Merck

Bioactive pyridine-N-oxide disulfides from Allium stipitatum.

Journal of natural products (2008-12-20)
Gemma O'Donnell, Rosemarie Poeschl, Oren Zimhony, Mekala Gunaratnam, Joao B C Moreira, Stephen Neidle, Dimitrios Evangelopoulos, Sanjib Bhakta, John P Malkinson, Helena I Boshoff, Anne Lenaerts, Simon Gibbons
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
8-Quinolinol, puriss. p.a., ACS reagent, reag. Ph. Eur., ≥99% (perchloric acid titration)
Supelco
8-Quinolinol, PESTANAL®, analytical standard
Supelco
Isoniazid, analytical standard, ≥99% (TLC)
Supelco
Norfloxacin, analytical standard, ≥98% (TLC)
Sigma-Aldrich
Menadione, crystalline
Sigma-Aldrich
Menadione, meets USP testing specifications
Sigma-Aldrich
8-Hydroxyquinoline, crystalline
Sigma-Aldrich
8-Hydroxyquinoline, ACS reagent, 99%
Supelco
Menadione (K3), analytical standard
Supelco
Norfloxacin, VETRANAL®, analytical standard