Harmonizing neuropathic pain research: outcomes of the London consensus meeting on peripheral tissue studies

Neuropathic pain remains difficult to treat, with drug development hampered by an incomplete understanding of the pathogenesis of the condition, as well as a lack of biomarkers. The problem is compounded by the scarcity of relevant human peripheral tissues, including skin, nerves, and dorsal root ganglia. Efforts to obtain such samples are accelerating, increasing the need for standardisation across laboratories. In this white paper, we report on a consensus meeting attended by neuropathic pain experts, designed to accelerate protocol alignment and harmonization of studies involving relevant peripheral tissues. The meeting was held in London in March 2024 and attended by 28 networking partners, including industry and patient representatives. We achieved consensus on minimal recommended phenotyping, harmonised wet laboratory protocols, statistical design, reporting, and data sharing. Here, we also share a variety of relevant standard operating procedures as supplementary protocols. We envision that our recommendations will help unify human tissue research in the field and accelerate our understanding of how abnormal interactions between sensory neurons and their local peripheral environment contribute towards neuropathic pain

Singlet oxygen and natural substrates: functional polyunsaturated models for the photooxidative degradation of carotenoids

The primary chemical reactions of singlet molecular oxygen with polyunsaturated carotenoids are the focus of this research report. Model compounds that exhibit electronic properties and substituent pattern similar to natural carotenes, xanthophylls or apocarotenoids, respectively, were investigated with regard to photooxygenation reactivity. For dienes and trienes as substrates, high tandem reactivity was observed and hydroperoxy-endoperoxides were isolated as the secondary products of singlet oxygen reaction. The electronic gem-effect on the regioselectivity of the ene reaction is conserved also in vinylogous positions and thus appears to originate from a radical-stabilizing effect. In an attempt to combine different peroxide groups derived from natural products as a tool for new pharmaceutically active products, a dyade synthesis of an artemisinine-safranol with subsequent singlet oxygen addition was realized

ChemInform Abstract: Singlet Oxygen and Natural Substrates: Functional Polyunsaturated Models for the Photooxidative Degradation of Carotenoids

The primary chemical reactions of singlet molecular oxygen with polyunsaturated carotenoids are the focus of this research report. Model compounds that exhibit electronic properties and substituent pattern similar to natural carotenes, xanthophylls or apocarotenoids, respectively, were investigated with regard to photooxygenation reactivity. For dienes and trienes as substrates, high tandem reactivity was observed and hydroperoxy-endoperoxides were isolated as the secondary products of singlet oxygen reaction. The electronic gem-effect on the regioselectivity of the ene reaction is conserved also in vinylogous positions and thus appears to originate from a radical-stabilizing effect. In an attempt to combine different peroxide groups derived from natural products as a tool for new pharmaceutically active products, a dyade synthesis of an artemisinine-safranol with subsequent singlet oxygen addition was realized

Ene-Diene Transmissive Cycloaddition Reactions with Singlet Oxygen: The Vinylogous Gem Effect and Its Use for Polyoxyfunctionalization of Dienes

The singlet oxygen reactivities and regioselectivities of the model compounds 1b-d were compared with those of the geminal (gem) selectivity model ethyl tiglate (1a). The kinetic cis effect is k(E)/k(Z) = 5.2 for the tiglate/angelate system 1a/1a' without a change in the high gem regioselectivity. Further conjugation to vinyl groups enabled mode-selective processes, namely, [4 + 2] cycloadditions versus ene reactions. The site-specific effects of methylation on the mode selectivity and the regioselectivity of the ene reaction were studied for dienes 1e-g. A vinylogous gem effect was observed for the gamma,delta-dimethylated and alpha,gamma,delta-trimethylated substrates 1h and 1i, respectively. The corresponding phenylated substrates 1j-1 showed similar mode selectivity, as monomethylated 1j exhibited exclusively [4 + 2] reactivity while the tandem products 12 and 14 were isolated from the di- and trimethylated substrates 1k and 1l, respectively. The vinylogous gem effect favors the formation of 1,3-dienes from the substrates, and thus, secondary singlet oxygen addition was observed to give hydroperoxy-1,2-dioxenes 19 and 20 in an ene-diene transmissive cycloaddition sequence. These products were reduced to give alcohols (16, 17, and 18) or furans (24 and 25), respectively, or treated with titanium(IV) alkoxides to give the epoxy alcohols 26 and 27. The vinylogous gem effect is rationalized by DFT calculations showing that biradicals are the low-energy intermediates and that no reaction path bifurcations compete

Spirofused and Annulated 1,2,4-Trioxepane-, 1,2,4-Trioxocane-, and 1,2,4-Trioxonane-Cyclohexadienones: Cyclic Peroxides with Unusual Ring Conformation Dynamics

C3- or C4-hydroxyalkylated phenols are highly reactive towards peroxidation with oxone, which results in the formation of tertiary C3 hydroperoxides. This reaction can also be performed with photochemically generated singlet oxygen. However, other characteristic singlet oxygen reactions do not proceed with caroate. The initially formed hydroperoxides cyclize in the presence of a Lewis acid catalyst based on boron, indium, or iron to give spiroannulated peroxides. These exhibit restricted ring inversion whereas larger nine-membered-ring peroxides are thermally less stable and show higher ring flexibility (according to NMR analysis)

Ene–Diene Transmissive Cycloaddition Reactions with Singlet Oxygen: The <i>Vinylogous Gem Effect</i> and Its Use for Polyoxyfunctionalization of Dienes

The singlet oxygen reactivities and regioselectivities of the model compounds <b>1b</b>–<b>d</b> were compared with those of the geminal (gem) selectivity model ethyl tiglate (<b>1a</b>). The kinetic cis effect is <i>k</i>_<i>E</i>/<i>k</i>_<i>Z</i> = 5.2 for the tiglate/angelate system <b>1a</b>/<b>1a′</b> without a change in the high gem regioselectivity. Further conjugation to vinyl groups enabled mode-selective processes, namely, [4 + 2] cycloadditions versus ene reactions. The site-specific effects of methylation on the mode selectivity and the regioselectivity of the ene reaction were studied for dienes <b>1e</b>–<b>g</b>. A vinylogous gem effect was observed for the γ,δ-dimethylated and α,γ,δ-trimethylated substrates <b>1h</b> and <b>1i</b>, respectively. The corresponding phenylated substrates <b>1j</b>–<b>l</b> showed similar mode selectivity, as monomethylated <b>1j</b> exhibited exclusively [4 + 2] reactivity while the tandem products <b>12</b> and <b>14</b> were isolated from the di- and trimethylated substrates <b>1k</b> and <b>1l</b>, respectively. The vinylogous gem effect favors the formation of 1,3-dienes from the substrates, and thus, secondary singlet oxygen addition was observed to give hydroperoxy-1,2-dioxenes <b>19</b> and <b>20</b> in an ene–diene transmissive cycloaddition sequence. These products were reduced to give alcohols (<b>16</b>, <b>17</b>, and <b>18</b>) or furans (<b>24</b> and <b>25</b>), respectively, or treated with titanium­(IV) alkoxides to give the epoxy alcohols <b>26</b> and <b>27</b>. The vinylogous gem effect is rationalized by DFT calculations showing that biradicals are the low-energy intermediates and that no reaction path bifurcations compete

Ene–Diene Transmissive Cycloaddition Reactions with Singlet Oxygen: The <i>Vinylogous Gem Effect</i> and Its Use for Polyoxyfunctionalization of Dienes

The singlet oxygen reactivities and regioselectivities of the model compounds <b>1b</b>–<b>d</b> were compared with those of the geminal (gem) selectivity model ethyl tiglate (<b>1a</b>). The kinetic cis effect is <i>k</i>_<i>E</i>/<i>k</i>_<i>Z</i> = 5.2 for the tiglate/angelate system <b>1a</b>/<b>1a′</b> without a change in the high gem regioselectivity. Further conjugation to vinyl groups enabled mode-selective processes, namely, [4 + 2] cycloadditions versus ene reactions. The site-specific effects of methylation on the mode selectivity and the regioselectivity of the ene reaction were studied for dienes <b>1e</b>–<b>g</b>. A vinylogous gem effect was observed for the γ,δ-dimethylated and α,γ,δ-trimethylated substrates <b>1h</b> and <b>1i</b>, respectively. The corresponding phenylated substrates <b>1j</b>–<b>l</b> showed similar mode selectivity, as monomethylated <b>1j</b> exhibited exclusively [4 + 2] reactivity while the tandem products <b>12</b> and <b>14</b> were isolated from the di- and trimethylated substrates <b>1k</b> and <b>1l</b>, respectively. The vinylogous gem effect favors the formation of 1,3-dienes from the substrates, and thus, secondary singlet oxygen addition was observed to give hydroperoxy-1,2-dioxenes <b>19</b> and <b>20</b> in an ene–diene transmissive cycloaddition sequence. These products were reduced to give alcohols (<b>16</b>, <b>17</b>, and <b>18</b>) or furans (<b>24</b> and <b>25</b>), respectively, or treated with titanium­(IV) alkoxides to give the epoxy alcohols <b>26</b> and <b>27</b>. The vinylogous gem effect is rationalized by DFT calculations showing that biradicals are the low-energy intermediates and that no reaction path bifurcations compete