Bioactive pyridine-N-oxide disulfides from Allium stipitatum.
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.
O'Donnell
Gemma
G
Centre for Pharmacognosy and Phytotherapy, The School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, UK.
Poeschl
Rosemarie
R
Zimhony
Oren
O
Gunaratnam
Mekala
M
Moreira
Joao B C
JB
Neidle
Stephen
S
Evangelopoulos
Dimitrios
D
Bhakta
Sanjib
S
Malkinson
John P
JP
Boshoff
Helena I
HI
Lenaerts
Anne
A
Gibbons
Simon
S
D015082:2,2'-Dipyridyl / Q000031:analogs & derivatives / Q000737:chemistry / Q000302:isolation & purification / Q000633:toxicity; D000470:Alkaloids / Q000737:chemistry / Q000302:isolation & purification / Q000633:toxicity; D000490:Allium / Q000737:chemistry*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000302:isolation & purification / Q000633:toxicity; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000302:isolation & purification / Q000633:toxicity; D004195:Disease Models, Animal; D004220:Disulfides / Q000737:chemistry / Q000302:isolation & purification / Q000633:toxicity; D018432:Drug Resistance, Multiple / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006360:Heat-Shock Proteins / Q000096:biosynthesis / Q000187:drug effects; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D051379:Mice; D015394:Molecular Structure; D015125:Oxyquinoline / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry / Q000302:isolation & purification / Q000633:toxicity; D013879:Thioredoxins / Q000187:drug effects / Q000378:metabolism; D024483:Vitamin K 3 / Q000494:pharmacology
C541884:2,2'-dithiobispyridine-N-oxide; C548575:2-((methylthiomethyl)dithio)pyridine-N-oxide; C548574:2-(methyldithio)pyridine-N-oxide; D000470:Alkaloids; D000900:Anti-Bacterial Agents; D000972:Antineoplastic Agents, Phytogenic; D004220:Disulfides; D006360:Heat-Shock Proteins; D011725:Pyridines; D013879:Thioredoxins; D015082:2,2'-Dipyridyl; D015125:Oxyquinoline; D024483:Vitamin K 3; C013229:pyridine N-oxide