1. Synthesis of obovatol and related neolignan analogues as α-glucosidase and α-amylase inhibitors.
- Author
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Sciacca C, Cardullo N, Pulvirenti L, Travagliante G, D'Urso A, D'Agata R, Peri E, Cancemi P, Cornu A, Deffieux D, Pouységu L, Quideau S, and Muccilli V
- Subjects
- Structure-Activity Relationship, Humans, Molecular Structure, Dose-Response Relationship, Drug, Molecular Docking Simulation, Hypoglycemic Agents pharmacology, Hypoglycemic Agents chemical synthesis, Hypoglycemic Agents chemistry, Enzyme Inhibitors pharmacology, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, alpha-Amylases antagonists & inhibitors, alpha-Amylases metabolism, alpha-Glucosidases metabolism, Glycoside Hydrolase Inhibitors chemical synthesis, Glycoside Hydrolase Inhibitors pharmacology, Glycoside Hydrolase Inhibitors chemistry, Lignans pharmacology, Lignans chemistry, Lignans chemical synthesis
- Abstract
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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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