α-Methylene-β-Lactone Scaffold for Developing Chemical Probes at the Two Ends of the Selectivity Spectrum

The utilities of an α-methylene-β-lactone (MeLac) moiety as a warhead composed of multiple electrophilic sites are reported. We demonstrate that a MeLac-alkyne not only reacts with diverse proteins as a broadly reactive measurement probe, but also recruits reduced endogenous glutathione (GSH) to assemble a selective chemical probe of GSH-β-lactone (GSH-Lac)-alkyne in live cells. Tandem mass spectrometry reveals that MeLac reacts with nucleophilic cysteine, serine, lysine, threonine, and tyrosine residues, through either Michael or acyl addition. A peptide-centric proteomics platform demonstrates that the proteomic selectivity profiles of orlistat and parthenolide, which have distinct reactivities, are measurable by MeLac-alkyne as a high-coverage probe. The GSH-Lac-alkyne selectively probes the glutathione S-transferase P responsible for multidrug resistance. The assembly of the GSH-Lac probe exemplifies a modular and scalable route to develop selective probes with different recognizing moieties.     

Sesquiterpenoids Lactones: Benefits to Plants and People

Sesquiterpenoids, and specifically sesquiterpene lactones from Asteraceae, may play a highly significant role in human health, both as part of a balanced diet and as pharmaceutical agents, due to their potential for the treatment of cardiovascular disease and cancer. This review highlights the role of sesquiterpene lactones endogenously in the plants that produce them, and explores mechanisms by which they interact in animal and human consumers of these plants. Several mechanisms are proposed for the reduction of inflammation and tumorigenesis at potentially achievable levels in humans. Plants can be classified by their specific array of produced sesquiterpene lactones, showing high levels of translational control. Studies of folk medicines implicate sesquiterpene lactones as the active ingredient in many treatments for other ailments such as diarrhea, burns, influenza, and neurodegradation. In addition to the anti-inflammatory response, sesquiterpene lactones have been found to sensitize tumor cells to conventional drug treatments. This review explores the varied ecological roles of sesquiterpenes in the plant producer, depending upon the plant and the compound. These include allelopathy with other plants, insects, and microbes, thereby causing behavioural or developmental modification to these secondary organisms to the benefit of the sesquiterpenoid producer. Some sesquiterpenoid lactones are antimicrobial, disrupting the cell wall of fungi and invasive bacteria, whereas others protect the plant from environmental stresses that would otherwise cause oxidative damage. Many of the compounds are effective due to their bitter flavor, which has obvious implications for human consumers. The implications of sesquiterpenoid lactone qualities for future crop production are discussed.     

尿激酶型纤溶酶原激活剂在小白菊内酯抑制胃癌细胞转移中的作用

目的:探讨小白菊内酯(Par)抑制人胃癌SGC7901 细胞转移活性及对尿激酶型纤溶酶原激活剂(uPA)的调控作用。方法:MTT 法检测SGC7901 细胞增殖能力的变化;倒置显微镜下观察细胞形态;transwell 小室法检测细胞迁移和侵袭能力;Western blot 法检测细胞uPA蛋白表达;RT-PCR 法检测uPA的RNA表达。结果:在100～200 μmol/L 浓度范围内, Par以浓度和时间依赖方式抑制胃癌细胞增殖, 倒置显微镜下见到细胞生长明显受到抑制, 细胞的迁移能力和侵袭力均显著下降, 穿过人工基底膜的细胞数逐渐减少。随着Par作用时间的延长, SGC7901 细胞表达uPA水平逐渐下降。结论:Par可以抑制SGC7901 的增殖和转移, uPA在Par降低胃癌细胞转移活性中起重要作用。     

Processing of a Sesquiterpene Lactone by <Emphasis Type="Italic">Papilio glaucus</Emphasis> Caterpillars

Papilio glaucus caterpillars encounter a diverse array of sesquiterpene lactones, including parthenolide, in the leaves of host plants Liriodendron tulipifera and Magnolia virginiana. These compounds are toxic to unadapted herbivores, and the development of P. glaucus caterpillars likely depends on their ability to excrete or detoxify them efficiently. A new metabolite of parthenolide, 2-α-hydroxydihydroparthenolide, identified by crystal structure determination and nuclear magnetic resonance, was present in the waste of the caterpillars. The parent compound was modified by the reduction of an α-methylene group, rendering the compound less reactive, and the addition of a hydroxyl group, which increases the polarity and prepares it for the conjugation reactions of phase II metabolism. Unmetabolized parthenolide was also present in large amounts in waste. P. glaucus larvae are apparently capable of excreting intact sesquiterpene lactones and sesquiterpene lactone metabolites during consumption of foliage rich in these compounds.     

Biodegradable,Drug‐Loaded Nanovectors via Direct Hydration as a New Platform for Cancer Therapeutics

The stabilization and transport of low‐solubility drugs, by encapsulation in nanoscopic delivery vectors (nanovectors), is a key paradigm in nanomedicine. However, the problems of carrier toxicity, specificity, and producibility create a bottleneck in the development of new nanomedical technologies. Copolymeric nanoparticles are an excellent platform for nanovector engineering due to their structural versatility; however, conventional fabrication processes rely upon harmful chemicals that necessitate purification. In engineering a more robust (copolymeric) nanovector platform, it is necessary to reconsider the entire process from copolymer synthesis through self‐assembly and functionalization. To this end, a process is developed whereby biodegradable copolymers of poly(ethylene glycol)‐block‐poly(trimethylene carbonate), synthesized via organocatalyzed ring‐opening polymerization, undergo assembly into highly uniform, drug‐loaded micelles without the use of harmful solvents or the need for purification. The direct hydration methodology, employing oligo(ethylene glycol) as a nontoxic dispersant, facilitates rapid preparation of pristine, drug‐loaded nanovectors that require no further processing. This method is robust, fast, and scalable. Utilizing parthenolide, an exciting candidate for treatment of acute lymphoblastic leukemia (ALL), discrete nanovectors are generated that show strikingly low carrier toxicity and high levels of specific therapeutic efficacy against primary ALL cells (as compared to normal hematopoietic cells).