investigated in a series of synthetic TLR4 antagonists formed by a glucosamine core linked to two phosphate esters and two linear carbon chains. Molecular modeling showed that the compounds with 10, 12, and 14 carbons chains are associated with higher stabilization of the MD-2/TLR4 antagonist conformation than in the case of the C16 variant. Binding experiments with human MD-2 showed that the C12 and C14 variants have higher affinity than C10, while the C16 variant did not interact with the protein. The molecules, with the exception of the C16 variant, inhibited the LPS-stimulated TLR4 signal in human and murine cells, and the antagonist potency mirrored the MD-2 affinity calculated from in vitro binding experiments. Fourier-transform infrared, nuclear magnetic resonance, and small angle X-ray scattering measurements suggested that the aggregation state in aqueous solution depends on fatty acid chain lengths and that this property can influence TLR4 activity in this series of compounds.

New bismuth(III) bromine compounds of the heterocyclic thioamides were prepared and structurally characterized. The reaction of heterocyclic thioamides with bismuth(III) bromide resulted in the formation of the {[BiBr2(mu(2)-Br)(MMI)(2)](2)center dot CH3COCH3 center dot H2O} (1), {[BiBr2(MBZIM)(4)]center dot Br center dot 2H(2)O} (2), {[BiBr2(mu(2)-Br)(tHPMT)(2)](2)center dot CH3CN} (3), {[BiBr2(mu(2)-Br)(PYT)(2)](2)center dot CH3CN} (4) and {[BiBr2(mu(2)-Br)(MBZT)(2)](2) 2CH(3)OH} (5) complexes (MMI: 2-mercapto-1-methylimidazole, MBZIM: 2-mercaptobenzimidazole, tHPMT: 2-mercapto-3,4,5,6-tetrahydro-pyrimidine, PYT: 2-mercaptopyridine and MBZT: 2-mercaptobenzothiazole). The complexes 1-5 were characterized by melting point (m.p.), elemental analysis (c.a.), molar conductivity, Fourier-transform infrared (FT-IR), Fourier-transform Raman (FT-Raman), nuclear magnetic resonance (H-1 and (CNMR)-C-13) spectroscopy, UV-Vis spectroscopy and thermogravimetric-differential thermal analysis (TG-DTA). The molecular structures of 1-5 were determined by single-crystal X-ray diffraction. Complex 2 is a first ionic monomuclear octahedral bismuth(III) bromide, while the complexes 1,3-5 are the first examples of dinuclear bismuth(III) bromide derivatives. Complexes 1-5 were evaluated in terms of their in vitro cytotoxic activity against human adenocarcinoma breast (MCF-7) and cervix (HeLa) cells. The toxicity on normal human fetal lung fibroblast cells (MRC-5) was also evaluated. Moreover, the complexes 1-5 and free heterocyclic thioamide ligands were studied upon the catalytic peroxidation of the linoleic acid by the enzyme lipoxygenase (LOX). Scientific and Technological Research Council of Turkey (TUBITAK)Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [114Z457] (a) I.I.O. and M.C. acknowledge the financial support from The Scientific and Technological Research Council of Turkey (TUBITAK, Project No. 114Z457). (b) CNB and SKH would like to thank the Unit of Bioactivity Testing of Xenobiotics of the University of Ioannina for providing access to their facilities. (c) The International Graduate Program in 'Biological Inorganic Chemistry', which operates at the University of Ioannina within the collaboration of the Departments of Chemistry of the Universities of Ioannina, Athens, Thessaloniki, Patras, Crete and the Department of Chemistry of the University of Cyprus (http://bic.chem.uoi.gr/BIC-En/index-en.html), is acknowledged for the stimulating discussion forum.

Ghrelin and obestatin are two gastrointestinal peptides, derived from a common precursor. Expression of both peptides have been found in breast cancer tissue and ghrelin has been associated with breast cancer development. Ghrelin expression is associated with longer survival in women diagnosed with invasive and node negative breast cancer. The clinical implications of the peptide expression in male breast cancer are unclear. The aim of this study was to investigate the role and potential clinical value of ghrelin and obestatin in male breast cancer. A tissue microarray of invasive male breast cancer specimens from 197 patients was immunostained with antibodies versus the two peptides. The expression of the peptides was correlated to previously known prognostic factors in breast cancer and to the outcome. No strong correlations were found between ghrelin or obestatin expression and other known prognostic factors. Only ghrelin expression was statistically significantly correlated to breast cancer-specific survival (HR 0.39, 95% CI 0.18-0.83) in univariate analyses and in multivariate models, adjusted for tumor size and node status (HR 0.38, 95% CI 0.17-0.87). HR for obestatin was 0.38 (95% CI 0.11-1.24). Ghrelin is a potential prognostic factor for breast cancer death in male breast cancer. Patients with tumors expressing ghrelin have a 2.5-fold lower risk for breast cancer death than those lacking ghrelin expression. Drugs targeting ghrelin are currently being investigated in clinical studies treating metabolic or nutritional disorders. Ghrelin should be further evaluated in forthcoming studies as a prognostic marker with the aim to be included in decision algorithms.

In a search for new potential multitarget anti-HIV compounds from natural products, we have identified in Hypericum scruglii, an endemic and exclusive species of Sardinia (Italy), a potent plant lead. The phytochemical study of the hydroalcoholic extract obtained from its leaves led to the isolation of its most abundant secondary metabolites, belonging to different chemical classes. In particular, three phloroglucinols derivatives were identified, confirming their significance as chemotaxonomic markers of the Hypericum genus. Among them, the 3-(13-hydroxygeranyl)-1-(2'-methylbutanoyl) phloroglucinol was reported here for the first time. All six isolated compounds have been evaluated firstly for the inhibition of both Human Immunodeficiency Virus type 1 (HIV-1) Reverse Transcriptase (RT)-associated DNA Polymerase (RDDP) and Ribonuclease H (RNase H) activities, for the inhibition of HIV-1 integrase (IN) in biochemical assays, and also for their effect on viral replication. Among the isolated metabolites, three phloroglucinol derivatives and quercitrin were effective on both RT-associated RDDP and RNase H activities in biochemical assays. The same active compounds affected also HIV-1 IN strand transfer function, suggesting the involvement of the RNase H active site. Furthermore, phloroglucinols compounds, included the newly identified compound, were able to inhibit the HIV-1 replication in cell based assays.

A series of six new bis(thiosemicarbazone) copper(I) complexes of the type [Cu(L1-6)(2)Cl] (1-6) were synthesized and characterized. The complexes adopted trigonal planar 'Y' shaped geometry coordinating through two thione sulphur atoms of two ligand molecules and one chloride ion. All the complexes intercalatively bind with calf thymus DNA (CT-DNA) as evidenced by spectral and molecular docking studies. The absorption and emission spectral techniques confirmed the strong interaction of the complexes with BSA via static quenching mode. The complexes efficiently cleave pBR322 DNA via hydrolytic pathway, and significantly interact with epidermal growth factor receptor. All the complexes were assessed for their anti-proliferative activity, in which the complexes 2, 3 and 4 containing methyl, methoxy and hydroxyl groups, respectively, showed significant activity. The complexes induce apoptosis in EAC cells as evidenced by acridine orange (AO)/ethidium bromide (EB), Hoechst 33258 and propidium iodide (PI) staining methods, and cell cycle analysis. Cellular uptake studies revealed the ability of the complexes to go into the cytoplasm and accumulation in the cell nuclei. The complexes are involved in the generation of reactive oxygen species (ROS), mitochondrial mediated and caspase-dependent apoptosis. Further, using a female Swiss albino mice model, we found that the complexes 2 and 3 inhibited Ehrlich ascites carcinoma (EAC) tumour cell growth in vivo.

Compounds designed to display polypharmacology may have utility in treating complex diseases, where activity at multiple targets is required to produce a clinical efect. In particular, suitable compounds may be useful in treating neurodegenerative diseases by promoting neuronal survival in a synergistic manner via their multi-target activity at the adenosine A1 and A2A receptors (A1R and A2AR) and phosphodiesterase 10A (PDE10A), which modulate intracellular cAMP levels. Hence, in this work we describe a computational method for the design of synthetically feasible ligands that bind to A1 and A2A receptors and inhibit phosphodiesterase 10A (PDE10A), involving a retrosynthetic approach employing in silico target prediction and docking, which may be generally applicable to multi-target compound design at several target classes. This approach has identifed 2-aminopyridine-3-carbonitriles as the frst multi-target ligands at A1R, A2AR and PDE10A, by showing agreement between the ligand and structure based predictions at these targets. The series were synthesized via an efcient one-pot scheme and validated pharmacologically as A1R/A2AR–PDE10A ligands, with IC50 values of 2.4–10.0 μM at PDE10A and Ki values of 34–294 nM at A1R and/or A2AR. Furthermore, selectivity profling of the synthesized 2-amino-pyridin-3-carbonitriles against other subtypes of both protein families showed that the multi-target ligand 8 exhibited a minimum of twofold selectivity over all tested oftargets. In addition, both compounds 8 and 16 exhibited the desired multi-target profle, which could be considered for further functional efcacy assessment, analog modifcation for the improvement of selectivity towards A1R, A2AR and PDE10A collectively, and evaluation of their potential synergy in modulating cAMP levels LK thanks the IDB Cambridge International Scholarship for support. This work was fnancially supported by the ERC Starting Grant to AB (No. 336159), the Consellería de Cultura, Educación e Ordenación Universitaria of the Galician Government: (Grant: GPC2014/03), Centro singular de investigación de Galicia accreditation 2016–2019 (ED431G/09) and the European Regional Development Fund (ERDF) SI

A methodology for the lithiation of pyrimidine (1a) was developed and used for the synthesis of pyrimidylselenium compounds. The procedure involved prior complexation of 1a with 2.2 equiv. of BF3 center dot Et2O followed by a reaction with LDA or LTMP. The pyrazinylselenium derivatives were synthesized from the direct lithiation of pyrazine (1b) as the BF3-directed lithiation failed to give the desired products. All the synthesized compounds were characterized by elemental analysis, NMR (H-1 and C-13) and Mass spectroscopy. In addition, 2,5-bis(methylselenenyl)pyrazine (9b) was characterized by single crystal X-ray crystallography. (C) 2014 Elsevier B.V. All rights reserved.

In this article, we present OntoDM-core, an ontology of core data mining entities. OntoDM-core defines the most essential data mining entities in a three-layered ontological structure comprising of a specification, an implementation and an application layer. It provides a representational framework for the description of mining structured data, and in addition provides taxonomies of datasets, data mining tasks, generalizations, data mining algorithms and constraints, based on the type of data. OntoDM-core is designed to support a wide range of applications/use cases, such as semantic annotation of data mining algorithms, datasets and results; annotation of QSAR studies in the context of drug discovery investigations; and disambiguation of terms in text mining. The ontology has been thoroughly assessed following the practices in ontology engineering, is fully interoperable with many domain resources and is easy to extend. OntoDM-core is available at http://www.ontodm.com .

Biological activities of flavonoids in vivo are ultimately dependent on the systemic bioavailability of the aglycones as well as their metabolites. In the present study, a physiologically based kinetic (PBK) model was developed to predict plasma concentrations of the flavonoid quercetin and its metabolites and to tentatively identify the regiospecificity of the major circulating metabolites. The model was developed based on in vitro metabolic parameters and by fitting kinetic parameters to literature available in vivo data. Both exposure to quercetin aglycone and to quercetin-4'-O-glucoside, for which in vivo data were available, were simulated. The predicted plasma concentrations of different metabolites adequately matched literature reported plasma concentrations of these metabolites in rats exposed to 4'-O-glucoside. The bioavailability of aglycone was predicted to be very low ranging from 0.004%-0.1% at different oral doses of quercetin or quercetin-4'-O-glucoside. Glucuronidation was a crucial pathway that limited the bioavailability of the aglycone, with 95–99% of the dose being converted to monoglucuronides within 1.5–2.5 h at different dose levels ranging from 0.1 to 50 mg/kg bw quercetin or quercetin-4'-O-glucoside. The fast metabolic conversion to monoglucuronides allowed these metabolites to further conjugate to di- and tri-conjugates. The regiospecificity of major circulating metabolites was observed to be dose-dependent. As we still lack in vivo kinetic data for many flavonoids, the developed model has a great potential to be used as a platform to build PBK models for other flavonoids as well as to predict the kinetics of flavonoids in humans.

Photochemical reactions of ferrocenylacetylene with dialkyldithiophosphoric acid in hexane at low temperature led to the formation of (E)-[FcC(PS2(OR)(2))-CH(PS2(OR)(2))] (R = Me, Et, Pr-i). Formation of these compounds have been studied experimentally and computationally in different solvents. (C) 2013 Elsevier B.V. All rights reserved.

The ability of peforelin (l-GnRH-III) to stimulate follicular growth, FSH release, and estrus in gilts after altrenogest treatment and in sows after weaning was investigated. In three farrow-to-wean herds, with at least 600 sows and average production performance, 216 gilts, 335 primiparous, and 1299 pluriparous sows were randomly allocated to three treatments: peforelin (M group: Maprelin), eCG (F group: Folligon), and physiological saline solution (C group). Animals were treated 48 hours after their last altrenogest treatment (gilts) or 24 hours after weaning (sows). The weaning-to-estrus interval, estrus duration, estrus rate (ER), pregnancy rate, and total born (TB), live born, and stillborn (SB) numbers were recorded and compared between treatments for the different parity groups (gilts and primiparous and pluriparous sows). Follicle sizes were measured in representative animals from each group on the occasion of their last altrenogest treatment or at weaning, and also on the occasions of their first (FS1) and second (FS2) attempted inseminations. Blood samples were taken to determine FSH concentrations at weaning and 2 hours after injection, and progesterone concentrations 10 days after the first insemination attempt. The relative change in FSH concentrations was calculated. Significant differences were found for ER within 7 days of weaning in pluriparous sows (95%, 91%, and 90% for the M, F, and C groups, respectively, P = 0.005). Gilts in the F-group had high TB numbers, and pluriparous sows in the M group had high SB numbers (TB gilts = 13.6, 15.4, and 14.9 [P = 0.02] and SB pluriparous sows = 1.8, 1.4, and 1.7 [P = 0.05] for the M, F, and C groups, respectively). The M group had the highest FS1 (for gilts) and FS2 (for pluriparous sows) values: FS1 = 5.4, 4.9, and 4.9 mm [P = 0.02] and FS2 = 6.8, 5.3, and 6.3 mm [P = 0.03] for the M, F, and C groups, respectively. There were no significant differences between the different treatments within each parity group with respect to any of the other variables. Overall, peforelin treatment had small but positive effects on the ER and follicle growth in certain parity groups but did not seem to affect litter sizes or FSH and progesterone levels in sows on the occasions of the corresponding examinations.

A concise and highly diastereoselective synthesis of (+)-astropaquinone B and (+)-astropaquinone C is reported. The synthetic strategy is based on an efficient combination of Dotz benzannulation using a chiral alkyne to construct the naphthalene unit and a highly diastereoselective oxa-Pictet-Spengler reaction to install the trans-configured pyran ring as the key steps. (C) 2013 Elsevier Ltd. All rights reserved.

A novel synthesis of natural drimanic compounds, (-)-albrassitriol (2) and (-)-6-epi-albrassitriol (3), has been carried out starting from an easily available labdane diterpenoid, (+)-larixol (1). In a two-step procedure, (+)-larixol (1) was converted into 14,15-bisnorlab-7-ene-6,13-dione (9), which was then submitted to a Norrish type II photochemical degradation yielding drim-7,9(11)-diene-6-one (10), whose treatment with OsO4 led selectively to the formation of drim-7-ene-9α,11-diol-6-one (12). The same compound was obtained by selective epoxidation of the C(9)-C(11) double bond in drim-7,9(11)-diene-6-one (10) with monoperphtalic acid. Treatment of the resulting mixture of α- and β-epoxides (13 and 14) with HClO4 yielded drim-7-ene-9α,11-diol-6-one (12). Reduction of the C6-carbonyl group in drim-7-ene-9α,11-diol-6-one (12) with LiAlH4 afforded (-)-albrassitriol (2) and (-)-6-epi-albrassitriol (3), 12.4% and 13.6% overall yields, respectively.

8-Quinolinecarboxaldehyde selenosemicarbazone (H8qasesc) and its octahedral Co(III) complex were characterized by single crystal X-ray diffraction analysis, spectroscopy methods and cyclic voltammetry. The antineoplastic activity of the ligand and the complex has been assessed on an acute monocytic leukemia cell line (THP-1) and AsPC-1 cancer stem cell (CSC) line derived from a patient suffering from pancreatic adenocarcinoma, with cisplatin (CDDP) as a reference compound. Evaluation involved determination of pro-apoptotic activity, changes in cell cycle distribution, the role of caspase activation in the process of cell death, and the ability of the investigated compounds to challenge reprogramming of the CSC phenotype. Compared to CDDP, treatment with H8qasesc induced a higher apoptotic response in both investigated cell lines. Apoptosis triggered by H8qasesc was highly caspase-dependent but did not include activation of either caspase-8 or -9. According to cell cycle changes H8qasesc delayed the transition of cells during DNA replication but in a manner different from that of CDDP. The ligand did not show nuclease activity on pUC19 plasmid, while docking studies disclosed that it does not have intercalating properties. Treatment of THP-1 cells with the Co(III) complex resulted in a strong toxic response, whereas cell death in the treated AsPC-1 line was not achieved for 24 h. Additionally, the complex concentration-dependently digested plasmid DNA which might be the cause of its cytotoxic activity. Finally, H8qasesc successfully initiated reprogramming of the CSC phenotype in the AsPC-1 cell line. This is peer-reviewed version of the following article: Filipović, N. R.; Bjelogrlić, S.; Portalone, G.; Pelliccia, S.; Silvestri, R.; Klisurić, O.; Senćanski, M.; Stanković, D.; Todorović, T. R.; Muller, C. D. Pro-Apoptotic and pro-Differentiation Induction by 8-Quinolinecarboxaldehyde Selenosemicarbazone and Its Co(III) Complex in Human Cancer Cell Lines. MedChemComm 2016, 7 (8), 1604–1616. [https://doi.org/10.1039/c6md00199h] Supplementary material: [http://cherry.chem.bg.ac.rs/handle/123456789/3599]

Here we report the solid phase synthesis and characterization (LC-ESIMS, CD) of a cationic nucleobase-containing α-peptide, composed of both L-arginine residues and L-lysine-based nucleoamino acids sequentially present in the structure. The binding properties of this novel basic nucleopeptide towards nucleic acids were investigated by CD spectroscopy which revealed the ability of the thymine-containing oligomer to bind both adenine-containing DNA (dA12) and RNA (poly rA) molecules inducing high conformational variations in the nucleic acid structures. Moreover, the artificial oligonucleotide inhibited the enzymatic activity of HIV reverse transcriptase, opening the door to the exploitation of novel antiviral strategies inspired to this molecular tool.

A facile and efficient method for the construction of 3-alkyl/aryl substituted 1,4-benzoxazine and benzoxazepine via AgNO3 catalyzed cyclization of propargyloxy sulfonamides and their anti-tubercular activity against Mycobacterium tuberculosis H37RV is described. This cyclization proceeds through 6-exo-dig manner to generate the products in moderate to good yields.

A highly efficient synthesis of C3-arylbutenolides by Suzuki-Miyaura coupling is described. We developed a simple protocol to accomplish scaffolds of C3-arylbutenolides which include antifungal agent (−)-incrustoporin and twelve analogues by Pd-catalyzed Suzuki-Miyaura cross coupling reaction between chiral 3-iodobutenolide and various aryl boronic acids under aerobic conditions in good to quantitative yields.

A one-pot, two-step, three-component method for the conversion of commercially available aldehydes to phosphonylpyrazoles has been developed, demonstrating, for the first time, the dual reactivity of the Bestmann-Ohira reagent (BOR) in a single-pot transformation. This method, extended to the synthesis of sulfonylpyrazoles by employing BOR in the first step and a diazomethyl sulfone in the second step, is complementary, with regard to regioselectivity, to the previous methods for the synthesis of such functionalized pyrazoles.

An efficient one-step synthesis of piperidin-2-yl and pyrrolidin-2-yl flavonoid alkaloids was achieved in good to excellent yields by a highly regioselective phenolic Mannich reaction of chrysin with cyclic imines or iminium salts. Performing the reaction in a mixture of H2O/THF in the absence of an external reagent afforded the C-6 alkylated product exclusively. The same reaction in water in the presence of NaOH provided the C-8 alkylated flavonoid as a major product. The reaction has been successfully extended to simple phenols.

Protein kinase C (PKC) isoforms play a pivotal role in the regulation of numerous cellular functions, making them extensively studied and highly attractive drug targets. Utilizing the crystal structure of the PKC delta C1B domain, we have developed hydrophobic isophthalic acid derivatives that modify PKC functions by binding to the C1 domain of the enzyme. In the present study, we aimed to improve the drug-like properties of the isophthalic acid derivatives by increasing their solubility and enhancing the binding affinity. Here we describe the design and synthesis of a series of multisubstituted pyrimidines as analogs of C1 domain - targeted isophthalates and characterize their binding affinities to the PKC alpha isoform. In contrast to our computational predictions, the scaffold hopping from phenyl to pyrimidine core diminished the binding affinity. Although the novel pyrimidines did not establish improved binding affinity for PKC alpha compared to our previous isophthalic acid derivatives, the present results provide useful structure-activity relationship data for further development of ligands targeted to the C1 domain of PKC.

Four novel mononuclear coordination compounds namely: [Fe(Hthpy)(2)](SO(4))(1/2)center dot 3.5H(2)O 1, [Fe(Hthpy)(2)]NO(3)center dot 3H(2)O 2, [Fe(H(2)mthpy)(2)](CH(3)C(6)H(4)SO(3))(3)center dot CH(3)CH(2)OH 3 and [Fe(Hethpy)(ethpy)]center dot 8H(2)O 4, (H(2)thpy = pyridoxalthiosemicarbazone, H(2)mthpy = pyridoxal-4-methylthiosemicarbazone, H(2)ethpy = pyridoxal-4-ethylthiosemicarbazone), were synthesized in the absence or presence of organic base, Et(3)N and NH(3). Compounds 1 and 2 are monocationic, and were prepared using the singly deprotonated form of pyridoxalthiosemicarbazone. Both compounds crystallise in the monoclinic system, C2/c and P2(1)/c space group for 1 and 2, respectively. Complex 3 is tricationic, it is formed with neutral bis(ligand) complex and possesses an interesting 3D channel architecture, the unit cell is triclinic, P (1) over bar space group. For complex 4, the pH value plays an important role during its synthesis; 4 is neutral and crystallises with two inequivalent forms of the ligand: the singly and the doubly deprotonated chelate of H(2)ethpy, the unit cell is monoclinic, C2/c space group. Notably, in 1 and 4, there is an attractive infinite three dimensional hydrogen bonding network in the crystal lattice. Magnetic measurements of 1 and 4 revealed that a rather steep spin transition from the low spin to high spin Fe(III) states occurs above 300 K in the first heating step. This transition is accompanied by the elimination of solvate molecules and thus, stabilizes the high spin form due to the breaking of hydrogen bonding networks; compared to 2 and 3, which keep their low spin state up to 400 K.