α-Glucosidase Inhibitors from Two Mangrove-Derived Actinomycetes

Abstract

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.

Genus Acrostalagmus: A Prolific Producer of Natural Products

“…Compound 35 exhibited enzyme inhibition against α -glucosidase (AGS) with an IC 50 value of 164.5 ± 15.5 µM, stronger than that of the positive control acarbose (IC 50 = 422.3 ± 8.44 µM). In addition, 35 showed no cytotoxicity to the human normal hepatocyte (LO2) cells, suggesting its safety to be developed into hypoglycemic agent [ 58 ]. Compound 36 showed antibacterial activity against Bacillus cereus and Proteus vulgaris with MIC values of 1.56 and 3.13 µM (the MIC of positive control ciprofloxacin was 0.78 and 0.20 µM) [ 59 ].…”

Marine-Derived Leads as Anticancer Candidates by Disrupting Hypoxic Signaling through Hypoxia-Inducible Factors Inhibition

“…geldanus var. nova [214], the ansamycin antibiotic geldanamycin (38) (Figure 4) is commonly described in marine strains of Streptomyces [215][216][217][218]. The pivotal work of Whitesell and Neckers demonstrated that 38 inhibited the formation of a v-Src-HSP90 complex through binding to the ATP-binding site in the N-terminal domain of HSP90 [219,220].…”

Screening of α-Glucosidase Inhibitors in Cichorium glandulosum Boiss. et Huet Extracts and Study of Interaction Mechanisms

“…α-glucosidase inhibitors have been identified as a viable option for managing type 2 diabetes mellitus due to their ability to slow carbohydrate digestion and decrease the absorption of monosaccharides. This is due to their ability to maintain a stable blood glucose level within tolerable limits . Therefore, one of the most important ways to stop diabetes from developing is to reduce postprandial hyperglycemia. , α-Glucosidase is found in a wide range of organisms .…”

“…This is due to their ability to maintain a stable blood glucose level within tolerable limits. 2 Therefore, one of the most important ways to stop diabetes from developing is to reduce postprandial hyperglycemia. 3 , 4 α-Glucosidase is found in a wide range of organisms.…”