Aromatic sulphonamides of aziridine-2-carboxylic acid derivatives as novel PDIA1 and PDIA3 inhibitors.

In this study, we report a series of newly synthesised sulphonamides of aziridine-2-carboxylic acid (Az-COOH) ester and amide analogues as potent protein disulphide isomerase (PDI, EC 5.3.4.1) inhibitors. The inhibitory activity on PDI was determined against recombinant human PDIA1 and PDIA3 proteins using an insulin reduction assay. These compounds in low micromolar to low nanomolar concentrations showed the effective in vitro inhibitory properties of PDIA1 with weaker effects on PDIA3. Complexes of 15N- and 15N,13C- uniformly labelled recombinant human PDIA1a with two PDIA1 inhibitors were produced and investigated by a protein nuclear magnetic resonance (NMR) spectroscopy. It was found that both C53 and C56 of the PDIA1 enzyme were involved in covalent binding. Finally, in a range of pharmacological studies, we demonstrated that investigated compounds displayed anti-cancer and anti-thrombotic activity. These findings demonstrate that sulphonamides of Az-COOH derivatives are promising candidates for the development of novel anti-cancer and anti-thrombotic agents.

The cognition-enhancing activity of E1R, a novel positive allosteric modulator of sigma-1 receptors.

BACKGROUND AND PURPOSE: Here, we describe the in vitro and in vivo effects of (4R,5S)-2-(5-methyl-2-oxo-4-phenyl-pyrrolidin-1-yl)-acetamide (E1R), a novel positive allosteric modulator of sigma-1 receptors. EXPERIMENTAL APPROACH: E1R was tested for sigma receptor binding activity in a [³H](+)-pentazocine assay, in bradykinin (BK)-induced intracellular Ca²âº concentration ([Ca²âº](i)) assays and in an electrically stimulated rat vas deferens model. E1R's effects on cognitive function were tested using passive avoidance (PA) and Y-maze tests in mice. A selective sigma-1 receptor antagonist (NE-100), was used to study the involvement of the sigma-1 receptor in the effects of E1R. The open-field test was used to detect the effects of E1R on locomotion. KEY RESULTS: Pretreatment with E1R enhanced the selective sigma-1 receptor agonist PRE-084's stimulating effect during a model study employing electrically stimulated rat vasa deferentia and an assay measuring the BK-induced [Ca²âº](i) increase. Pretreatment with E1R facilitated PA retention in a dose-related manner. Furthermore, E1R alleviated the scopolamine-induced cognitive impairment during the PA and Y-maze tests in mice. The in vivo and in vitro effects of E1R were blocked by treatment with the selective sigma-1 receptor antagonist NE-100. E1R did not affect locomotor activity. CONCLUSION AND IMPLICATIONS: E1R is a novel 4,5-disubstituted derivative of piracetam that enhances cognition and demonstrates efficacy against scopolamine-induced cholinergic dysfunction in mice. These effects are attributed to its positive modulatory action on the sigma-1 receptor and this activity may be relevant when developing new drugs for treating cognitive symptoms related to neurodegenerative diseases.

Plasma NO-binding activity in patients with hematological malignancies: suppressive effect of glucocorticoids.

Plasma NO-binding activity was studied in patients with various forms of hematological malignancies. The method used in the study quantitatively evaluated the plasma capacity to bind NO, which reflects the intensity of NO production and the degree of patient's stress resistance. Plasma NO-binding activity significantly decreases in patients with hematological malignancies. Glucocorticoid treatment promotes the decrease in plasma NO-binding activity, which was dose-dependent.

Synthesis and antitumour activity of trimethylsilylpropyl substituted benzimidazoles.

The quaternisation of N-substituted benzimidazoles by heating with various alkyl, allyl, propargyl and benzyl chlorides and bromides leads to the formation of benzimidazolinium salts. The interaction of N-monosubstituted benzimidazoles with various salts (CuCl2, ZnCl2, CoCl2, PdCl2 and AgNO3) yielded stable solid complexes. Potential cytotoxic activity of synthesised benzimidazolinium salts and benzimidazole metal complexes was tested in vitro on four monolayer tumour cell lines: MG-22A (mouse hepatoma), HT-1080 (human fibrosarcoma), B16 (mouse melanoma), Neuro 2A (mouse neuroblastoma) and normal mouse fibroblast cells. A preliminary analysis of the structure-activity relationship for the benzimidazole derivatives clearly indicates that the character of substituents in the benzimidazole ring has strong influence on the cytotoxic activity. The insertion of the silicon atom into the N-alkyl chain increases the cytotoxic activity of benzimidazolinium salts significantly, which show a very significant potency in vitro against all studied tumour cell lines, being particularly active in experiments with B16 (mouse melanoma). TD50 for the most active compounds are in the range 0.001-0.008 microg x ml(-1). Cytotoxicity of benzimidazole metal complexes (L2MX2) strongly depends on the metal nature. 1-(3-trimethylsilylpropyl)benzimidazole in dose 1 mg x kg(-1) inhibits carcinoma S-180 tumour growth by 62% (on ICR mice).