Bioactive pyridine-N-oxide disulphides from Allium stipitatum.

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

DOI: 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 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.

Item Type:Article
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
ID Code:1200
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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