The total synthesis of sevanol, a novel lignan isolated from the thyme plant (Thymus armeniacus)

Belozerova, Olga A.; Дейгин, В. И.; Khrushchev, A. Y.; Dubinnyi, Maxim A.; Kublitski, Vadim S.

doi:10.1016/j.tet.2018.02.005

Cited by 4 publications

(12 citation statements)

References 22 publications

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“…Thus, we achieved a more optimized route to produce key intermediate 4. Due to the use of acetyl protecting groups for the phenolic hydroxyls of intermediates 2 and 3, the overall yield of preparation 4 was significantly increased from 7% to 30% compared to the method we described earlier [27].…”

Section: Sevanol Productionmentioning

confidence: 94%

“…We modified the carboxylic part of I and obtained sevanol derivatives: s788 (II), s590 (III) and epiphyllic acid EA (IV) (Figure 1). The synthesis of sevanol (I) was completed based on the method described previously [27]. The synthetic path included the parallel synthesis of two molecules: the t-butyl isocitrate 1 and the suitably protected caffeic acid 2 (Scheme I).…”

Section: Sevanol Productionmentioning

confidence: 99%

“…The method of obtaining the intermediate 4 included removing protecting groups (PG) from the phenolic hydroxyls of 3. Our careful search for the optimal protecting group has been discussed elsewhere [27]. The synthesis of sevanol (I) was completed based on the method described previously [27].…”

Section: Sevanol Productionmentioning

confidence: 99%

“…Our careful search for the optimal protecting group has been discussed elsewhere [27]. The synthesis of sevanol (I) was completed based on the method described previously [27]. The synthetic path included the parallel synthesis of two molecules: the t-butyl isocitrate 1 and the suitably protected caffeic acid 2 (Scheme 1).…”

Section: Sevanol Productionmentioning

confidence: 99%

“…The crucial coupling step of compound 4 was carried out according to the procedure we described previously [27]. The optimal reaction medium was carefully selected, and included the dimerization of compound 4 with 2.5 equivalents of iron (III) chloride in acetonitrile in the absence of light at 5 • C for 2 h. After treating the resulting intermediate with 80% aqueous TFA for 1 h at 50 • C, a crude deprotected substance of the target sevanol I was identified by 1 H NMR spectra.…”

Section: Sevanol Productionmentioning

confidence: 99%

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Sevanol and Its Analogues: Chemical Synthesis, Biological Effects and Molecular Docking

et al. 2020

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Among acid-sensing ion channels (ASICs), ASIC1a and ASIC3 subunits are the most widespread and prevalent in physiological and pathophysiological conditions. They participate in synaptic plasticity, learning and memory, as well as the perception of inflammatory and neurological pain, making these channels attractive pharmacological targets. Sevanol, a natural lignan isolated from Thymus armeniacus, inhibits the activity of ASIC1a and ASIC3 isoforms, and has a significant analgesic and anti-inflammatory effect. In this work, we described the efficient chemical synthesis scheme of sevanol and its analogues, which allows us to analyze the structure–activity relationships of the different parts of this molecule. We found that the inhibitory activity of sevanol and its analogues on ASIC1a and ASIC3 channels depends on the number and availability of the carboxyl groups of the molecule. At the structural level, we predicted the presence of a sevanol binding site based on the presence of molecular docking in the central vestibule of the ASIC1a channel. We predicted that this site could also be occupied in part by the FRRF-amide peptide, and the competition assay of sevanol with this peptide confirmed this prediction. The intravenous (i.v.), intranasal (i.n.) and, especially, oral (p.o.) administration of synthetic sevanol in animal models produced significant analgesic and anti-inflammatory effects. Both non-invasive methods of sevanol administration (i.n. and p.o.) showed greater efficacy than the invasive (i.v.) method, thus opening new horizons for medicinal uses of sevanol.

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Section: Sevanol Productionmentioning

confidence: 94%

Section: Sevanol Productionmentioning

confidence: 99%

Section: Sevanol Productionmentioning

confidence: 99%

Section: Sevanol Productionmentioning

confidence: 99%

Section: Sevanol Productionmentioning

confidence: 99%

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Sevanol and Its Analogues: Chemical Synthesis, Biological Effects and Molecular Docking

et al. 2020

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Lignans as Pharmacological Agents in Disorders Related to Oxidative Stress and Inflammation: Chemical Synthesis Approaches and Biological Activities

Osmakov

Kalinovskii

Belozerova

et al. 2022

IJMS

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Plant lignans exhibit a wide range of biological activities, which makes them the research objects of potential use as therapeutic agents. They provide diverse naturally-occurring pharmacophores and are available for production by chemical synthesis. A large amount of accumulated data indicates that lignans of different structural groups are apt to demonstrate both anti-inflammatory and antioxidant effects, in many cases, simultaneously. In this review, we summarize the comprehensive knowledge about lignan use as a bioactive agent in disorders associated with oxidative stress and inflammation, pharmacological effects in vitro and in vivo, molecular mechanisms underlying these effects, and chemical synthesis approaches. This article provides an up-to-date overview of the current data in this area, available in PubMed, Scopus, and Web of Science databases, screened from 2000 to 2022.

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Dual Modulator of ASIC Channels and GABAA Receptors from Thyme Alters Fear-Related Hippocampal Activity

Kalinovskii,

Pushkarev,

Mikhailenko

et al. 2023

IJMS

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Acid-sensing ion channels (ASICs) are proton-gated ion channels that mediate nociception in the peripheral nervous system and contribute to fear and learning in the central nervous system. Sevanol was reported previously as a naturally-occurring ASIC inhibitor from thyme with favorable analgesic and anti-inflammatory activity. Using electrophysiological methods, we found that in the high micromolar range, the compound effectively inhibited homomeric ASIC1a and, in sub- and low-micromolar ranges, positively modulated the currents of α1β2γ2 GABAA receptors. Next, we tested the compound in anxiety-related behavior models using a targeted delivery into the hippocampus with parallel electroencephalographic measurements. In the open field, 6 µM sevanol reduced both locomotor and θ-rhythmic activity similar to GABA, suggesting a primary action on the GABAergic system. At 300 μM, sevanol markedly suppressed passive avoidance behavior, implying alterations in conditioned fear memory. The observed effects could be linked to distinct mechanisms involving GABAAR and ASIC1a. These results elaborate the preclinical profile of sevanol as a candidate for drug development and support the role of ASIC channels in fear-related functions of the hippocampus.

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The total synthesis of sevanol, a novel lignan isolated from the thyme plant (Thymus armeniacus)

Cited by 4 publications

References 22 publications

Sevanol and Its Analogues: Chemical Synthesis, Biological Effects and Molecular Docking

Sevanol and Its Analogues: Chemical Synthesis, Biological Effects and Molecular Docking

Lignans as Pharmacological Agents in Disorders Related to Oxidative Stress and Inflammation: Chemical Synthesis Approaches and Biological Activities

Dual Modulator of ASIC Channels and GABAA Receptors from Thyme Alters Fear-Related Hippocampal Activity

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