Centre for Pharmacognosy and Phytotherapy, The School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, UK.
J Nat Prod. 2009 Mar 27;72(3):360-5. doi: 10.1021/np800572r.
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.
从顶羽菊中分离得到三个具有二硫键功能的吡啶-N-氧化物生物碱（1-3）。这些天然产物的结构通过光谱手段阐明为 2-（甲硫基）吡啶-N-氧化物（1）、2-[(甲硫基甲基)二硫]吡啶-N-氧化物（2）和 2,2'-二硫代双吡啶-N-氧化物（3）。1 的建议结构通过商业 2-巯基吡啶-N-氧化物的 S-甲基硫代化得到证实。化合物 1 和 2 是新的天然产物，3 是首次从葱属植物中报道的。所有化合物均针对快速生长的分枝杆菌、耐甲氧西林金黄色葡萄球菌和金黄色葡萄球菌的多药耐药（MDR）变体进行了活性评估。化合物 1 和 2 对这些菌株的最小抑菌浓度（MIC）为 0.5-8 μg/mL。为了优化抗菌活性，合成了一系列 1 的类似物，尽管天然产物具有最强的体外活性。在 30 μg/mL 的全细胞测定中，1 被证明完全抑制（14）C 标记的醋酸盐掺入可溶脂肪酸，表明它可能是脂肪酸生物合成的抑制剂。在人癌细胞系增殖抑制测定中，1 和 2 在与人体成纤维细胞系相比时，显示出 0.3 至 1.8 μM 的 IC50 值，选择性指数为 2.3。1 进行了微阵列分析，表明其作用模式与甲萘醌和 8-喹啉醇相似，通过干扰硫氧还蛋白系统并上调各种热休克蛋白的产生。该化合物还在体内毒性小鼠模型中进行了评估。
