The utility of nitric oxide (NO)-releasing silica nanoparticles as a novel antibacterial is demonstrated against Pseudomonas aeruginosa. Nitric oxide-releasing nanoparticles were prepared via co-condensation of tetraalkoxysilane with aminoalkoxysilane modified with diazeniumdiolate NO donors, allowing for the storage of large NO payloads. Comparison of the bactericidal efficacy of the NO-releasing nanoparticles to 1-[2-(carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate (PROLI/NO), a small molecule NO donor, demonstrated enhanced bactericidal efficacy of nanoparticle-derived NO and reduced cytotoxicity to healthy cells (mammalian fibroblasts). Confocal microscopy revealed that fluorescently-labeled NO-releasing nanoparticles associated with the bacteria, providing rationale for the enhanced bactericidal efficacy of the nanoparticles. Intracellular NO concentrations were measurable when the NO was delivered from nanoparticles as opposed to PROLI/NO. Collectively, these results demonstrate the advantage of delivering NO via nanoparticles for antimicrobial applications.Keywords nitric oxide; silica nanoparticle; antibacterial; bactericidal; cytotoxicity; reactive nitrogen species; reactive oxygen species Antibiotic resistance has resulted in bacterial infections becoming the most common cause of infectious disease-related death. 1,2 In the United States alone, nearly 2 million people per year acquire infections during a hospital stay, of which approximately 90,000 die. 2 The primary culprits behind such deadly infections are antibiotic-resistant pathogens, which are responsible for approximately 70% of all lethal nosocomial infections. The growing danger of life-threatening infections and the rising economic burden of resistant bacteria have created a demand for new antibacterial therapeutics.The use of nanoparticles as delivery vehicles for bactericidal agents represents a new paradigm in the design of antibacterial therapeutics. To date, most antibacterial nanoparticles have been engineered using traditional antibiotics that are either incorporated within the particle scaffold or attached to the exterior of the particle. In many cases, such particles have exhibited greater efficacy than their constituent antibiotics alone. For example, Gu et al. reported that vancomycin-capped gold nanoparticles exhibited a 64-fold improvement in efficacy over vancomycin alone. 3 Similarly, silver nanoparticles have schoenfisch@unc.edu. Supporting Information Available: Synthesis of FITC-modified silica nanoparticles, AFM analysis of nanoparticle dimensions, scavenging of NO by TSB, and confocal fluorescence microscopy images of PROLI/NO-treated P. aeruginosa cells. This material is available free of charge via the Internet at http://pubs.acs.org. NIH Public AccessAuthor Manuscript ACS Nano. Author manuscript; available in PMC 2013 February 13. shown greater antibacterial activity than silver ion (Ag + ) in solution due to the direct toxicity of the particles and tunable release of Ag + based on nanocomposite size. [4][...

The first total synthesis of the unique terpene rippertenol, a molecule with dense stereochemical complexity arrayed on a compact framework largely devoid of functional groups, is described. Key elements include orchestrated and unique applications of aldol condensations, Diels-Alder chemistry, and a ring expansion to advance a chiral starting material containing a single chiral center into the final target in a concise and diastereocontrolled manner.

Dedicated to Professor Ronald Breslow on the occasion of his 82nd birthdayPlants of the Euphorbiaceae family are sources of several important collections of secondary metabolites, one being the securinega alkaloids (1-5 [2] and 7, Scheme 1). [1] These materials possess unique frameworks typically characterized by a bridged, tetracyclic substructure bearing a strained a,b,g,dunsaturated lactone motif (as in 1-5), though rearranged variants of such domains (such as in 7) [3] also exist. They also display intriguing biological activity; [4] for instance, securinine (1), the most abundant member of the family, is a potent GABA antagonist. Given these attributes, it is unsurprising that the synthetic community has devoted significant attention to this collection of compounds, [5] particularly to the challenges posed by the key shared domains within 1-5. Indeed, since the inaugural total synthesis of securinine (1) by Horii in 1966, [5a] several other successful and highly creative approaches for forging their fused bicyclic butenolide domains have been disclosed, efforts that include selenoxide eliminations, [5b,e,f,h,i,r] intramolecular Wittig olefinations, [5e,f,o,p,t-v] ring-closing metatheses, [5j-p,s,x] and alkylation of allylic bromides or mesylates. [5a,h,i-m,q,t-v,x] However, most of these strategies require multiple steps to execute, typically constituting the longest (and least efficient) portion of the overall route. Here, we disclose a new disconnection for this critical domain, one that uses a simple, acyclic starting material and a novel N-heterocyclic carbene (NHC)-catalyzed reaction [6,7] to forge the entire butenolide system in a single step. We highlight its utility through a concise and efficient synthesis of 3-deshydroxy-secuamamine A (6, an analog of 5 [2] and a structural isomer of 1) as well as the core framework of 1-3, and indicate preliminary results of the components necessary for its successful application in other contexts.Our generalized approach to quickly fashion the butenolide domains of the securinega class is shown in the lower half of Scheme 1, using target 6 for purposes of illustration. As indicated, we envisioned that this entire key motif could be accessed from an appropriate linear enynal precursor (8) through an intramolecular NHC-catalyzed homoenolate addition onto the lone ketone followed by lactonization.

Alles fügt sich zusammen: Die meisten der bisherigen Synthesen der Securinega‐Alkaloide erforderten längere Sequenzen zum Aufbau der verbrückenden Butenolid‐Domäne. Ein neuartiger Ansatz wird nun beschrieben, der mithilfe von N‐heterocyclischen Carbenen (NHCs) und Lewis‐Säuren die gesamte Domäne in einem einzigen Schritt aufbaut (siehe Schema). Die Synthese demonstriert, dass von Inalen abgeleitete Homoenolate als Nucleophile an intramolekularen Reaktionen teilnehmen können.

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