A Decarboxylative Cross-Coupling Platform To Access 2-Heteroaryl Azetidines: Building Blocks with Application in Medicinal Chemistry.

Photoredox-transition metal dual catalysis provides a unique platform for constructing sp3-rich chemical matter. Here, we report a nickel-catalyzed cross-coupling of commercially available or easily prepared redox-active NHP azetidine-2-carboxylates with commercially available heteroaryl iodides to yield 2-heteroaryl azetidines. This "off-the-shelf" approach yielded products amenable to diversification giving access to novel saturated heterocyclic scaffolds useful for medicinal chemistry programs. An alternative mechanism for Hantzsch ester within nickel-catalyzed cross-coupling of heteroaryl halides and α-amino radicals is also presented.

A novel method for conjugating the terminal amine of peptide ligands to cholesterol: synthesis iRGD-cholesterol.

AIM: Conventional conjugation reactions often involve the use of activated PEG as a linker, but concerns about PEG-mediated reduction in intracellular delivery and enhanced immunogenicity have generated interest in developing methods that eliminate the need for a PEG linker. MATERIALS & METHODS: Reaction conditions were identified that specifically couples the terminal amine of a cyclic iRGD peptide (CRGDRGPDC) to the hydroxyl moiety of cholesterol through a short carbamate linker. RESULTS & CONCLUSION: Using this method for synthesizing iRGD-cholesterol, peptide ligands can be incorporated into lipid-based delivery systems, thereby eliminating concerns about adverse reactions to PEG. Toxicity and stability data indicate low toxicity and adequate serum stability at low ligand levels.

Effect of Conformational Chirality on Optical Activity Observed in a Smectic of Achiral, Bent-Core Molecules.

Smectics of achiral, tilted bent-core liquid crystal molecules are chiral, but their optical activity is generally small. Here, we study the effect of conformational chirality on optical activity in smectic phases of an achiral, bent-core mesogen, W513. The neat material has a modulated B4 phase, which appears dark under crossed polarizers and shows no observable optical rotation under decrossed polarizers. However, mixtures of W513 with a rod-like mesogen, 8CB, show a conventional B4 phase, in which distinct left- and right-handed chiral domains with opposite optical activity are observed. The optical behavior of the mixtures is consistent with NMR results, which show a splitting of the carbonyl peak of the bent-core molecules into two, indicating a twisted conformation between the two molecular arms of the bent-core molecules as in conventional B4 materials.

A Point System as Catalyst to Increase Resident Scholarship: An MPCRN Study.

INTRODUCTION: Encouraging resident scholarly activity has been a longstanding challenge for medical educators. The Accreditation Council for Graduate Medical Education (ACGME) has been increasing its emphasis on scholarly activity, forcing programs to evaluate their existing processes. This study sought to evaluate the impact of a scholarly activity point system on the resident scholarly productivity at multiple programs. METHODS: Five military family medicine residencies evaluated resident outcomes 2 years before and 2 years after the introduction of a scholarly activity point system. Outcome measures included peer-reviewed publications with a resident as first author, peer-reviewed publications with a resident as any author, resident presentation of scholarship at a regional, national, and international conference, IRB-approved protocols with a resident as principal investigator, and IRB-approved protocols with a resident in any role. RESULTS: Four of the five programs experienced substantial increases in nearly every outcome. The fifth program, which had a more robust culture of inquiry at baseline, did not experience an increase in resident scholarly productivity. CONCLUSIONS: A scholarly activity point system was associated with an increase in resident scholarly production in family medicine programs. It appears to work best in programs that start from a lower level of scholarly productivity at baseline. A point system appears to be a useful addition to scholarly activity curricula.

Chemical Equilibria and Kinetics in Aqueous Solutions of Zymonic Acid.

The chemistry of pyruvic acid is of great interest due to its essential role in metabolism for all life and its role in atmospheric chemistry. Pyruvic acid under a wide range of conditions, including normal storage conditions, will spontaneously dimerize to form zymonic acid. We isolated zymonic acid and, using a variety of 1D and 2D NMR techniques, identified it as a single structure as a solid or dissolved in DMSO. When in aqueous solution, however, we identified a mixture of five different tautomers and hydrates in equilibrium with each other with no single dominant form. The kinetics of this conversion were studied in situ via NMR. The reactivity of the tautomers and hydrates in aqueous solution is investigated and discussed in terms of aqueous reaction mechanisms. There is strong evidence for a direct, reversible conversion from an enol to a geminal diol without passing through a ketone intermediate, which implies the reversible addition of water across a double bond under ambient conditions. Additionally, there is evidence for a base catalyzed lactone ring formation, which is in essence a base catalyzed esterification reaction. The equilibrium between pyruvic acid and its oligomers in aqueous solution is of consequence in the natural environment.

The Partitioning of Small Aromatic Molecules to Air-Water and Phospholipid Interfaces Mediated by Non-Hydrophobic Interactions.

Phenylalanine has an important role both in normal biological function and in disease states such as phenylketonuria (PKU) and amyloid fibril diseases. Two crucial aspects of phenylalanine behavior in biological systems are its preferential partitioning into membranes and its propensity to cluster. In order to examine the intermolecular interactions that give rise to this behavior, the surface partitioning behavior was investigated for a series of molecules structurally related to phenylalanine (phenylglycine, phenylacetic acid, and tyrosine) both experimentally and by molecular dynamics simulations. Surface tension measurements were performed over time for aromatic solutions both in the presence and in the absence of 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) monolayer films, which functioned as simple model membranes. The observed trends in surface activity defy simple predictions based on solubility and hydrophobicity. The possibility of clustering is investigated through a combination of Langmuir trough, nuclear magnetic resonance (NMR), fluorescence self-quenching, and mass spectroscopy measurements. It is concluded that clustering does not occur in solution to a significant extent for these molecules, but interfacial clustering is likely. An explanation for observed trends in surface activity is presented on the basis of cluster stability and molecular conformational flexibility.

Highly Active Multidentate Ligand-Based Alkyne Metathesis Catalysts.

Alkyne metathesis catalysts composed of molybdenum(VI) propylidyne and multidentate tris(2-hydroxylbenzyl)methane ligands have been developed, which exhibit excellent stability (remains active in solution for months at room temperature), high activity, and broad functional-group tolerance. The homodimerization and cyclooligomerization of monopropynyl or dipropynyl substrates, including challenging heterocycle substrates (e.g., pyridine), proceed efficiently at 40-55 °C in a closed system. The ligand structure and catalytic activity relationship has been investigated, which shows that the ortho groups of the multidentate phenol ligands are critical to the stability and activity of such a catalyst system.

All Military Adolescents Are Not the Same: Sexuality and Substance Use among Adolescents in the U.S. Military Healthcare System.

Data examining sexuality and substance use among active duty and military-dependent youth is limited; however, these psychosocial factors have military implications. Adolescents and young adults aged 12-23 were recruited from an active-duty trainee clinic (n = 225) and a military pediatric clinic (n = 223). Active duty participants were more likely to be older, male, White, previous tobacco users, and report a history of sexual activity and less contraception use at their most recent intercourse, compared to the dependent group. Over 10% of all participants indicated attraction to members of the same gender or both genders. In logistic regression analysis, non-White participants were less likely to use contraception compared to White participants. Adolescents and young adults seen in military clinics frequently engage in high-risk behavior. Clinicians who care for military youth should assess their patient's psychosocial history. Further study of this population is warranted to identify factors that may influence risk and resilience.

Influence of 5-N-carboxamide modifications on the thermodynamic stability of oligonucleotides.

We have recently shown that the incorporation of modified nucleotides such as 5-N-carboxamide-deoxyuridines into random nucleic acid libraries improves success rates in SELEX experiments and facilitates the identification of ligands with slow off-rates. Here we report the impact of these modifications on the thermodynamic stability of both duplexes and intramolecular 'single-stranded' structures. Within duplexes, large, hydrophobic naphthyl groups were destabilizing relative to the all natural DNA duplex, while the hydrophilic groups exhibited somewhat improved duplex stability. All of the significant changes in stability were driven by opposing contributions from the enthalpic and entropic terms. In contrast, both benzyl and naphthyl modifications stabilized intramolecular single-stranded structures relative to their natural DNA analogs, consistent with the notion that intramolecular folding allows formation of novel, stabilizing hydrophobic interactions. Imino proton NMR data provided evidence that elements of the folded structure form at temperatures well below the Tm, with a melting transition that is distinctly less cooperative when compared to duplex DNA. Although there are no data to suggest that the unmodified DNA sequences fold into structures similar to their modified analogs, this still represents clear evidence that these modifications impart thermodynamic stability to the folded structure not achievable with unmodified DNA.

Time-Resolved Fluorescence Anisotropy of Bicyclo[1.1.1]pentane/Tolane-Based Molecular Rods Included in Tris(o-phenylenedioxy)cyclotriphosphazene (TPP).

We examine the fluorescence anisotropy of rod-shaped guests held inside the channels of tris(o-phenylenedioxy)cyclotriphosphazene (TPP) host nanocrystals, characterized by powder X-ray diffraction and solid state NMR spectroscopy. We address two issues: (i) are light polarization measurements on an aqueous colloidal solution of TPP nanocrystals meaningful, or is depolarization by scattering excessive? (ii) Can measurements of the rotational mobility of the included guests be performed at low enough loading levels to suppress depolarization by intercrystallite energy transfer? We find that meaningful measurements are possible and demonstrate that the long axis of molecular rods included in TPP channels performs negligible vibrational motion.

Oxidative substitution of boranephosphonate diesters as a route to post-synthetically modified DNA.

The introduction of modifications into oligonucleotides is important for a large number of applications in the nucleic acids field. However, the method of solid-phase DNA synthesis presents significant challenges for incorporating many useful modifications that are unstable to the conditions for preparing synthetic DNA. Here we report that boranephosphonate diesters undergo facile nucleophilic substitution in a stereospecific manner upon activation by iodine. We have subsequently used this reactivity to post-synthetically introduce modifications including azides and fluorophores into DNA by first synthesizing boranephosphonate-linked 2'-deoxyoligonucleotides and then treating these oligomers with iodine and various nucleophiles. In addition, we show that this reaction is an attractive method for preparing stereodefined phosphorus-modified oligonucleotides. We have also examined the mechanism of this reaction and show that it proceeds via an iodophosphate intermediate. Beyond nucleic acids synthesis, due to the ubiquity of phosphate derivatives in natural compounds and therapeutics, this stereospecific reaction has many potential applications in organophosphorus chemistry.

Photochemical kinetics of pyruvic acid in aqueous solution.

Pyruvic acid in the atmosphere is found in both the gas and aqueous phases, and its behavior gives insight into that of other α-keto acids. Photolysis is a significant degradation pathway for this molecule in the environment, and in aqueous solution the major photoproducts are higher-molecular-weight compounds that may contribute to secondary organic aerosol mass. The kinetics of the aqueous-phase photolysis of pyruvic acid under aerobic and anaerobic conditions was investigated in order to calculate the first-order rate constant, Jaq, in solution. Analysis of the exponential decay of pyruvic acid was performed by monitoring both pyruvic acid and its photolytic products over the course of the reaction by (1)H NMR spectroscopy. Detection of major and minor products in the 0.1, 0.05, and 0.02 M pyruvic acid photolyses clearly demonstrates that the primary reaction pathways are highly dependent on the initial pyruvic acid concentration and the presence of dissolved oxygen. The Jaq values were calculated with approximations based on the dominant pathways for limiting cases of the mechanism. Finally, a model study using the calculated rate constants demonstrates the importance of aqueous-phase photolysis as a sink for pyruvic acid in the atmosphere, compared with gas-phase photolysis and OH oxidation.

Nanoscale structure-activity relationships, mode of action, and biocompatibility of gold nanoparticle antibiotics.

The emergence of resistance to multiple antimicrobial agents by pathogenic bacteria has become a significant global public health threat. Multi-drug-resistant (MDR) Gram-negative bacteria have become particularly problematic, as no new classes of small-molecule antibiotics for Gram-negative bacteria have emerged in over two decades. We have developed a combinatorial screening process for identifying mixed ligand monolayer/gold nanoparticle conjugates (2.4 nm diameter) with antibiotic activity. The method previously led to the discovery of several conjugates with potent activity against the Gram-negative bacterium Escherichia coli. Here we show that these conjugates are also active against MDR E. coli and MDR Klebsiella pneumoniae. Moreover, we have shown that resistance to these nanoparticles develops significantly more slowly than to a commercial small-molecule drug. These results, combined with their relatively low toxicity to mammalian cells and biocompatibility in vivo, suggest that gold nanoparticles may be viable new candidates for the treatment of MDR Gram-negative bacterial infections.

Photoinitiated synthesis of self-assembled vesicles.

The aqueous photochemistry of 2-oxooctanoic acid (a single-tailed surfactant) results in the synthesis of a double-tailed surfactant product followed by spontaneous self-assembly into vesicles. The photochemical mechanism is detailed here, and the reaction products are identified using mass spectrometry. Then, the self-assembled vesicles are characterized using dynamic light scattering, fluorescence microscopy, and NMR. Further, their stability over time and in the presence of MgCl2 salt is demonstrated. This work contributes to membrane evolution through the provision of a prebiotic route for the synthesis of plausible membrane components and subsequent self-assembly of a primitive enclosure.

Sunlight-initiated chemistry of aqueous pyruvic acid: building complexity in the origin of life.

Coupling chemical reactions to an energy source is a necessary step in the origin of life. Here, we utilize UV photons provided by a simulated sun to activate aqueous pyruvic acid and subsequently prompt chemical reactions mimicking some of the functions of modern metabolism. Pyruvic acid is interesting in a prebiotic context due to its prevalence in modern metabolism and its abiotic availability on early Earth. Here, pyruvic acid (CH3COCOOH, a C3 molecule) photochemically reacts to produce more complex molecules containing four or more carbon atoms. Acetoin (CH3CHOHCOCH3), a C4 molecule and a modern bacterial metabolite, is produced in this chemistry as well as lactic acid (CH3CHOHCOOH), a molecule which, when coupled with other abiotic chemical reaction pathways, can provide a regeneration pathway for pyruvic acid. This chemistry is discussed in the context of plausible environments on early Earth such as near the ocean surface and atmospheric aerosol particles. These environments allow for combination and exchange of reactants and products of other reaction environments (such as shallow hydrothermal vents). The result could be a contribution to the steady increase in chemical complexity requisite in the origin of life.