Preparation of 1,7- and 3,9-Dideazapurines from 2‑Amino-3-iodo- and 3‑Amino-4-iodopyridines and Activated Acetylenes by Conjugate Addition and Copper-Catalyzed Intramolecular Arylation

The conjugate addition of <i>N</i>-formyl derivatives of 2-amino-3-iodo- and 3-amino-4-iodopyridines to acetylenes activated by sulfone, ester, or ketone groups, followed by intramolecular arylation, affords variously substituted 1,7- and 3,9-dideazapurines. The method employs DMF–water as the solvent and copper­(II) acetate as the catalyst for the cyclization step. Neither added ligands nor the exclusion of oxygen is necessary. The process therefore provides a simple, convenient, and inexpensive route to this biologically interesting class of products

Fluxional Cyclic Seleninate Ester: NMR and Computational Studies, Glutathione Peroxidase-like Behavior, and Unexpected Rearrangement

The oxidation of allyl selenide <b>12</b> with hydrogen peroxide produced the corresponding allyl selenurane <b>14</b>, the cyclic seleninate ester <b>4</b>, or the rearranged <i>O</i>-allyl seleninate ester <b>18</b>, dependng on the conditions. Crossover experiments with selenide <b>12</b> and its deuterated crotyl analogue <b>27</b> indicated an intramolecular rearrangement that proceeds by an intramolecular pathway where the allyl or crotyl group is translocated via its distal carbon atom to the hydroxy­methyl functionality. Variable-temperature NMR experiments with cyclic seleninate ester <b>4</b> revealed fluxional behavior at room temperature that was catalyzed by trifluoro­acetic acid. Computational studies indicated an activation energy of 12.3 kcal mol^–1 for hydroxyl interchange at selenium, comparable to the value of 15.5 kcal mol^–1 derived from the NMR experiments. The glutathione peroxidase-like activity of <b>4</b> was measured in an assay where the catalysis of the reduction of hydrogen peroxide with benzyl thiol was monitored by the appearance of dibenzyl disulfide. The catalytic activity of <b>4</b> was double that observed with the unsubstituted seleninate ester <b>2</b> but was limited by the competing accumulation of the relatively inert selenenyl sulfide <b>32</b>, resulting in a deactivation pathway that competes with the primary catalytic cycle

Cyclic Seleninate Esters as Catalysts for the Oxidation of Sulfides to Sulfoxides, Epoxidation of Alkenes, and Conversion of Enamines to α-Hydroxyketones

Cyclic seleninate esters serve as catalysts for the rapid oxidation of sulfides to sulfoxides, alkenes to epoxides, and enamines to α-hydroxyketones. Optimal conditions were found that minimize the overoxidation of the product sulfoxides to sulfones and the hydrolysis of epoxides to diols. In some examples such as styrene derivatives, oxidative cleavage was observed instead of epoxidation. The enamine oxidations proceed via the initial formation of dimeric 2,5-diamino-1,4-dioxane species, which were hydrolyzed <i>in situ</i> to the final products. The structure of one such dimer was confirmed by X-ray crystallography

Cyclic Seleninate Esters as Catalysts for the Oxidation of Sulfides to Sulfoxides, Epoxidation of Alkenes, and Conversion of Enamines to α-Hydroxyketones

Cyclic seleninate esters serve as catalysts for the rapid oxidation of sulfides to sulfoxides, alkenes to epoxides, and enamines to α-hydroxyketones. Optimal conditions were found that minimize the overoxidation of the product sulfoxides to sulfones and the hydrolysis of epoxides to diols. In some examples such as styrene derivatives, oxidative cleavage was observed instead of epoxidation. The enamine oxidations proceed via the initial formation of dimeric 2,5-diamino-1,4-dioxane species, which were hydrolyzed <i>in situ</i> to the final products. The structure of one such dimer was confirmed by X-ray crystallography

NMR and Computational Studies of the Configurational Properties of Spirodioxyselenuranes. Are Dynamic Exchange Processes or Temperature-Dependent Chemical Shifts Involved?

Spirodioxyselenurane <b>4a</b> and several substituted analogs revealed unexpected ¹H NMR behavior. The diastereotopic methylene hydrogens of <b>4a</b> appeared as an AB quartet at low temperature that coalesced to a singlet upon warming to 267 K, suggesting a dynamic exchange process with a relatively low activation energy. However, DFT computational investigations indicated high activation energies for exchange via inversion through the selenium center and for various pseudorotation processes. Moreover, the NMR behavior was unaffected by the presence of water or acid catalysts, thereby ruling out reversible Se–O or benzylic C–O cleavage as possible stereomutation pathways. Remarkably, when <b>4a</b> was heated beyond 342 K, the singlet was transformed into a new AB quartet. Further computations indicated that a temperature dependence of the chemical shifts of the diastereotopic protons results in convergence upon heating, followed by crossover and divergence at still higher temperatures. The NMR behavior is therefore not due to dynamic exchange processes, but rather to temperature dependence of the chemical shifts of the diastereotopic hydrogens, which are coincidentally equivalent at intermediate temperatures. These results suggest the general need for caution in ascribing the coalescence of variable-temperature NMR signals of diastereotopic protons to dynamic exchange processes that could instead be due to temperature-dependent chemical shifts and highlight the importance of corroborating postulated exchange processes through additional computations or experiments wherever possible

Effects of Methoxy Substituents on the Glutathione Peroxidase-like Activity of Cyclic Seleninate Esters

Cyclic seleninate esters function as mimetics of the antioxidant enzyme glutathione peroxidase and catalyze the reduction of hydrogen peroxide with a stoichiometric thiol. While a single electron-donating methoxy substituent <i>para</i> to the selenium atom enhances the catalytic activity, <i>m</i>-methoxy groups have little effect and <i>o</i>-methoxy substituents suppress activity. The effects of multiple methoxy groups are not cumulative. This behavior can be rationalized by opposing mesomeric and steric effects. Oxidation of the product disulfide via its thiolsulfinate was also observed

Enhanced Glutathione Peroxidase Activity of Water-Soluble and Polyethylene Glycol-Supported Selenides, Related Spirodioxyselenuranes, and Pincer Selenuranes

Diaryl selenides containing <i>o</i>-hydroxymethylene substituents function as peroxide-destroying mimetics of the antioxidant selenoenzyme glutathione peroxidase (GPx), via oxidation to the corresponding spirodioxyselenuranes with hydrogen peroxide and subsequent reduction back to the original selenides with glutathione. Parent selenides with 3-hydroxypropyl or 2,3-dihydroxypropyl groups produced the novel compounds <b>10</b> and <b>11</b>, respectively, with greatly improved aqueous solubility and catalytic activity. The phenolic derivative <b>28</b> displayed similarly ameliorated properties and also modest radical-inhibiting antioxidant activity, as evidenced by an assay based on phenolic hydrogen atom transfer to the stable free radical DPPH. In contrast, several selenides that afford pincer selenuranes (e.g., <b>20</b> and <b>21</b>) instead of spiroselenuranes upon oxidation showed inferior catalytic activity. Several selenide analogues were attached to polyethylene glycol (PEG) oligomers, as PEG substituents can improve water solubility and bioavailability, while retarding clearance. Again, the PEG derivatives afforded remarkable activity when oxidation generated spirodioxyselenuranes and diminished activity when pincer compounds were produced. Several such compounds proved to be ca. 10- to 100-fold catalytically superior to the diaryl selenides and their spirodioxyselenurane counterparts investigated previously. Finally, an NMR-based assay employing glutathione in D₂O was designed to accommodate the faster reacting water-soluble mimetics and to more closely duplicate in vivo conditions

The concentration-response relationship of MC-II-157c.

<p>Panel A shows the raw currents elicited by the protocol shown in the inset. Panels B-E show the concentration-response relationships for mean tail current amplitude (Panel B), mean Δ shift in V_1/2 of activation (Panel C), mean Δ shift in V_1/2 of inactivation in Panel D and mean prolongation of the deactivation in Panel E.</p

Schematic representation of the studied compounds topology showing the different R1, R2 and R3.

<p>The groups were identified to be critical determinants of high-affinity/high-specificity binding of activator to site located in S4–S5 linker of the hERG1 channel. Atom N* depicted in blue represents tentative protonation site. The black arrow represents the versor (∧b) perpendicular to the plane defined by atoms N, C, O, N, C and O of the polyamide moiety, common structure element present in all molecules structure. Top panel shows NS-1643 and chemical group identification. Bottom panel illustrates compound groups synthesized.</p

Pharmacologic response (Δ) to NS1643 (open white bars at 10 µM), MC-II-157c (black bars at 10 µM) and MC-II-159C (grey bars at 10 µM) are compared in wild type (WT) versus E544L.

<p>Panel A: In WT, NS1643 MC-II-157c and MC-II-159c, all shift voltage-dependence of activation and Panel B: slow deactivation. (top) In E544L, pharmacologic response to NS1643 is exaggerated whereas Δ response to MC-II-157c and Δ MC-II-159c were markedly diminished. (bottom-left) Panel C: In terms of amplitude of the tail current, in E544L response to NS1643 is exaggerated whereas response to MC-II-157c and MC-II-159C is markedly diminished. Pharmacologic response in terms of inactivation is complex. Panel D: In WT, MC-II-157c shifts voltage-dependence of inactivation to depolarized potentials whereas MC-II-159C shifts voltage dependence to hyperpolarized potentials. Pharmacologic response to NS1643 is exaggerated in E544L whereas for MC-II-157c and MC-II-159C responses are diminished. (bottom-right) * evaluates the statistical significance of the Δ response to NS1643 compared to Δ response to MC-II-157c or Δ response MC-II-159c. * designates p<0.05; ** designates p<0.01. n values were: For Activation panel in WT n = 10,8 and 3; for E544L n = 9,6 and 3. For deactivation in WT n = 8,8,3 respectively and for E544L n = 4,6,3. For tail current amplitude, in WT n = 9,8,3 and in E544L n = 8,6,2. For inactivation, n = 9,8,3 and for E544L n = 5,6,2.</p