Nematode Extracellular Protein Interactome Expands Connections between Signaling Pathways.

Multicellularity was accompanied by the emergence of new classes of cell surface and secreted proteins. The nematode is a favorable model to study cell surface interactomes, given its well-defined and stereotyped cell types and intercellular contacts. Here we report our extracellular interactome dataset, the largest yet for an invertebrate.

Neuronal Wiring Receptors Dprs and DIPs Are GPI Anchored and This Modification Contributes to Their Cell Surface Organization.

The Dpr and DIP proteins belong to the immunoglobulin superfamily of cell surface proteins (CSPs). Their hetero- and homophilic interactions have been implicated in a variety of neuronal functions, including synaptic connectivity, cell survival, and axon fasciculation. However, the signaling pathways underlying these diverse functions are unknown.

Phosphoantigen-induced conformational change of butyrophilin 3A1 (BTN3A1) and its implication on Vγ9Vδ2 T cell activation.

Human Vγ9Vδ2 T cells respond to microbial infections as well as certain types of tumors. The key initiators of Vγ9Vδ2 activation are small, pyrophosphate-containing molecules called phosphoantigens (pAgs) that are present in infected cells or accumulate intracellularly in certain tumor cells. Recent studies demonstrate that initiation of the Vγ9Vδ2 T cell response begins with sensing of pAg via the intracellular domain of the butyrophilin 3A1 (BTN3A1) molecule.

Identification of Natural Regulatory T Cell Epitopes Reveals Convergence on a Dominant Autoantigen.

Regulatory T (Treg) cells expressing the transcription factor Foxp3 are critical for the prevention of autoimmunity and the suppression of anti-tumor immunity. The major self-antigens recognized by Treg cells remain undefined, representing a substantial barrier to the understanding of immune regulation. Here, we have identified natural Treg cell ligands in mice.

SYNTHESIS AND IN VITRO ANTIPROLIFERATIVE ACTIVITY OF NOVEL 2-ARYLIDENEAMINOBENZIMIDAZOLE DERIVATIVES.

A new class of Mannich bases 9-26, derivatives of 2-amino-1H-benzimidazole, were obtained in the condensation of Schiff bases 1-4 or 2-benzylaminobenzimidazoles 5-8 with selected secondary amines: morpholine, piperidine, N-methylpiperazine, N-phenylpiperazine, 1-(2-pyridyl)piperazine, 1(2-methoxyphenyl)piperazine, 1-(2-pyrimidinyl)piperazine and formaldehyde in ethanol. The pyrimido[1,2-albenzimidazole derivatives 27-29 have been synthesized in the reactions of Schiff base 2 with selected compounds containing active methylene group: acetylacetone, benzoylacetone and malononitrile. The structures 1-29 were confirmed by the results of elementary analysis and their IR, 1H- and 13C-NMR spectra.

Synthesis and antiproliferative activity in vitro of new 2-thioxoimidazo[4,5-B]pyridine derivatives.

Two series of 2-thioxoimidazo[4,5-b]pyridine derivatives have been synthesized from 2,3-diaminopyridine (1) and 5-halogenosubstituted-2,3-diaminopyridines 2, 3. Mannich bases 7 - 12 and 24 - 29, derivatives of 1-arylamino-6-halogeno-2-thioxoimidazo[4,5-b]pyridine were obtained with selected secondary amines: morpholine, piperidine, 2-methoxyphenylpiperazine, pyrimidyn-2-yl-piperazine and formaldehyde in ethanol. The structures 7 - 12 and 24 - 29 were confirmed by the results of elementary analysis and their IR, 1H-NMR and MS spectra.

Sensing of Pyrophosphate Metabolites by Vγ9Vδ2 T Cells.

The predominant population of γδ T cells in human blood express a T cell receptor (TCR) composed of a Vγ9 (Vγ2 in an alternate nomenclature) and Vδ2 domains. These cells came into the limelight when it was discovered they can respond to certain microbial infections and tumorigenic cells through the detection of small, pyrophosphate containing organic molecules collectively called "phosphoantigens" or "pAgs." These molecules are intermediates in both eukaryotic and prokaryotic metabolic pathways.

Synthesis and antiproliferative activity in vitro of new pyrido[1,4-b]diazepine derivatives and imidazo[4,5-b]pyridine.

A novel series of esters 8-10 and hydrazones 4-6 was synthesized from 4-aryl-2-phenacylidene-1,3,4,5-tetrahydropyrido[2,3-b][1,4]diazepine (1-3). Subsequent treatment of hydrazone 4 with p-chlorbenzaldehyde furnished azine 7. Long-standing heating of ester 8 with hydrazine hydrate afforded 3-[1-(p-chlorophenylene)-2-(5-phenyl-1H-pyrazol-3-yl)-ethyl]-1,3-dihydroimidazo[4,5-b]pyridin-2-one (11).

Synthesis and antiproliferative activity in vitro of 2-aminobenzimidazole derivatives.

A novel series of Schiff bases 1-11, the derivatives of 2-aminobenzimidazole and substituted aromatic aldehydes, has been synthesised. Compounds 1-11 reduced by NaBH(4) formed 2-benzylaminobenzimidazoles 12-21. 2-(o-Bromobenzylamino)benzimidazole (15) acylated by cinnamoyl chloride gave 2-(o-bromobenzylamino)-1-cinnamoylbenzimidazole (22).

4(3H)-Quinazolinones. Antimicrobial 4(3H)-quinazolinones. Part III.

The authors present recent works published world-wide presenting 4(3H)-quinazolinones of antimicrobial activities. Structures and syntheses of pharmacologically active compounds are described.

Polycyclic 4(3h)-quinazolinones survey of biological properties (Part II).

The authors present examples of polycyclic 4(3H)-quinazolinones of natural origin. Structures and syntheses of pharmacologically active (antibacterial, antifungal, antihypertensive and cardiovascular, antiasthmatic, anti-inflamatory, CNS-depresant, secretion of gastric acid inhibitors) compounds are described.

Synthesis and antiproliferative activity in vitro of novel 1,5-benzodiazepines. Part II.

The reaction of 2,2,4-trimethyl-1H-2,3-dihydro-1,5-benzodiazepine (1) with cinnamoyl chloride leading to the formation of 1-cinnamoyl derivative 2 is described. Two novel benzodiazepines, 2,2,4-trimethyl-1H-2,3,4,5-tetrahydro-1,5-benzodiazepine (3) and 1-cinnamoyl-2,2,4-trimethyl-1H-2,3,4,5-tetrahydro-1,5-benzodiazepine (4), were synthesized by the reduction of 1 and 2 using NaBH4 in i-PrOH and two other derivatives 5 and 6 were obtained by reaction of 4 with equimolar and dimolar quantity of cinnamoyl chloride, respectively. The structures of 1-6 were confirmed by analytical and spectral data (IR, 1H NMR, and MS).

Synthesis and immunotropic properties of 5-substituted 1,5-benzodiazepin-2-ones derivatives in cultures of human peripheral blood cells, Part III.

The reaction of 4-methyl-(A) and 3-methyl-1H-2,3,4,5-tetrahydro-1,5-benzodiazepin-2-one (B) with selected alpha,beta-unsaturated acid chlorides: crotonoyl, cinnamoyl, and 4-nitrocinnamoyl is described. We have also characterized immunotropic activities of these compounds in the proliferative response of human lymphocytes to phytohemagglutinin A (PHA) or to allogeneic cells in one-way mixed lymphocyte reaction (MLR), as well as their action on tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) production in peripheral blood mononuclear cells (PBMC) and mixed lymphocyte cultures (MLC). Some of the compounds exhibited regulatory activities in the proliferative response of cells to PHA depending on the reactivity of cells to PHA.

Immunotropic properties of 2-aminobenzimidazole derivatives in cultures of human peripheral blood cells, Part 5.

The reaction of 2-aminobenzimidazole with selected 4-methoxy-,2,4-dimethoxy-, 4-chloro-, 4-nitro-, and 2-nitrocinnamic acid under different conditions has been described. Two series of derivatives were obtained: 4-aryl-1,2,3,4-tetrahydropyrimido[1,2-a]-benzimidazol-2-ones (1-3) or substituted amides 4, 5, 7. The following compounds: 4-(p-methoxyphenyl)- (1), 4-(2,4-dimethoxyphenyl)- (2), 4-(p-chlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazo l-2-one (3), amides: 2-(p-nitrocinnamoylamino)- (4), 2-(p-methoxycinnamoylamino)-benzimidazole (5), and 3-methyl-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-2-one (6), recently synthesized, have been selected for further studies.

Synthesis of new derivatives of 4-methyl-5-ethoxalyl-1H-2,3,4,5- tetrahydro-1,5-benzodiazepin-2-one and their psychotropic and anti-proliferative activities.

5-Ethoxalyl-4-methyl-1H-2,3,4,5-tetrahydro-1,5-benzodiazepin -2-one [I] was treated with some selected secondary amines (dimethyl-, diethyl-, dipropyl-, disobutylamine or with morpholine) and methyl-hydrazine. Amides II-IV and hydrazide VII were obtained. Compounds II, IV and VI were tested for their psychotropic activity; they showed a weak toxicity.

Synthesis and immunotropic activity of some 2-aminobenzimidazoles, Part 4.

2-Aminobenzimidazole reacted with selected esters of alpha, beta-unsaturated acids and alpha, beta-unsaturated ketones to form derivatives of 1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-2-ones, 1,4-dihydropyrimido[1,2-a]benzimidazoles, and 2-acetylaminobenzimidazole. 2-Cinnamoylaminobenzimidazole, 4-phenyl-1,2,3,4-tetrahydropyrimido[1,2,-a]benzimidazol-2-on e, 4-(benzimidazol-2-ylamino)-4-phenylbutan-2-one, and 4-methyl-2-phenyl-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole were tested for their potential activity in immunological assays in the mouse model. Compound 1, at a dose of 100 micrograms/mouse, significantly inhibited the humoral immune response and, at the same time, stimulated the cellular type of that response.

New quinazolinones-4. Antiinflammatory and anticonvulsant agents. New classes of pharmacologically active compounds.

The authors present the most interesting examples of anticonvulsant and antiinflammatory active quinazolinones-4 synthesized after 1990. There are also presented quinazolinones-4 belonging to new classes of pharmacologically active compounds-angiotensin II receptors antagonists and cholecystokinin receptors antagonists.

Syntheses of novel 3-amino-2(1H)-thioxo-4(3H)-quinazolinones and evaluation of their immunotropic activity. Part III.

The synthesis of two series of derivatives containing the quinazolinone-4 moiety is described. 3-Amino-2(1H)-thioxo-4(3H)-quinazolinone (1) was subjected to reactions with halogenoketones and halogenoaldehydes, leading to the production of the corresponding ketones, aldehydes, Schiff bases, and 6-oxo-1,4,5-thiadiazin[2,3-b]quinazoline derivatives. Subsequently, 1 was condensed with selected alpha, beta-unsaturated carbonyl compounds, aldehydes, ketones, acid chlorides, and esters.

Synthesis and pharmacological properties of new derivatives of 4-methyl-5-oxalo-1H-2,3,4,5-tetrahydro-1,5-benzodiazepin-2-one and beta-oxo-5-(4-methyl-1H-2,3,4,5-tetrahydro-1,5-benzodiazepin-2 -one)propionic acid.

5-Ethoxalyl 4-methyl-1H-2,3,4,5-tetrahydro 1,5-benzodiazepin-2 -one [I] and 5-ethoxymalonyl-4-methyl-1H-2,3,4,5-tetrahydro-1,5-benzodiazepi n-2-one [IV] were subjected to transesterification using alcohols (propanol, butanol, pentanol) giving derivatives II-IV, VII, VIII. The derivatives I and VI were caused to undergo ammonolysis giving 4-methyl-5-oxamoyl-1H-2,3,4,5 tetrahydro 1,5-benzodiazepin-2-one [V] and 5-malonamoyl-4-methyl-1H-2,3,4,5-tetrahydro-1,5-benzodiazepin++ +-2-one [IX]. The compounds I-IX were tested towards their psychotropic activity.

Syntheses and pharmacological properties of new 2-aminobenzimidazole derivatives.

The paper reports the structures, syntheses and pharmacological properties of new compounds having a 2-aminobenzimidazole group. They exhibit various activities: histamine H1- and H2-receptors blocking activities, antilipidemic and platelet antiaggregatory, anti-inflammatory and analgesic properties, antimicrobial, fungicidal, parasiticide, antiarrythmic activity and muscle relaxant, comparable to those of drugs used in therapy.

Carboxylic esters derivatives of 2-thioxo-1H-2,3,4,5-tetrahydropyrido-[2,3-e]-1,3,4-triazepin-5-ones and 2-thioxo-1H-2,3,4,5-tetrahydro-1,3,4-benzotriazepin-5-ones.

2-Thioxo-1H-2,3,4,5-tetrahydropyrido[2,3-e]-1,3,4-triazep in -5-ones [I] and 2-thioxo-1H-2,3,4,-5-tetrahydro-1,3,4-benzotriazepin-5-ones [V] furnish with methyl, ethyl and phenyl chloroformates two series of the corresponding 3-methoxy-, ethoxy- and phenoxycarbonyl triazepines. In the pharmacological screening, compounds [I], [V] and [II] showed an antianxiety activity in the four plate test, compounds [II] and [III] inhibited the 5-HTP- induced head twitches, and compound [VI] showed an analgesic activity in the "writing" test. The replacement of the benzene ring by the pyridine one in triazepines is accompanied by the enhancement of anxiolytic activity as well as toxicity.

Acylated derivatives of 1,5-benzodiazepines. Part II.

Acylated derivatives of 4-methyl-1H-tetrahydro-1,5-benzodiazepin-2-one (1) and of 2-methyl-4-phenyl-1H-tetrahydro-1,5-benzodiazepino-2-carboxylic acid ethyl ester (10) were synthesized and preliminarily tested on their central activity. Acylation was carried out with alpha, beta-unsaturated acid chlorides, dicarboxylic acid monoester monochlorides, and dicarboxylic acid dichlorides. Compounds 2, 3, 11 and 12 had analgesic, compounds 4, 11 and 12--anticonvulsant, and compounds 3 and 11--antiaggressive properties.

Acyl derivatives of 1,5-benzodiazepines. III. Acyl derivatives of ethyl ester of 4-methyl-1H-tetrahydro-1,5-benzodiazepine-2-carboxylic acid.

Two series of derivatives of ethyl ester of 4-methyl-1H-tetrahydro-1,5-benzodiazepine-2-carboxylic acid (1) have been synthesized. The acetyl derivative (2) of ester 1 in preliminary pharmacological screening showed analgesic activity in the "writhing" test and the benzoyl derivative (5) exhibited antianxiety properties in the four plate test, while N,N-disubstituted aminoacetyl derivatives of 1 showed analgesic and anticonvulsant activity (10).

Aminoacetyl derivatives of 1,5-benzodiazepin-2-one.

A series of six compounds, 5-chloroacetyl-4-methyl-1H-tetrahydro-1,5-benzodiazepin-2-one and 5-dialkilaminoacetyl derivatives of 4-methyl-1H-tetrahydro-1,5-benzodiazepin-2-one, have been synthesized. 5-Diizobutylaminoacetyl-4-methyl-1H-tetrahydro-1,5-benzodiazepi n-2-one showed weak analgesic and antiinflammatory activity.

Synthesis and preliminary pharmacological studies on dihydropyrido-1,3,4-triazepinone derivatives.

New 4,5-dihydropyrido-[2,3-e]-1,3,4-triazepin-5-one derivatives (2-9) were synthesized. The preliminary pharmacological tests revealed antinociceptive action of compounds 4-7 and 9 and antianxiety action of compound 4.