Highly Selective MIF Ketonase Inhibitor KRP-6 Diminishes M1 Macrophage Polarization and Metabolic Reprogramming.

Macrophage polarization is highly involved in autoimmunity. M1 polarized macrophages drive inflammation and undergo metabolic reprogramming, involving downregulation of mitochondrial energy production and acceleration of glycolysis. Macrophage migration inhibitory factor (MIF), an enigmatic tautomerase (ketonase and enolase), was discovered to regulate M1 polarization.

Synthesis and evaluation of a new class of MIF-inhibitors in activated macrophage cells and in experimental septic shock in mice.

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with enzymatic activities. Anti-inflammatory effects of MIF enzyme inhibitors indicate a link between its cytokine- and catalytic activities. Herein the synthesis, docking, and bioactivity of substituted benzylidene-1-indanone and -1-tetralone derivatives as MIF-tautomerase inhibitors is reported.

Tetralone derivatives are MIF tautomerase inhibitors and attenuate macrophage activation and amplify the hypothermic response in endotoxemic mice.

Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine playing crucial role in immunity. MIF exerts a unique tautomerase enzymatic activity that has relevance concerning its multiple functions and its small molecule inhibitors have been proven to block its pro-inflammatory effects. Here we demonstrate that some of the -2-arylmethylene-1-tetralones and their heteroanalogues efficiently bind to MIF's active site and inhibit MIF tautomeric (enolase, ketolase activity) functions.

Continuum Model Applied to Granular Analogs of Droplets and Puddles.

We investigate the growth of aggregates made of adhesive frictionless oil droplets, piling up against a solid interface. Monodisperse droplets are produced one by one in an aqueous solution and float upward to the top of a liquid cell where they accumulate and form an aggregate at a flat horizontal interface. Initially, the aggregate grows in 3D until its height reaches a critical value.

Study on the Synthesis, Antioxidant Properties, and Self-Assembly of Carotenoid-Flavonoid Conjugates.

Flavonoids and carotenoids possess beneficial physiological effects, such as high antioxidant capacity, anticarcinogenic, immunomodulatory, and anti-inflammatory properties, as well as protective effects against UV light. The covalent coupling of hydrophobic carotenoids with hydrophilic flavonoids, such as daidzein and chrysin, was achieved, resulting in new amphipathic structures. 7-Azidohexyl ethers of daidzein and chrysin were prepared in five steps, and their azide-alkyne [4 + 2] cycloaddition with pentynoates of 8'-apo-β-carotenol, zeaxanthin, and capsanthin afforded carotenoid-flavonoid conjugates.

Novel Cell Wall Antifungals Reveal a Special Synergistic Activity in Mutants Resistant to the Glucan Synthesis Antifungals Papulacandins and Echinocandins.

A series of 4(arylmethylene)-3-isochromanones have been prepared with base-catalyzed Knoevenagel condensation starting from 3-isochromanone and aromatic aldehydes. The outcome of the reaction- the isomeric composition of the products depends on the aromatic aldehyde applied. These reactions afforded mostly the more stable -diastereoisomer, but some condensations resulted in the Z-diastereoisomer or mixture of the stereoisomers (-).

Mannich Ketones as Possible Antimycobacterial Agents.

Twenty-three known unsaturated and fused Mannich ketones and their reduced derivatives (amino alcohols) were selected for an antituberculotic study. They were screened against several mycobacterial strains including Mycobacterium tuberculosis, M. xenopi, and M.

3-benzylidene-4-chromanones: a novel cluster of anti-tubercular agents.

In a quest for developing novel anti-tubercular agents, a series of 3-benzylidene-4-chromanones 1a-l were evaluated for growth inhibition of Mycobacterium tuberculosis H37Rv. Three promising compounds 1d, g, j emerged as the lead compounds with the IC50 and IC90 values of less than 1 µg/mL. Evaluation of the potent compounds 1d, g, j and k against Vero monkey kidney cells revealed that these compounds are far more toxic to M.

Antifungal activity of fused Mannich ketones triggers an oxidative stress response and is Cap1-dependent in Candida albicans.

We investigated the antifungal activity of fused Mannich ketone (FMK) congeners and two of their aminoalcohol derivatives. In particular, FMKs with five-membered saturated rings were shown to have minimum inhibitory concentration (MIC90s) ranging from 0.8 to 6 µg/mL toward C.

Novel dating method to distinguish between forensic and archeological human skeletal remains by bone mineralization indexes.

The fast, high-throughput distinction between paleoanthropological remains and recent forensic/clinical bone samples is of vital importance in the field of medicolegal science. In this paper, a novel screening method has been described, using the crystallinity index (C.I.

Protective effect of the poly(ADP-ribose) polymerase inhibitor PJ34 on mitochondrial depolarization-mediated cell death in hepatocellular carcinoma cells involves attenuation of c-Jun N-terminal kinase-2 and protein kinase B/Akt activation.

Background: 2,4-Dimethoxyphenyl-E-4-arylidene-3-isochromanone (IK11) was previously described to induce apoptotic death of A431 tumor cells. In this report, we investigated the molecular action of IK11 in the HepG2 human hepatocellular carcinoma cell line to increase our knowledge of the role of poly (ADP-ribose)-polymerase (PARP), protein kinase B/Akt and mitogen activated protein kinase (MAPK) activation in the survival and death of tumor cells and to highlight the possible role of PARP-inhibitors in co-treatments with different cytotoxic agents in cancer therapy.

Results: We found that sublethal concentrations of IK11 prevented proliferation, migration and entry of the cells into their G2 phase.

Amphotericin B and fluconazole susceptibility of Candida species determined by cell-chip technology.

The aim of this study was to apply the microfluidic cell-chip technology for susceptibility testing. The cell-chip technology was tested with ATCC Candida strains to determine their viability and susceptibility against amphotericin B and fluconazole. Fungal cells were labelled by Sytox Green, and measurements were carried out in the cell chips of the Agilent Bioanalyzer 2100 system.

Hormonal action of plant derived and anthropogenic non-steroidal estrogenic compounds: phytoestrogens and xenoestrogens.

Herbivorous and omnivorous vertebrates have evolved in the presence of a variety of phytoestrogens, i.e., plant-derived compounds that can mimic, modulate or disrupt the actions of endogenous estrogens.

Comparative characterization of experimental and calculated lipophilicity and anti-tumour activity of isochromanone derivatives.

Compound lipophilicity connected to ADME(T)(a) has great importance in drug development and it has to be evaluated by the generally used drug developmental process. In addition to the importance of lipophilicity in ADMET, recently it has been reported that lipophilicity of small molecules correlates with their antiproliferative activity because of certain specific hydrophobic and lipophilic interactions. Due to the complexity of ADME(T) parameters an efficient and fast method is needed to characterize the many promising candidate lead molecules as a preselection in order not to be rejected from the latter phase of drug development.

Macrophage migration inhibitory factor (MIF) tautomerase inhibitors as potential novel anti-inflammatory agents: current developments.

Macrophage migration inhibitory factor (MIF), the pro-inflammatory cytokine, first described in 1966, plays an essential role in both, innate and adaptive immune response. It has been implicated in tumour growth and angiogenesis and it exerts an antagonistic action against glucocorticoid immunosuppressive effect. Its perplexing enzymatic tautomerase activity has attracted considerable interest in the last decade.

Antifungal unsaturated cyclic Mannich ketones and amino alcohols: study of mechanism of action.

The antifungal activity of some known unsaturated Mannich ketones and their amino alcohols has been reported and the mechanism of antifungal action has been studied. The inhibition of the fungal ergosterol, chitin, protein synthesis and pseudohypha formation was investigated. According to our results, Mannich ketones can influence the development of pseudohyphae of Candida albicans strains.

MIF tautomerase inhibitor potency of alpha,beta-unsaturated cyclic ketones.

The pro-inflammatory cytokine, macrophage migration inhibitory factor (MIF), is currently enjoying a renewed interest owing to its recently revealed functions. Among these its enzymatic tautomerase activity remains the most perplexing. There is a notion that some aspects of MIF signaling might involve its catalytic action.

Recent advances in antifungal agents.

New antifungals are needed in the medicine because of more aggressive and invasive diagnostic and therapeutic methods used, rapid emergence of resistant and new opportunistic fungi, increasing number of patients suffering from immunosuppressive situations e.g., AIDS, transplantation, cancer, etc.

Design, synthesis and antiproliferative activity of some 3-benzylidene-2,3-dihydro-1-benzopyran-4-ones which display selective toxicity for malignant cells.

A series of 3-benzylidene-4-chromanones 1a-l were prepared and their cytotoxicity towards human Molt 4/C8 and CEM T-lymphocytes as well as murine L1210 lymphoid leukemia cells were compared to the previously generated biodata in these three assays for the isosteric 2-benzylidene-1-tetralones 2a-l. Over 40% of the compounds in series 1 were more potent than their counterparts in series 2, while equipotency was noted in one-third of the comparisons made. In general the IC(50) values of 1a-l towards the human T-lymphocytes were in the low micromolar range.

Lipophilicity and antiproliferative activity profiling of 2-benzylidencycloalkanones.

High performance liquid chromatographic (HPLC) method has been developed to separate the members of a library including 24 benzylidenecycloalkanone-type structures and to characterize their lipophilicity. The experimental lipophilicity data (k) of the compounds have been compared with their calculated lipophilicity parameters (CLOGP). In general, good correlations between the measured and calculated lipophilicities have been found and these results were in good accordance with our previously data obtained in case of structurally related molecular libraries.

Analysis of pathological and non-pathological human skeletal remains by FT-IR spectroscopy.

In this study, we report the chemical analyses of various non-pathological, tuberculosis and syphilis infected bone samples from different burial environments by Fourier transform infrared spectroscopy (FT-IR), in the framework of a general study of diagenesis. Dating human skeletal remains is one of the most important and yet unreliable aspects of forensic anthropology. In this paper, a new method has been suggested, using the crystallinity index and carbonate-phosphate index as a means of distinction between recent and archaeological, anthropological bone samples.

Reactions of 3-isochromanone with aromatic aldehydes--microwave assisted condensations performed on solid basic inorganic supports.

An improved Knoevenagel condensation of 3-isochromanone and aromatic aldehydes can be achieved by microwave irradiation on solid supports in the presence of various catalysts. This synthetic method offers some major advantages, especially the possibility to change the ratio of E/Z isomers.

Analysis of the vibrational spectra of new OH-containing E-4-arylmethylene-3-isochromanones and 3-arylcoumarins.

A combined experimental and theoretical approach is presented to structural characterization of fairly large, newly synthesized organic molecules in order to enhance the effectiveness of their instrumental analysis by vibrational spectroscopy. The method consists of measurement of FT-IR and Raman spectra of the reaction products and subsequent ab initio or DFT quantum mechanical calculations (prediction) of the vibrational spectra for any anticipated structural varieties of the synthesized molecules. Comparison of the measured and computed frequencies as well as the observed and simulated spectra is performed to resolve any uncertainties in identifying the reaction products.

Effect of antifungal agents on protein composition of Candida albicans studied by capillary electrophoresis and chip technology.

In the present study protein profile of a Candida albicans strain had been examined by chip technology and conventional capillary electrophoresis (CE). Profiles could be characterised by the presence of ten dominating protein peaks. These proteins could be distinguished by both techniques, but their quantity showed significant differences in the electropherograms obtained by CE and chip method.

Cinnamylidene ketones as potential modulators of multidrug resistance in mouse lymphoma and human colon cancer cell lines.

The resistance to chemotherapy of cancer cells is mediated by the overexpression of P-glycoprotein, as an ATP-dependent membrane efflux pump. Two families of compounds have been screened, the cinnamylidenecycloalkanones and cinnamylidenebenzocycloalkanones, as promising multidrug resistance (MDR) reversal agents on mouse lymphoma and human colon cancer (COL0320) cell lines. The antiproliferative effects of the cinnamylidene derivatives were tested with the MTT method The MDR effect on drug accumulation was tested by flow cytometry.