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[Display omitted] • Obovatol's role as α-glucosidase (α-Glu) and α-amylase (α-Amy) inhibitor was assessed. • Synthesis of ten obovatol analogous for α-Glu and α-Amy inhibition. • Compounds 1 , 11 , 22 , 26 and 27 were effective inhibitors and were tested for cytotoxicity. • Interaction with the enzyme was studied by CD analysis, SPR imaging and molecular docking studies. • Obovatol-based neolignans are promising structures for developing novel hypoglycemic drugs. Diabetes mellitus is a metabolic disease characterized by hyperglycemia, which can be counteracted by the inhibition of α-glucosidase (α-Glu) and α-amylase (α-Amy), enzymes responsible for the hydrolysis of carbohydrates. In recent decades, many natural compounds and their bioinspired analogues have been studied as α-Glu and α-Amy inhibitors. However, no studies have been devoted to the evaluation of α-Glu and α-Amy inhibition by the neolignan obovatol (1). In this work, we report the synthesis of 1 and a library of new analogues. The synthesis of these compounds was achieved by implementing methodologies based on: phenol allylation, Claisen/Cope rearrangements, methylation, Ullmann coupling, demethylation, phenol oxidation and Michael-type addition. Obovatol (1) and ten analogues were evaluated for their in vitro inhibitory activity towards α-Glu and α-Amy. Our investigation highlighted that the naturally occurring 1 and four neolignan analogues (11 , 22 , 26 and 27) were more effective inhibitors than the hypoglycemic drug acarbose (α-Amy: 34.6 µM; α-Glu: 248.3 µM) with IC 5O value of 6.2–23.6 µM toward α-Amy and 39.8–124.6 µM toward α-Glu. Docking investigations validated the inhibition outcomes, highlighting optimal compatibility between synthesized neolignans and both the enzymes. Concurrently circular dichroism spectroscopy detected the conformational changes in α-Glu induced by its interaction with the studied neolignans. Detailed studies through fluorescence measurements and kinetics of α-Glu and α-Amy inhibition also indicated that 1 , 11 , 22 , 26 and 27 have the greatest affinity for α-Glu and 1 , 11 and 27 for α-Amy. Surface plasmon resonance imaging (SPRI) measurements confirmed that among the compounds studied, the neolignan 27 has the greater affinity for both enzymes, thus corroborating the results obtained by kinetics and fluorescence quenching. Finally, in vitro cytotoxicity of the investigated compounds was tested on human colon cancer cell line (HCT-116). All these results demonstrate that these obovatol-based neolignan analogues constitute promising candidates in the pursuit of developing novel hypoglycemic drugs. [ABSTRACT FROM AUTHOR]

Many natural products of plant or microbial origins are derived from enzymatic dearomative oxygenation of 2‐alkylphenolic precursors into 6‐alkyl‐6‐hydroxycyclohexa‐2,4‐dienones. These so‐called ortho‐quinols cyclodimerize via a remarkably selective bispericyclic Diels–Alder reaction. Whether or not the intervention of catalytic or dirigent proteins is involved during this final step of the biosynthesis of these natural products, this cyclodimerization of ortho‐quinols can be chemically reproduced in the laboratory with the same strict level of site‐specific regioselectivity and stereoselectivity. This unique yet unified process, which finds its rationale in the inherent chemical reactivity of those ortho‐quinols, is illustrated herein by an efficient and bioinspired first chemical synthesis of one of the most structurally complex and synthetically challenging examples of such natural cyclodimers, the bisditerpenoid (+)‐maytenone. [ABSTRACT FROM AUTHOR]

Many natural products of plant or microbial origins are derived from enzymatic dearomative oxygenation of 2‐alkylphenolic precursors into 6‐alkyl‐6‐hydroxycyclohexa‐2,4‐dienones. These so‐called ortho‐quinols cyclodimerize via a remarkably selective bispericyclic Diels–Alder reaction. Whether or not the intervention of catalytic or dirigent proteins is involved during this final step of the biosynthesis of these natural products, this cyclodimerization of ortho‐quinols can be chemically reproduced in the laboratory with the same strict level of site‐specific regioselectivity and stereoselectivity. This unique yet unified process, which finds its rationale in the inherent chemical reactivity of those ortho‐quinols, is illustrated herein by an efficient and bioinspired first chemical synthesis of one of the most structurally complex and synthetically challenging examples of such natural cyclodimers, the bisditerpenoid (+)‐maytenone. [ABSTRACT FROM AUTHOR]

Under high pressure, this transition state leads to the product, the natural (+)-maytenone, which was first isolated from the plant I Maytenus dispermus i , here appearing in the background image. Asymmetric synthesis, cycloaddition, hypervalent compounds, total synthesis, transition states Keywords: asymmetric synthesis; cycloaddition; hypervalent compounds; total synthesis; transition states EN asymmetric synthesis cycloaddition hypervalent compounds total synthesis transition states 15111 15111 1 06/23/21 20210625 NES 210625 B From the teaching class b with the bispericyclic Diels-Alder reaction of I ortho i -quinols drawn on the chalk board to the laboratory with the (+)-ferruginol substrate and a chiral bisiodyl reagent in the flask: The single I ortho i -quinol diastereomer thus produced combines in pairs to reach a I C i SB 2 sb -symmetric transition state in which [4+2] and [2+4] processes are equivalent, as described by Laurent Pouységu, Stéphane Quideau, and co-workers in their Research Article on page 14967. [Extracted from the article]

Keywords: asymmetric synthesis; cycloaddition; hypervalent compounds; total synthesis; transition states EN asymmetric synthesis cycloaddition hypervalent compounds total synthesis transition states 15239 15239 1 06/23/21 20210625 NES 210625 B Von der Kreidetafel b mit der bispericyclischen Diels-Alder-Reaktion von I ortho i -Chinolen zum Labor mit dem (+)-Ferruginol-Substrat und einem chiralen Bisiodyl-Reagenz im Kolben: Die so erzeugten I ortho- i Chinol-Diastereomere verbinden sich paarweise zu einem C SB 2 sb -symmetrischen Übergangszustand, in dem [4+2]- und [2+4]-Prozesse äquivalent sind, wie Laurent Pouységu, Stéphane Quideau et al. im Forschungsartikel auf S. 15094 berichten. Innenrücktitelbild: Bispericyclic Diels-Alder Dimerization of ortho-Quinols in Natural Product (Bio)Synthesis: Bioinspired Chemical 6-Step Synthesis of (+)-Maytenone (Angew. Asymmetric synthesis, cycloaddition, hypervalent compounds, total synthesis, transition states. [Extracted from the article]

Diabetes mellitus is a metabolic disorder characterized by hyperglycemia, which can be counteracted by inhibition of α-glucosidase and α-amylase, both involved in the carbohydrate metabolism. Fourteen C -glucosidic ellagitannins and three galloylated glucoses were studied as potential α-glucosidase and α-amylase inhibitors. Most of the compounds were found to be moderate inhibitors of α-amylase, but potent inhibitors of α-glucosidase, showing low-micromolar IC 50 values, far lower than that of the antidiabetic drug acarbose. This selectivity can be an advantage for their possible application as functional food ingredients with anti-diabetic properties because strong α-amylase inhibition generally causes undesired side effects. The best inhibitors were selected for further studies. Intrinsic fluorescence measurements confirmed their high affinity towards α-glucosidase, highlighting a static quenching mechanism. Circular dichroism measurements and kinetics of inhibition indicated that the most active C -glucosidic ellagitannin roburin D (RobD) is a competitive inhibitor, whereas α-pentagalloylglucose (α-PGG) acts as a mixed-type inhibitor. [ABSTRACT FROM AUTHOR]