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Bioactive Pyridine-N-oxide Disulfides from Allium stipitatum

O’Donnell, G. and Poeschl, R. and Zimhony, O. and Gunaratnam, M. and Moreira, J.B.C. and Neidle, S. and Evangelopoulos, Dimitrios and Bhakta, Sanjib and Malkinson, J. and Boshoff, H.I. and Lenaerts, A. and Gibbons, S. (2009) Bioactive Pyridine-N-oxide Disulfides from Allium stipitatum. Journal of Natural Products 72 (3), pp. 360-365. ISSN 0163-3864.

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Official URL: http://dx.doi.org/10.1021/np800572r

Abstract

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 μg/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 μg/mL, 1 was shown to give complete inhibition of the incorporation of 14C-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 IC50 values ranging from 0.3 to 1.8 μM 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.

Item Type: Article
School or Research Centre: Birkbeck Schools and Research Centres > School of Science > Biological Sciences
Depositing User: Administrator
Date Deposited: 04 Aug 2010 14:09
Last Modified: 06 Sep 2013 08:30
URI: http://eprints.bbk.ac.uk/id/eprint/1000

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