Synthesis and cytotoxicity of novel simplified eleutherobin analogues as potential antitumour agents.

Mixed simplified structures containing the paclitaxel and eleutherobin pharmacophore moieties were analyzed using molecular docking techniques and synthesized based on adamantane and 8-oxabicyclo[3.2.1]octane scaffolds. The crucial role of substituents' stereochemistry in biological activity is discussed. At micromolar concentrations the selected analogues interfered with tubulin dynamics in vitro and in a living organism. Furthermore, new compounds were cytotoxic against human tumour cell lines. The simplified eleutherobin analogues may be considered as prototypes of a new class of antitumour agents.

Oxindole-based intraocular pressure reducing agents.

The study represents the new findings at the crossroads of chemistry and medicine, particularly between medicinal and organic chemistry and ophthalmology. In this work we describe how the chemical reactivity of indolinone scaffold may be used to create small molecule ligands with strong biological response comparable with and larger than that of endogenous hormone. The synthesis of oxindole-based melatonin and 5-methoxycarbonylamino-N-acetyltryptamine (5-MCA-NAT) analogues was proposed and their ability to influence intraocular pressure (IOP) was studied in vivo. Time-dependent study revealed the prolonged effect (more than 6h) of the lead-compound. This effect in combination with high IOP reducing effect (41±6%) in low concentrations of the active compound (0.1wt%) and with high water solubility represents a great potential of low-cost oxindole derivatives as potent antiglaucoma agents.

Substituent effects on stereoselectivity of dihalocarbene reactions with cyclohexadiene and on the reactivity of bis-dihalocyclopropanes in electrophilic nitrations en route to pyrimidine N-oxides.

Tricyclic bis-adducts of cyclohexa-1,4-diene with bromofluorocarbene and non-symmetric adducts with both bromofluoro- and dichlorocarbenes were synthesised selectively. The treatment of the bis-adducts with nitrating reagents in acetonitrile affords the products of heterocyclization of a sole dihalogenocyclopropane into 4-fluoropyrimidine N-oxide. The difference in the reactivity of bis-cyclopropanes with different sets of halogen substituents leads to selective heterocyclization of bromofluorocyclopropanes without affecting the dichlorocyclopropane moiety.

Threshold concentration in the nonlinear absorbance law.

A new nonlinear relationship of the absorption coefficient with the concentration was proposed, allowing the calculation of the threshold concentration, which shows that there is a deviation from the Beer-Lambert law. The nonlinear model was successfully tested on a stable dimeric phthalocyanine ligand of J-type in solvents with different polarity. It was shown that deviation from the linearity is connected with a specific association of the macrocyclic molecules, which, in the case of non-polar solvents, leads to the formation of H-aggregates composed of J-type dimeric molecules. The aggregation number was estimated to be less than 1.5, which has allowed us to conduct a series of analytical experiments in a wide range of concentrations (1 × 10-6-5 × 10-4 mol L-1).

Novel antimitotic agents related to tubuloclustin: synthesis and biological evaluation.

Tubuloclustin [N-(7-adamant-2-yloxy-7-oxoheptanoyl)-N-deacetylcolchicine], a highly cytotoxic anti-tubulin compound is known for its ability to promote microtubule disassembly followed by the formation of tubulin clusters of unique morphology. Three series of antimitotic agents related to tubuloclustin were designed and synthesized in order to enhance the molecular diversity of "tubuloclustin-like" family of compounds. The series of compounds with modified adamantane moiety was highly potent in cytotoxic effect on human lung carcinoma A549 cells (EC50 = 6-400 nM) and was active in affecting the microtubule arrays and induction of strong tubulin clusterization. In two other sets of compounds, the colchicine moiety of tubuloclustin was replaced by podophyllotoxin or combretastatin A-4. All combretastatin A-4 derivatives displayed noticeable cytotoxic activity ([Formula: see text]) but their effect on microtubules depended on the position of the linker attachment. Podophyllotoxin derivatives were also toxic to A549 cells ([Formula: see text]) and caused both microtubule depolymerization and some tubulin clustering. The data obtained gave additional evidence that the whole panel of C7-colchicine, podophyllotoxin and combretastatin derivatives could manifest clustering effect, and the strength of this effect correlated with cytotoxic activity of the compounds.

Beyond the Dimer and Trimer: Tetraspiro[2.1.2(5).1.2(9).1.2(13).1(3)] hexadecane-1,3,5,7-tetraone--the Cyclic Tetramer of Carbonylcyclopropane.

Tetraspiro[2.1.2(5).1.2(9).1.2(13).1(3)]hexadecane-1,3,5,7-tetraone 4, a unique tetraketone containing a cyclooctane core and four spiroannelated cyclopropane moieties, represents the previously unknown cyclotetramer of carbonylcyclopropane. For this purpose oxidation of the parent polyspirocyclic hydrocarbon was examined under various oxidative conditions, and the reactivity of oxidants towards methylene groups of the eight-membered cycle, activated by adjacent spirocyclopropane rings, was evaluated and contrasted. Whereas the treatment of tetraspirohexadecane with ozone resulted in monooxidation, its reaction with methyl(trifluoromethyl)dioxirane afforded the product of four-fold oxidation, triketoalcohol 10. Subsequent oxidation of the latter with Dess-Martin periodinane gave the target tetraketone 4.

Complex formation of albumin with tricarbocyanine dyes containing phosphonate groups.

The spectral characteristics, binding constants with bovine (BSA) and human serum albumin (HSA) and lifetimes of fluorescence in PBS and EtOH solutions and in the presence of BSA in PBS were measured for novel indotricarbocyanine dyes bearing remote phosphonate groups. These parameters are close to those for indocyanine green (ICG) indicating that the Coulomb interaction does not play a significant role in complex formation, and the binding is determined by the interaction of the dye polymethine chain with albumin. The fluorescence lifetimes of the complexes with BSA strongly indicate the formation of complexes of two types with different lifetimes. The complex with a longer fluorescence lifetime (740-800 ps) and major contribution (up to 88%) is bound to the more hydrophobic site and that with a shorter fluorescence lifetime (300-340 ps) to the more hydrophilic site.

Synthesis and biological evaluation of novel 5-hydroxylaminoisoxazole derivatives as lipoxygenase inhibitors and metabolism enhancing agents.

A versatile synthesis of novel 5-hydroxylaminoisoxazoles bearing adamantane moieties has been accomplished using the heterocyclization reactions of readily available unsaturated esters by the treatment with tetranitromethane in the presence of triethylamine and subsequent reduction of resulting 5-nitroisoxazoles by SnCl2 with the participation of THF. A number of obtained isoxazole derivatives were evaluated for their antioxidative activity, inhibition of lipoxygenases and impact on the rat liver mitochondria. The majority of tested compounds demonstrated moderate antiradical activity in DPPH test (up to EC50 16µM). The same compounds strongly inhibited soybean lipoxygenase (up to IC50 0.4µM) and Fe(2+)- and Fe(3+)-induced lipid peroxidation (LP) of rat brain cortex homogenate (up to IC50 0.3µM). All tested isoxazole derivatives promoted the phosphorylating respiratory activity simultaneously with maximal stimulated respiratory activity of mitochondria and do not reveal any toxicity towards the primary culture of rat cortex neurons.

Thermally stable J-type phthalocyanine dimers as new non-linear absorbers for low-threshold optical limiters.

The possibility of developing new advanced optical limiters of laser radiation at 532 nm with low limiting thresholds has been demonstrated on thermally stable phthalocyanine J-type dimeric complexes of Mg, Zn, Cu, Ni, and Co. A new "threshold" model based on radiative transfer phenomena in nonlinear optical media was suggested for the exact definition of nonlinear absorption coefficient ß and optical limiting threshold Ic. This model allows the determination of the optical characteristics of the limiter in the same active material with layers of different thicknesses, as well as the use of different parameters of laser radiation, such as cross-sectional spatial profiles of the laser beam and shapes of the laser pulse over time. The maximum value of the nonlinear absorption coefficient (ß = 360 cm GW(-1)) and the lowest limiting threshold (Ic = 0.03 J cm(-2)) were estimated for a J-type zinc phthalocyanine dimer.

Synthesis and assessment of 4-aminotetrahydroquinazoline derivatives as tick-borne encephalitis virus reproduction inhibitors.

Tick-borne encephalitis virus (TBEV) belonging to Flavivirus genus causes severe infection in humans. The search for therapeutically relevant compounds targeting TBEV requires the exploration of novel chemotypes. A versatile synthesis of previously unknown 4-aminopyrimidines and 4-aminopyrimidine N-oxides based on a fluorosubstituted heterocyclic core is described. A representative series of 4-aminotetrahydroquinazoline derivatives, containing aliphatic and aromatic substituents as well as the adamantane framework, was obtained and their activity against tick-borne encephalitis virus reproduction was studied. Nine compounds were found to inhibit TBEV entry into the host cells. A bulky hydrophobic adamantyl group was identified to be important for the antiviral activity. The developed synthetic route allowed an easy access to a consistent compound library for further structure-activity relationship studies.

symm-Tetramethylenecyclooctane: en route to polyspirocycles.

A straightforward gram-scale synthesis of 1,3,5,7-tetrakis(methylidene)cyclooctane (TMCO) from commercial adamantane-1,3-dicarboxylic acid has been developed. TMCO exhibits high reactivity toward a number of carbenes and epoxidizing reagents, undergoing multiple cyclopropanations, dihalocyclopropanations, or epoxidations of four double bonds to yield polyspirocyclic products. Stereochemical features of polyspirocyclopropanated compounds have been thoroughly examined in experimental (NMR) and theoretical (DFT) studies. Comprehensive stereochemical assignment of TMCO adducts with dihalocarbenes and spiroepoxy products was achieved. The conditions of the formation of 1-methyl-3,7-bis(methylidene)bicyclo[3.3.1]nonane from the adamantane derivative were optimized, and diadducts of this diene with dihalocarbenes were isolated and characterized.

Pharmacological correction of stress-induced gastric ulceration by novel small-molecule agents with antioxidant profile.

This study was designed to determine novel small-molecule agents influencing the pathogenesis of gastric lesions induced by stress. To achieve this goal, four novel organic compounds containing structural fragments with known antioxidant activity were synthesized, characterized by physicochemical methods, and evaluated in vivo at water immersion restraint conditions. The levels of lipid peroxidation products and activities of antioxidative system enzymes were measured in gastric mucosa and correlated with the observed gastroprotective activity of the active compounds. Prophylactic single-dose 1 mg/kg treatment with (2-hydroxyphenyl)thioacetyl derivatives of L-lysine and L-proline efficiently decreases up to 86% stress-induced stomach ulceration in rats. Discovered small-molecule antiulcer agents modulate activities of gastric mucosa tissue superoxide dismutase, catalase, and xanthine oxidase in concerted directions. Gastroprotective effect of (2-hydroxyphenyl)thioacetyl derivatives of L-lysine and L-proline at least partially depends on the correction of gastric mucosa oxidative balance.

Unusual tubulin-clustering ability of specifically c7-modified colchicine analogues.

Highly cytotoxic C7-modified colchicine analogues, exemplified by tubuloclustin, promote microtubule disassembly followed by the formation of very stable tubulin clusters, both in vitro and in cells. The proposed mechanism of action of tubuloclustin and its analogues, beyond that of colchicine, includes additional specific interactions with the α-tubulin subunit.

Phosphonium-iodonium ylides with heteroatomic groups in the synthesis of annelated P-containing heterocycles.

The preparation and chemistry of novel sulfonyl- and phosphoryl-derived λ(3)-iodanes are reported. These compounds with three different heteroatoms attached to a negatively charged C atom represent potentially useful reagents that combine in one molecule the synthetic advantages of a phosphonium ylide and an iodonium salt. Specifically, they can react with a number of acetylenes, leading to hitherto unknown sulfonyl- and phosphoryl-substituted phosphinolines, phosphininothiophenes, and a novel type of annelated P-containing heterocycle--phosphininopyrazole.

Signatures of the ATP-binding pocket as a basis for structural classification of the serine/threonine protein kinases of gram-positive bacteria.

Eukaryotic-like serine/threonine protein kinases (ESTPKs) are widely spread throughout the bacterial genomes. These enzymes can be potential targets of new antibacterial drugs useful for the treatment of socially important diseases such as tuberculosis. In this study, ESTPKs of pathogenic, probiotic, and antibiotic-producing Gram-positive bacteria were classified according to the physicochemical properties of amino acid residues in the ATP-binding site of the enzyme. Nine residues were identified that line the surface of the adenine-binding pocket, and ESTPKs were classified based on these signatures. Twenty groups were discovered, five of them containing >10 representatives. The two most abundant groups contained >150 protein kinases that belong to the various branches of the phylogenetic tree, whereas certain groups are genus- or even species-specific. Homology modeling of the typical representatives of each group revealed that the classification is reliable, and the differences between the protein kinase ATP-binding pockets predicted based on their signatures are apparent in their structure. The classification is expected to be useful for the selection of targets for new anti-infective drugs.

A molecular model and Monte Carlo simulation of flavivirus envelope building block.

A molecular model of mature dengue virus envelope building block consisting of two E and two M protein subunits is constructed. Monte Carlo optimisation is performed for the model in the implicit membrane system. Interactions between the ectodomains and membrane parts of E and M proteins are studied, and possible role of conserved residues is suggested. The opening of E protein detergent binding site and its fixation in the open state by the M non-structured loop is observed.

Sandwich double-decker lanthanide(III) "intracavity" complexes based on clamshell-type phthalocyanine ligands: synthesis, spectral, electrochemical, and spectroelectrochemical investigations.

Phthalocyanine compounds of novel type based on a bridged bis-ligand, denoted "intracavity" complexes, have been prepared. Complexation of clamshell ligand 1,1'-[benzene-1,2-diylbis(methanediyloxy)]bis[9(10),16(17),23(24)-tri-tert-butylphthalocyanine] ((clam,tBu)Pc(2)H(4), 1) with lanthanide(III) salts [Ln(acac)(3)]⋅n H(2)O (Ln = Eu, Dy, Lu; acetylacetonate) led to formation of double-deckers (clam,tBu)Pc(2)Ln (2 a-c). Formation of high molecular weight oligophthalocyanine complexes was demonstrated as well. The presence of an intramolecular covalent bridge affecting the relative arrangement of macrocycles was shown to result in specific physicochemical properties. A combination of UV/Vis/NIR and NMR spectroscopy, MALDI-TOF mass-spectrometry, cyclic voltammetry, and spectroelectrochemistry provided unambiguous characterization of the freshly prepared bis-phthalocyanines, and also revealed intrinsic peculiarities in the structure-property relationship, which were supported by theoretical calculations. Unexpected NMR activity of the paramagnetic dysprosium complex 2 b in the neutral π-radical form was observed and examined as well.

Three-component heterocyclization of gem-bromofluorocyclopropanes with NOBF4: access to 4-fluoropyrimidine N-oxides.

Novel three-component heterocyclization involving gem-bromofluorocyclopropanes, nitrosyl tetrafluoroborate, and a molecule of the solvent (nitrile) yielding previously unknown fluorinated pyrimidine N-oxides is described. A two-step synthetic approach to 4-fluoropyrimidine N-oxides from alkenes under mild conditions is developed using this reaction. Mechanistic aspects of the heterocyclization are discussed.

Hetaryl-substituted phosphonium-iodonium ylides in synthesis of heterocycles.

A series of hitherto unknown hetaryl-substituted (in phosphonium part) phosphonium-iodonium ylides were synthesized. The reaction of these mixed phosphonium-iodonium ylides with acetylenes opens a way to new furyl annelated phosphinolines or unusually substituted phosphininofurans.

Synthesis of novel МТ3 receptor ligands via an unusual Knoevenagel condensation.

New 5-acetamido-substituted melatonin derivatives were efficiently synthesized in excellent yields via Knoevenagel condensation. The relative binding affinity of new synthesized compounds to MT3 receptor was tested via enzymatic assays and the X-ray structures of the most potent compounds were determined in complex with MT3.