Nature-Inspired 1-Phenylpyrrolo[2,1-]isoquinoline Scaffold for Novel Antiproliferative Agents Circumventing P-Glycoprotein-Dependent Multidrug Resistance.

Previous studies have shown that some lamellarin-resembling annelated azaheterocyclic carbaldehydes and related imino adducts, sharing the 1-phenyl-5,6-dihydropyrrolo[2,1-]isoquinoline (1-Ph-DHPIQ) scaffold, are cytotoxic in some tumor cells and may reverse multidrug resistance (MDR) mediated by P-glycoprotein (P-gp). Herein, several novel substituted 1-Ph-DHPIQ derivatives were synthesized which carry carboxylate groups (COOH, COOEt), nitrile (CN) and Mannich bases (namely, morpholinomethyl derivatives) in the C2 position, as replacements of the already reported aldehyde group. They were evaluated for antiproliferative activity in four tumor cell lines (RD, HCT116, HeLa, A549) and for the ability of selectively inhibiting P-gp-mediated MDR.

[The influence of pseudoexfoliation syndrome on central retina in elderly patients.].

to evaluate the effect of pseudoexfoliation syndrome (PXF) on the stage of age-related macular degeneration (AMD) and central retinal thickness, measured by optical coherence tomography (OCT) in elderly patients living in Saint-Petersburg. 25 elderly patients (30 eyes) with PXF and 25 age-matched patients (29 eyes) without PXF (control group) were included in the study. Retinal thickness in fovea and parafovea as well as AMD stage were compared in the groups.

N-Alkylation of Anthracycline Antibiotics by Natural Sesquiterpene Lactones as a Way to Obtain Antitumor Agents with Reduced Side Effects.

Anthracycline antitumor antibiotics are one of the promising classes of chemotherapeutic agents for cancer treatment. The main deterrent to their use is high toxicity to a healthy environment, including cumulative cardiotoxicity. In our work, bipharmacophore molecules containing in their structure a fragment of the known anthracycline antibiotics daunorubicin and doxorubicin and natural sesquiterpene lactones were obtained for the first time.

Homobivalent Lamellarin-Like Schiff Bases: In Vitro Evaluation of Their Cancer Cell Cytotoxicity and Multitargeting Anti-Alzheimer's Disease Potential.

Marine alkaloids belonging to the lamellarins family, which incorporate a 5,6-dihydro-1-phenylpyrrolo[2,1-]isoquinoline (DHPPIQ) moiety, possess various biological activities, spanning from antiviral and antibiotic activities to cytotoxicity against tumor cells and the reversal of multidrug resistance. Expanding a series of previously reported imino adducts of DHPPIQ 2-carbaldehyde, novel aliphatic and aromatic Schiff bases were synthesized and evaluated herein for their cytotoxicity in five diverse tumor cell lines. Most of the newly synthesized compounds were found noncytotoxic in the low micromolar range (<30 μM).

Synthesis and antitumor activity of daunorubicin conjugates with of 3,4-methylendioxybenzaldehyde.

The design of hybrid (chimeric) molecules containing two different pharmacophores connected via a spacer (linker) is a promising approach to the functionalization of natural compounds and potentially of drug molecules. These are important examples for the use of this approach with anthracycline antibiotics. The use of this methodology may help to eliminate some of the drawbacks of anthracycline drugs, e.

2,4,5-Tris(alkoxyaryl)imidazoline derivatives as potent scaffold for novel p53-MDM2 interaction inhibitors: Design, synthesis, and biological evaluation.

Imidazoline-based small molecule inhibitors of p53-MDM2 interaction intended for the treatment of p53 wild-type tumors are the promising structures for design of anticancer drugs. Based on fragment approach we have investigated a key role of substituents in cis-imidazoline core for biological activity of nutlin family compounds. Although the necessity of the substituents in the phenyl rings of cis-imidazoline has been shown, there are no studies in which the replacements of a halogen by other substituents have been investigated.

Synthesis and biological evaluation of 3-substituted 2-oxindole derivatives as new glycogen synthase kinase 3β inhibitors.

Glycogen synthase kinase 3β (GSK-3β) is a widely investigated molecular target for numerous diseases including Alzheimer's disease, cancer, and diabetes mellitus. Inhibition of GSK-3β activity has become an attractive approach for treatment of diabetes and cancer. We report the discovery of novel GSK-3β inhibitors of 3-arylidene-2-oxindole scaffold with promising activity.

The influence of substituents on the reactivity and cytotoxicity of imidazothiazolotriazinones.

A series of tetrahydroimidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazine-2,7(1H, 6H)-diones were synthesized via the reaction of imidazotriazinethiones and bromoacetic acid followed by condensation with isatins. Amidine skeletal rearrangement of 3,3a,9,9a-tetrahydroimidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazine-2,7 (1H, 6H)-diones into 1,3a,4,9a-tetrahydroimidazo[4,5-e]thiazolo[2,3-c]-1,2,4-triazine-2,8 (3H, 7H)-diones under KOH treatment has been studied. The influence of substituents at positions 1,3,3a,6,9a of imidazothiazolotriazine on the ability to undergo rearrangement was analyzed based on experimental data and theoretical calculations.

Synthesis and biological evaluation of new substituted thioglycolurils, their analogues and derivatives.

A novel series of substituted N-aminothioglycolurils was synthesized by tandem hydrazone formation - ring contraction reaction of 3-thioxoperhydroimidazo[4,5-e]-1,2,4-triazin-6-ones with (E)-3-phenyl(furan-2-yl)acrylaldehyde derivatives. S-Alkyl substituted N-aminothioglycolurils were prepared through alkylation of corresponding thioglycolurils with iodoalkane or 4-chlorobenzylchloride. Methylthio group in S-methyl derivatives can be substituted with hydroxyl group in acid medium to give N-aminoglycolurils.

Substituted N-aminothioglycolurils containing thiosemicarbazone moiety and their cytotoxic activity in vitro.

A library of hybrid molecules bearing thioglycoluril and (hetero)aromatic aldehyde thiosemicarbazone moieties was synthesized via a tandem hydrazone formation-ring contraction reaction of 5,7-dialkyl-3-thioxoperhydroimidazo[4,5-e]-1,2,4-triazin-6-ones with (hetero)aromatic aldehydes. All synthesized compounds were tested for their cytotoxic activity against rhabdomyosarcoma, A549, and MS human cancer cell lines by MTT-assay. Among the derivatives, (E)-4-benzylideneamino-1,3-dimethyl-5-thioxohexahydroimidazo[4,5-d]imidazol-2(1H)-one 1f was found to have the most marked antiproliferative activity toward the tested cell lines (1f: IC[Formula: see text] 23.

Synthesis, transformation and biological evaluation of 2,3-secotriterpene acetylhydrazones and their derivatives.

It has been previously shown that semi-synthetic A-secotriterpene acetylhydrazones of 1-cyano-28-methoxy-28-oxo-2,3-seco-2-norlup-20(29)-en-3-al and 1-cyano-2,3-seco-2-nor-19β,28-epoxy-18αH-olean-3-al (1, 2) inhibit the vesicular stomatitis virus (VSV) replication. To improve the antiviral activity against VSV, structural modifications of compounds 1 and 2 were performed, and new A-secoderivatives containing the acetylhydrazone fragment were obtained from betulonic acid and its methyl ester, allobetulone, and 3-oxo-18βH-glycyrrhetinic acid methyl ester. The inhibitory effects of these compounds on VSV replication in porcine embryo kidney (PEK) cells were determined after infection.

Polysulfones of new structural types as perspective antioxidant agents.

A series of polysulfones of new structural types on the basis of azanorbornenes, 2,2-diallyl-1,1,3,3-tetraethylguanidiniumchloride and tris(diethylamino)diallylaminophosphonium salts were obtained by free radical polymerization reaction. Their antioxidant properties in lipid peroxidation induced by iron/ascorbate and in erythrocyte hemolysis by H2O2 were evaluated. The polysulfone of 2,2-diallyl-1,1,3,3-tetraethylguanidinium chloride showed protection of erythrocytes against hydrogen peroxide and thermal shock, protected epithelial cells against UV irradiation, was not toxic for erythrocytes, epithelial cells SPEV and 3T3 fibroblasts.

[Ionic conjugates of sulfate carboxymethyl cellulose with dialkylaminomethyl derivatives of 2-isobornyl-4-methylphenol: synthesis and study of anti-inflammatory and analgesic activity].

Water-soluble sulfate polysalts of carboxymethyl cellulose and tertiary aminomethyl derivatives of 2-isobornyl-4-methylphenol was obtained. For the synthesized conjugates investigated in vivo anti-inflammatory activity in the test of acute formalin inflammation and analgesic activity in tests the "hot plate" and "vinegar cramps".

[The neuroprotective action of enantiomers and racemate of 2-(3,7-dioxo-2,4,6,8-tetraazabicyclo[3.3.0]oct-2-yl)-4-methylthiobutanoic acid].

Neurotropic, neuroprotective and antioxidant actions of the enantiomers and the racemate of 2-(3,7-dioxo-2,4,6,8-tetraazabicyclo[3.3.0]oct-2-yl)-4-methylthiobutanoic acid were investigated.

[The immunotropic activity of lupane and oleanane 2,3-seco-triterpenoids].

The immunotropic effect of the 2,3-seco derivatives of allobetulon, betulonic acid, and the methyl ester of betulonic acid were studied. It was found that the highest activity is shown by compounds with an oleanane fragment. The presence of a free C28-carboxyl group enhances the activity of lupeolic 2,3-seco derivatives.

[Synthesis and immunotropic activity of methyl esters of 2-alkylaminomethylene-3-oxolup-20(29)-en-28-ic acids].

New lupane beta-enaminoketones were synthesized by interaction of methyl 2-hydroxymethylene-3-oxolup-20(29)-en-28-oate with aliphatic amines. Immunotropic activity was found for some of these compounds.

[Synthesis and immunotropic activity of 2-alkylaminomethylene-19beta,28-epoxyolean-3-ones].

2-Alkylaminomethylene-19beta,28-epoxyolean-3-ones were obtained by interaction of 2-hydroxymethylene-19beta,28-epoxyolean-3-one with aliphatic amines. Some of the resulting substances exhibit immunotropic activity.

The effects of fluoxetine and its complexes with glycerrhizic acid on behavior in rats and brain monoamine levels.

The effects of the serotonin reuptake inhibitor fluoxetine (FL) and its complexes with glycyrrhizic acid (GA) in molar ratios of 1:1 (FLG-1) and 4:1 (FLG-4) on the behavior of adult rats were studied in an elevated cross maze, with measurement of brain monoamine and monamine metabolite levels. Agents were given via the intragastric route using a cannula at a dose of 25 mg/kg 1 h before testing. FL increased anxiety in the rats and decreased their movement activity; FLG-1 and FLG-4 had no effect on behavior.

[Effects of fluoxetine and its complexes with glycyrrizhinic acid on behavior and brain monoamine levels in rats].

Effects of serotonin uptake inhibitor fluoxetine (F) and it's complexes with glycyrrizhinic acid (GA) in molar proportions 1GA : 1F (FGA-1) and 4GA : 1F (FGA-4) on rat behavior in elevated plus-maze and brain monoamine concentrations were studied. Drugs (25 mg/kg) were administered per os 1 h before investigations. F-treated rats showed increased anxiety and reduced locomotor activity, whereas FGA-1 and FGA-4 had no effects on the behaviors.

[Changes in the mineral metabolic indices of osteoarthrosis patients with the use of radon therapy and mud therapy].

As shown by investigations of alkaline phosphatase, plasma levels of calcium, non-organic phosphorus, coefficient Ca/P in 58 patients with osteoarthrosis deformans before and after radon baths, mud applications or their combination, the highest biochemical effect was achieved in a group of patients on mud therapy.

[Characteristics of the expression of globin genes in blood cells of patients with homozygotic beta-thalassemia from Tadzhikistan].

The synthesis of globin protein in blood reticulocytes of patients from Tajikistan suffering from homozygous beta-thalassemia was studied. Beta-thalassemia has been revealed in all cases, with synthesis of beta-globin being retained though essentially reduced. It was shown that, unlike homozygous beta+-thalassemia of other populations, beta +thalassemia with sharp inhibition of the beta-globin protein synthesis is most representative for the region (alpha/beta greater than 10).