Promising Compound For Development Research Articles

Schizandrin reduces cytoplasmic TDP-43 accumulation in hippocampal neuronal cells

Transactive response DNA binding protein 43 kDa (TDP-43, encoded by the TARDBP gene) is involved in transcriptional regulation and alternative splicing process. TDP-43 proteins are located in the nucleus and shuttles transcripts to the cytoplasm in normal neurons; however, they are observed in the forms of cytoplasmic inclusions in the degenerating cells. The abnormal accumulation of TDP-43 proteins is a pathologic feature of neurodegenerative diseases, such as Lou Gehrig’s disease and dementia including frontotemporal lobar degeneration and Alzheimer’s disease. In this study, we examined whether schizandrin, a main effective compound of Schisandra chinensis (Turcz.), so called omija in Korean, reduces TDP-43 accumulation in the hippocampal neurons in vitro. An immortalized mouse hippocampal neuronal cell line, HT22 cells, were treated with a proteasome inhibitor, MG132, in the absence or presence of schizandrin. We found that schizandrin treatment increased HT22 cell viability and reduced MG132-induced cytoplasmic accumulation of TDP-43. Our results suggest that schizandrin may be a promising compound for development of functional food materials beneficial to the neuronal protection against TDP-43 proteinopathies.

Indirubin 3'-(O-oxiran-2-ylmethyl)oxime: a novel anticancer agent.

Indirubin is a potent inhibitor of cell cycle-related protein kinases by binding to the ATP-binding site and thus is a promising compound for development as an antitumor drug. We prepared indirubin 3'-(O-oxiran-2-ylmethyl)oxime (Epox/Ind), in which the ATP-binding site orientated part was attached by non-specific alkylating group. The IC50 value of Epox/Ind at 1.7 μM in HepG2 cells is comparable to that of cisplatin (4.0 μM). Furthermore, Epox/Ind was shown to be metabolized by a HepG2 cell lysate into indirubin 3'-(O-2,3-dihydroxypropyl)oxime (E804), the sole extractable metabolite. The lower toxicity of this metabolite may explain the lack of cytotoxicity of 1 μM Epox/Ind observed in HepG2 cells beyond an initial loss of viability in the first 24h of treatment.

Systematic in Vivo Screening of a Series of 1-Propyl-4-arylpiperidines against Dopaminergic and Serotonergic Properties in Rat Brain: A Scaffold-Jumping Approach

A series of 1-propyl-4-arylpiperidines were synthesized and their effects on the dopaminergic and serotonergic systems tested in vivo and in vitro. Scaffold jumping among five- and six-membered bicyclic aryl rings attached to the piperidine ring had a marked impact on these effects. Potent and selective dopamine D(2) receptor antagonists were generated from 3-indoles, 3-benzoisoxazoles, 3-benzimidazol-2-one, and 3-benzothiophenes. In contrast, 3-benzofuran was a potent and selective inhibitor of monoamine oxidase (MAO) A. The effects of the synthesized compounds on 3,4-dihydroxyphenylacetic acid (DOPAC) levels correlated very well with their affinity for dopamine D(2) receptors and MAO A. In the 4-arylpiperidine series, the most promising compound for development was the 6-chloro-3-(1-propyl-4-piperidyl)-1H-benzimidazol-2-one (19), which displayed typical dopamine D(2) receptor antagonist properties in vivo but produced only a partial reduction on spontaneous locomotor activity. This indicates that the compound may have a lower propensity to induce parkinsonism in patients.

Stelleralides A-C, novel potent anti-HIV daphnane-type diterpenoids from Stellera chamaejasme L.

Three novel 1-alkyldaphnane-type diterpenes, stelleralides A-C (4-6), and five known compounds were isolated from the roots of Stellera chamaejasme L. The structures of 4-6 were elucidated by extensive spectroscopic analyses. Several isolated compounds showed potent anti-HIV activity. Compound 4 showed extremely potent anti-HIV activity (EC(90) 0.40 nM) with the lowest cytotoxicity (IC(50) 4.3 μM) and appears to be a promising compound for development into anti-AIDS clinical trial candidates.

Efficiency of bioelectrocatalytic oxidation of ethanol by whole cells and membrane fractions of Gluconobacter Oxydans bacteria in the presence of mediators of ferrocene series

Bioelectrocatalytic oxidation of ethanol by whole cells and membrane fraction of Gluconobacteroxydans bacteria is studied on modified graphite-paste electrodes in mediator biosensors. Ferrocene derivatives are used as electron transport mediators for effective coupling of enzymatic and electrochemical processes on graphite electrodes. Electrochemical kinetics of the processes are studied; the obtained data are interpreted in the terms of the mechanism of two-substrate enzymatic reaction. It is shown that mediators of ferrocene series are promising compounds for development of mediator biosensors based both on whole cells of Gluconobacter oxydans bacteria and on membrane fractions of these bacteria. Bioelectrocatalytic processes of ethanol oxidation on graphite paste electrodes occur more efficiently when the bacterial membrane fraction is used as a biocatalyst and ferrocenemonocarboxylic acid is used as a mediator.

Activity of 7-methyljuglone in combination with antituberculous drugs against Mycobacterium tuberculosis

The recent increase in the incidence of tuberculosis with the emergence of multidrug-resistant (MDR) cases has lead to the search for new drugs that are effective against MDR strains of Mycobacterium tuberculosis and can augment the potential of existing drugs against tuberculosis. In the present study, we investigated the activities of a naphthoquinone, 7-methyljuglone, isolated from the roots of Euclea natalensis alone and in combination with other antituberculous drugs against extracellular and intracellular M. tuberculosis. Combinations of 7-methyljuglone with isoniazid or rifampicin resulted in a four to six-fold reduction in the minimum inhibitory concentration of each compound. Fractional inhibitory concentration (FIC) indexes obtained were 0.2 and 0.5, respectively, for rifampicin and isoniazid, suggesting a synergistic interaction between 7-methyljuglone and these anti-TB drugs. The ability of 7-methyljuglone to enhance the activity of isoniazid and rifampicin against both extracellular and intracellular organisms suggests that 7-methyljuglone may serve as a promising compound for development as an anti-tuberculous agent.