Nα-arylsulfonyl histamines as selective β-glucosidase inhibitors† † Electronic supplementary information (ESI) available. See DOI: 10.1039/c8ra06625f
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ABSTRACT:
SUBMITTER: Salazar M
PROVIDER: S-EPMC9088825 | biostudies-literature | 2018 Oct
REPOSITORIES: biostudies-literature
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Project description:A series of simple N-arylbenzenesulfonyl histamine derivatives were prepared and screened against α-glucosidase. Inhibition was in the micromolar range for several N α,N τ-di-arylsulfonyl compounds, with N α,N τ-di-4-trifluorobenzenesulfonyl histamine (IId) being the best inhibitor. Compound IId is a reversible and competitive α-glucosidase inhibitor, and presented good selectivity with respect to other target enzymes, including β-glucosidase and α-amylase, and interesting predicted physicochemical properties. Docking studies have been run to postulate ligand-enzyme interactions to account for the experimental results. In vivo, compound IId produced a similar hypoglycemic effect to acarbose with half of its dose.
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Project description:Natural meroterpenes derived from phloroglucinols and β-caryophyllene have shown high inhibitory activity against α-glucosidase or cancer cells, however, the chemical diversity of this type of skeletons in Nature is limited. To expand the chemical space and explore their inhibitory activities against α-glucosidase (EC 3.2.1.20), we employed β-caryophyllene and some natural moieties (4-hydroxycoumarins, lawsone or syncarpic acid) to synthesize new types of meroterpene-like skeletons. All the products (including side products) were isolated and characterized by NMR, HR-MS, and ECD. In total, 17 products (representing seven scaffolds) were generated through a one-pot procedure. Most products (12 compounds) showed more potential activity (IC50 < 25 μM) than the positive controls (acarbose and genistein, IC50 58.19, and 54.74 μM, respectively). Compound 7 exhibited the most potent inhibition of α-glucosidase (IC50 3.56 μM) in a mixed-type manner. The CD analysis indicated that compound 7 could bind to α-glucosidase and influence the enzyme's secondary structure. Compound 7 could serve as a new type of template compound to develop α-glucosidase inhibitors. Full investigation of a biomimic reaction can be used as a concise strategy to explore diverse natural-like skeletons and search for novel lead compounds.
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Project description:α-Glucosidase (AGS) is a therapeutic target for Type 2 diabetes mellitus (T2DM) that tends to complicate with other diseases. Some medications for the treatment of T2DM complications have the risk of inducing severe adverse reactions such as diarrhea via the metabolism of intestinal bacterial β-glucuronidase (BGUS). The development of new AGS and/or BGUS inhibitors may improve the therapeutic effects of T2DM and its complications. The present work focused on the isolation and characterization of AGS and/or BGUS inhibitors from the medicinal plant Schisandra sphaerandra. A total of eight compounds were isolated and identified. Sphaerandralide A (1) was obtained as a previously undescribed triterpenoid, which may have chemotaxonomy significance in the authentication of the genus Schisandra and Kadsura. 2'-acetyl-4',4-dimethoxybiphenyl-2-carbaldehyde (8) was obtained from a plant source for the first time, while compounds 2-7 were isolated from S. sphaerandra for the first time. In the in vitro assay, compounds 1-5 showed potent to moderate activity against AGS. Interestingly, compound 3 also exhibited significant BGUS inhibitory activity, demonstrating the potential of being developed as a bifunctional inhibitor that may find application in the therapy of T2DM and/or the diarrhea induced by medications for the treatment of T2DM complications.
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Project description:α-Glucosidase (AGS) inhibitors have been regarded as an ideal target for the management of type 2 diabetes mellitus (T2DM) since they can maintain an acceptable blood glucose level by delaying the digestion of carbohydrates and diminishing the absorption of monosaccharides. In the process of our endeavor in mining AGS inhibitors from natural sources, the culture broth of two mangrove-derived actinomycetes Streptomyces sp. WHUA03267 and Streptomyces sp. WHUA03072 exhibited an apparent inhibitory activity against AGS. A subsequent chemical investigation into the two extracts furnished 28 secondary metabolites that were identified by spectroscopic methods as two previously undescribed linear polyketides 1-2, four benzenoid ansamycins 3-6, fourteen cyclodipeptides 7-18, one prenylated indole derivative 19, two fusicoccane-type diterpenoids 20-21, two hydroxamate siderophore 22-23, and five others 24-28. Among all of the isolates, 11 and 24 were obtained from actinomycetes for the first time, while 20-21 had never been reported to occur in a marine-derived microorganism previously. In the in vitro AGS inhibitory assay, compounds 3, 8, 9, 11, 14, 16, and 17 exhibited potent to moderate activity with IC50 values ranging from 35.76 ± 0.40 to 164.5 ± 15.5 μM, as compared with acarbose (IC50 = 422.3 ± 8.4 μM). The AGS inhibitory activity of 3, 9, 14, 16, and 17 was reported for the first time. In particular, autolytimycin (3) represented the first ansamycin derivative reported to possess the AGS inhibitory activity. Kinetics analysis and molecular docking were performed to determine the inhibition types and binding modes of these inhibitors, respectively. In the MTT assay, 3, 8, 9, 11, 14, 16, and 17 exhibited no apparent cytotoxicity to the human normal hepatocyte (LO2) cells, suggesting satisfactory safety of these AGS inhibitors.
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