A novel dihydroxylated derivative of artemisinin from microbial transformation.

Microbial transformation of artemisinin (1) by Cunninghamella elegans was investigated. Four isolated products were identified as 6ß-hydroxyartemisinin (2), 7α-hydroxyartemisinin (3), 7ß-hydroxyartemisinin (4), and 6ß,7α-dihydroxyartemisinin (5). The structures were elucidated by spectroscopic and X-ray crystallographic analysis. Product 5 is a novel compound and being reported here for the first time. It features two hydroxyl groups in its structure, and this is the first report on dihydroxylation of the artemisinin skeleton. Quantitative structure-activity relationship and molecular modeling studies indicate the modification of artemisinin skeleton will increase antimalarial activity and water solubility. The chemical syntheses of artemisinin derivatives at C6 or C7 position are impossible due to the lack of functional groups. 6ß,7α-Dihydroxyartemisinin is hydroxylated at both 6ß- and 7α-positions of artemisinin skeleton at the same time. Therefore, this new compound would be a good scaffold for further structural modification in the search for more potent antimalarial drugs.

The Challenge of Reproducibility and Accuracy in Nutrition Research: Resources and Pitfalls.

Inconsistent and contradictory results from nutrition studies conducted by different investigators continue to emerge, in part because of the inherent variability of natural products, as well as the unknown and therefore uncontrolled variables in study populations and experimental designs. Given these challenges inherent in nutrition research, it is critical for the progress of the field that researchers strive to minimize variability within studies and enhance comparability between studies by optimizing the characterization, control, and reporting of products, reagents, and model systems used, as well as the rigor and reporting of experimental designs, protocols, and data analysis. Here we describe some recent developments relevant to research on plant-derived products used in nutrition research, highlight some resources for optimizing the characterization and reporting of research using these products, and describe some of the pitfalls that may be avoided by adherence to these recommendations.

Discovery of thienoquinolone derivatives as selective and ATP non-competitive CDK5/p25 inhibitors by structure-based virtual screening.

Calpain mediated cleavage of CDK5 natural precursor p35 causes a stable complex formation of CDK5/p25, which leads to hyperphosphorylation of tau. Thus inhibition of this complex is a viable target for numerous acute and chronic neurodegenerative diseases involving tau protein, including Alzheimer's disease. Since CDK5 has the highest sequence homology with its mitotic counterpart CDK2, our primary goal was to design selective CDK5/p25 inhibitors targeting neurodegeneration. A novel structure-based virtual screening protocol comprised of e-pharmacophore models and virtual screening workflow was used to identify nine compounds from a commercial database containing 2.84 million compounds. An ATP non-competitive and selective thieno[3,2-c]quinolin-4(5H)-one inhibitor (10) with ligand efficiency (LE) of 0.3 was identified as the lead molecule. Further SAR optimization led to the discovery of several low micromolar inhibitors with good selectivity. The research represents a new class of potent ATP non-competitive CDK5/p25 inhibitors with good CDK2/E selectivity.

Xenobiotic biotransformation of 4-methoxy-N-methyl-2-quinolone, isolated from Zanthoxylum monophyllum.

Phytochemical evaluation of Zanthoxylum monophyllum has led to the isolation of the alkaloid 4-methoxy-N-methyl-2-quinolone (1) with a significant activity against methicillin-resistant Staphylococcus aureus (MRSA), with an IC50 value of 1.5 microg/mL. Xenobiotic biotransformation of 1 has been conducted with the general goal of increasing the bioactivity of the compound and contributing new leads for further pharmacological research. Twenty-nine microorganisms were used for screening and two (Aspergillus flavus and Cunninghamella echinulata var. echinulata) were able to transform compound 1 to 4-methoxy-2-quinolone (2). Structural identification of the compounds was based on NMR, IR, and MS data.