Gibbons, S., O'Donnell, G., Poeschl, R., Zimhony, O., Gunaratnam, M., Moreira, J.B., Neidle, S., Evangelopoulos, D., Bhakta, S., Malkinson, J.P., Boshoff, H. and Lenaerts, A. (2009) Bioactive pyridine-N-oxide disulphides from Allium stipitatum. Journal of Natural Products, 72 (3). pp. 360-365. 10.1021/np800572r.
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Official URL: http://www.ukpmc.ac.uk/articles/PMC2765505
From Allium stipitatum, three pyridine-N-oxide alkaloids (1-3) possessing disulfide functional groups were isolated. The structures of these natural products were elucidated by spectroscopic means as 2-(methyldithio)pyridine-N-oxide (1), 2-[(methylthiomethyl)dithio]pyridine-N-oxide (2), and 2,2'-dithio-bis-pyridine-N-oxide (3). The proposed structure of 1 was confirmed by synthetic S-methylthiolation of commercial 2-thiopyridine-N-oxide. Compounds 1 and 2 are new natural products, and 3 is reported for the first time from an Allium species. All compounds were evaluated for activity against fast-growing species of Mycobacterium, methicillin-resistant Staphylococcus aureus, and a multidrug-resistant (MDR) variants of S. aureus. Compounds 1 and 2 exhibited minimum inhibitory concentrations (MICs) of 0.5-8 microg/mL against these strains. A small series of analogues of 1 were synthesized in an attempt to optimize antibacterial activity, although the natural product had the most potent in vitro activity. In a whole-cell assay at 30 microg/mL, 1 was shown to give complete inhibition of the incorporation of (14)C-labeled acetate into soluble fatty acids, indicating that it is potentially an inhibitor of fatty acid biosynthesis. In a human cancer cell line antiproliferative assay, 1 and 2 displayed IC(50) values ranging from 0.3 to 1.8 microM with a selectivity index of 2.3 when compared to a human somatic cell line. Compound 1 was evaluated in a microarray analysis that indicated a similar mode of action to menadione and 8-quinolinol by interfering with the thioredoxin system and up-regulating the production of various heat shock proteins. This compound was also assessed in a mouse model for in vivo toxicity.
|Additional Information:||Full text available electronically from the School of Pharmacy Library.|
|Departments, units and centres:||Department of Pharmaceutical and Biological Chemistry > Cancer Research UK Biomolecular Structure Group|
|Journal or Publication Title:||Journal of Natural Products|
|Deposited By:||Library Staff|
|Deposited On:||30 Apr 2009 11:35|
|Last Modified:||03 Nov 2011 16:44|
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