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[Display omitted] Both concerted [4 + 2] cycloadditions and stepwise carbocation-alkene cyclizations have been proposed as means to construct the complex polycyclic cores of the artatrovirenols and daphenoid natural products during their biosyntheses. Here the energetic feasibility of each of these reactions is assessed using density functional theory calculations. While none of the previously proposed processes can be ruled out, an alternative process with a lower barrier is proposed. This process would allow for formation of a key C C bond during the cyclase phase of terpenoid biosynthesis. [ABSTRACT FROM AUTHOR]

Abstract: Quantum chemical calculations were used to characterize [4,5] sigmatropic shifts in systems containing butadiene and pentadienyl substructures. Cationic, anionic, and radical systems with various tethers connecting these substructures were examined. In many cases, concerted [4,5] sigmatropic shifts with asynchronous bond making and breaking events were observed. The fundamental connections between [4,5] sigmatropic shifts and (5+4) cycloadditions are highlighted. [Copyright &y& Elsevier]

Density functional theory calculations were carried out in order to determine the viability of putative mechanistic pathways for formation of the diterpenoid (+)-chatancin. It was found that a cycloaddition involving a pyrylium ion would have a lower energetic barrier than previously proposed cycloadditions involving a 2H-pyran or furan. All three reactions are predicted to be concerted. [ABSTRACT FROM AUTHOR]

S-Nitrosothiol (RS-NO) generation/levels have been implicated as being important to numerous physiological and pathophysiological processes. As such, the mechanism(s) of their generation and degradation are important factors in determining their biological activity. Along with the effects on the activity of thiol proteins, RS-NOs have also been reported to be reservoirs or storage forms of nitric oxide (NO). That is, it is hypothesized that NO can be released from RS-NO at opportune times to, for example, regulate vascular tone. However, to date there are few established mechanisms that can account for facile NO release from RS-NO. Recent discovery of the biological formation and prevalence of hydropersulfides (RSSH) and their subsequent reaction with RS-NO species provides a possible route for NO release from RS-NO. Herein, it is found that RSSH is capable of reacting with RS-NO to liberate NO and that the analogous reaction using RSH is not nearly as proficient in generating NO. Moreover, computational results support the prevalence of this reaction over other possible competing processes. Finally, results of biological studies of NO-mediated vasorelaxation are consistent with the idea that RS-NO species can be degraded by RSSH to release NO. [Display omitted] • Hydropersulfides (RSSH) react with S-nitrosothiols (RS-NO) leading to RS-NO degradation. • The RSSH/RS-NO reaction leads to the release of nitric oxide (NO). • NO release from the RSSH/RS-NO reaction is the predominant pathway. • The generation of NO from the RSSH/RS-NO reaction can result in vasorelaxation. [ABSTRACT FROM AUTHOR]

Abstract: The results of quantum chemical calculations on a previously proposed biosynthetic pathway for the formation of calophyline A from rhazimol, which features formally forbidden 4-electron [1,2] and [1,3] sigmatropic shifts, are discussed. The proposed pathway was not found to be energetically viable, despite a surprisingly low predicted barrier for the [1,3] shift, but an alternative route involving a series of tautomerizations and carbonyl addition reactions is shown to be more energetically feasible. [Copyright &y& Elsevier]

Abstract: Results from density functional theory calculations on a proton-promoted [2+2] cycloaddition to form plumisclerin A’s cyclobutane ring are described. On the basis of these results, it is proposed that protonation allows for an energetically viable stepwise cycloaddition that provides an alternative to photochemical cyclobutane formation. [Copyright &y& Elsevier]

Abstract: Syntheses of several (sulfonyl)methylphosphonate analogs of geranyl, neryl, and farnesyl diphosphates are described. Key steps include utilization of an (E)-selective Horner–Wadsworth–Emmons olefination which couples an aldehyde to the sulfone phosphonate moiety, and a selective reduction of the resulting dienyl sulfone phosphonate substrates. [Copyright &y& Elsevier]

Abstract: Quantum chemical calculations (B3LYP/6-31G(d)) on carbocation rearrangements that are proposed to occur in the biosynthesis of aspernomine are described. Based on these calculations, a pathway involving a concerted but asynchronous [4+2] cycloaddition that avoids the formation of a secondary carbocation is proposed for small model systems. [Copyright &y& Elsevier]

Abstract: 3,4-Dihydro-2H-pyrrole derivatives were synthesized by the 1,3-dipolar cycloaddition reaction of nitrile ylides with acrylamides. Acrylamide substitution patterns and benzimidoyl chloride equilibration were investigated. [Copyright &y& Elsevier]

The recent finding that hydropersulfides (RSSH) are biologically prevalent in mammalian systems has prompted further investigation of their chemical properties in order to provide a basis for understanding their potential functions, if any. Hydropersulfides have been touted as hyper-reactive thiol-like species that possess increased nucleophilicity and reducing capabilities compared to their thiol counterparts. Herein, using persulfide generating model systems, the ability of RSSH species to act as one-electron reductants has been examined. Not unexpectedly, RSSH is relatively easily oxidized, compared to thiols, by weak oxidants to generate the perthiyl radical (RSS·). Somewhat surprisingly, however, RSS· was found to be stable in the presence of both O 2 and NO and only appears to dimerize. Thus, the RSSH/RSS· redox couple is readily accessible under biological conditions and since dimerization of RSS· may be a rare event due to low concentrations and/or sequestration within a protein, it is speculated that the general lack of reactivity of individual RSS· species may allow this couple to be utilized as a redox component in biological systems. [ABSTRACT FROM AUTHOR]

[Display omitted] Oxidopyrylium-based [5 + 2] cycloadditions between diethanolamine appended silyloxypyrones and organoboronic acid derivatives were achieved. Evidence for the diethanolamine boronate (i.e. DABO) complex was observed by 1H NMR at room temperature with boronic acids and [5 + 2] cycloaddition was achieved in a single reaction mixture in DCE. Pinacol boronates required elevated temperature (140 °C) in refluxing p-xylene but afforded access to products not readily available with boronic acids. Theoretical calculations provide evidence for an asynchronous concerted transition state. Good functional group tolerance was observed and products were isolated as the oxabicyclo[3.2.1]-octane DABO cycloadducts. [ABSTRACT FROM AUTHOR]

Quantum chemical calculations coupled to experiments were used to predict covalent hydration propensities of biologically relevant α-ketoamides. Experimentally determined hydration equilibrium constants for related ketones and aldehydes were compared to computationally determined values to develop a method for predicting hydration equilibrium constants. This method was used on six newly synthesized α-ketoamides to experimentally verify computational predictions. A correlation between calculation and experiment was observed and applied to models of several pertinent APIs. Our results indicate that the keto form is favored for practically all α-ketoamides in biological environs. [ABSTRACT FROM AUTHOR]

The most common mutation causing cystic fibrosis (CF) is deletion of phenylalanine residue 508 in the cystic fibrosis transmembrane regulator conductance (CFTR) protein. Small molecules that are able to correct the misfolding of defective ΔF508-CFTR have considerable promise for therapy. Reported here are the design, preparation, and evaluation of five more hydrophilic bisazole analogs of previously identified bithiazole CF corrector 1 . Interestingly, bisazole ΔF508-CFTR corrector activity was not increased by incorporation of more H-bond acceptors (O or N), but correlated best with the overall bisazole molecular geometry. The structure activity data, together with molecular modeling, suggested that active bisazole correctors adopt a U-shaped conformation, and that corrector activity depends on the molecule’s ability to access this molecular geometry. [ABSTRACT FROM AUTHOR]

Hydrogen sulfide (H 2 S) is an endogenously generated and putative signaling/effector molecule. Despite its numerous reported functions, the chemistry by which it elicits its functions is not understood. Moreover, recent studies allude to the existence of other sulfur species besides H 2 S that may play critical physiological roles. Herein, the basic chemical biology of H 2 S as well as other related or derived species is discussed and reviewed. This review particularly focuses on the per- and polysulfides which are likely in equilibrium with free H 2 S and which may be important biological effectors themselves. [ABSTRACT FROM AUTHOR]

Myeloperoxidase (MPO) produces hypohalous acids as a key component of the innate immune response; however, release of these acids extracellularly results in inflammatory cell and tissue damage. The two-step, one-pot Davis–Beirut reaction was used to synthesize a library of 2 H -indazoles and 1 H -indazolones as putative inhibitors of MPO. A structure–activity relationship study was undertaken wherein compounds were evaluated utilizing taurine-chloramine and MPO-mediated H 2 O 2 consumption assays. Docking studies as well as toxicophore and Lipinski analyses were performed. Fourteen compounds were found to be potent inhibitors with IC 50 values <1 μM, suggesting these compounds could be considered as potential modulators of pro-oxidative tissue injury pertubated by the inflammatory MPO/H 2 O 2 /HOCl/HOBr system. [ABSTRACT FROM AUTHOR]

A hybrid sequential molecular mechanics and quantum mechanical approach to modeling cyclic peptides has led to an effective method for predicting their 1 H and 13 C NMR chemical shift values. The method was first developed to predict chemical shifts in chloroform before being adapted to a more peptide friendly solvent, DMSO. Finally the effectiveness of this method was tested in a blind fashion and excellent agreement with the experimental NMR chemical shifts was observed. [ABSTRACT FROM AUTHOR]

Abstract: Metal complexation to aryl (Ph, Cp, cyclobutadienyl) methylium cations, radicals, and anions was investigated using hybrid density functional theory methods (B3LYP/LANL2DZ), with a focus on the effects of substituents. The results of these calculations, in which both geometric and energetic consequences of adding substituents were examined, indicate that metal–methylium interactions are most sensitive to substituent effects for complexed cations. [Copyright &y& Elsevier]

Abstract: The Davis–Beirut reaction, which provides an efficient synthesis of 2H-indazoles and, subsequently, indazolones, is shown to proceed rapidly from o-nitrosobenzaldehyde and primary amines under both acid and base catalysis. Experimental and theoretical evidence in support of a reaction mechanism is provided in which o-nitrosobenzylidine imine is a pivotal intermediate in this N,N-bond forming heterocyclization reaction. The Davis–Beirut reaction is also shown to effectively synthesize a number of novel 3-amino-2H-indazole derivatives. [Copyright &y& Elsevier]

We previously identified a spiro [piperidine-4,1-pyrido [3,4- b indole] class of co-potentiators that function in synergy with existing CFTR potentiators such as VX-770 or GLGP1837 to restore channel activity of a defined subset of minimal function cystic fibrosis transmembrane conductance regulator (CFTR) mutants. Here, structure-activity studies were conducted to improve their potency over the previously identified compound, 20 (originally termed CP-A01). Targeted synthesis of 37 spiro [piperidine-4,1-pyrido [3,4- b indoles] was generally accomplished using versatile two or three step reaction protocols with each step having high efficiency. Structure-activity relationship studies established that analog 2i , with 6′-methoxyindole and 2,4,5-trifluorobenzyl substituents, had the greatest potency for activation of N1303K-CFTR, with EC 50 ∼600 nM representing an ∼17-fold improvement over the original compound identified in a small molecule screen. Image 1 [ABSTRACT FROM AUTHOR]

Microsomal epoxide hydrolase (mEH) hydrolyzes a wide range of epoxide containing molecules. Although involved in the metabolism of xenobiotics, recent studies associate mEH with the onset and development of certain disease conditions. This phenomenon is partially attributed to the significant role mEH plays in hydrolyzing endogenous lipid mediators, suggesting more complex and extensive physiological functions. In order to obtain pharmacological tools to further study the biology and therapeutic potential of this enzyme target, we describe the development of highly potent 2-alkylthio acetamide inhibitors of the human mEH with IC 50 values in the low nanomolar range. These are around 2 orders of magnitude more potent than previously obtained primary amine, amide and urea-based mEH inhibitors. Experimental assay results and rationalization of binding through docking calculations of inhibitors to a mEH homology model indicate that an amide connected to an alkyl side chain and a benzyl-thio function as key pharmacophore units. Image 1 • Designed 2-alkylthio acetamide inhibitors of microsomal epoxide hydrolase, low nanomolar IC 50 (0.94–11 nM). • Novel series, 2 orders of magnitude more potent than previous amines, amides and ureas (IC 50 ≥ 480 nM). • Best inhibitors possess amide with bulky α-substituent and, 3–4 bonds away, phenyl ring with lipophilic meta groups. • Docking simulations validate findings, favorable active site interactions (amide H-bonding, π–π stacking). [ABSTRACT FROM AUTHOR]