Synthesis and Structure−Activity Relationship Study of Antidiabetic Penta-<i>O</i>-galloyl-<scp>d</scp>-glucopyranose and Its Analogues

Ren, Yulin; Himmeldirk, Klaus; Chen, Xiaozhuo

doi:10.1021/jm060087k

Cited by 75 publications

(85 citation statements)

References 51 publications

(114 reference statements)

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“…We recently reported that a-PGG inhibits cancer cells through IR-mediated apoptosis in human colon cancer RKO cells (27). In the process of structural and function optimization for the anti-diabetes activity of PGG-derived compounds, numerous glucose transport inhibitory compounds were synthesized and tested in cancer cells (21,28). These compounds inhibited cancer cell growth in a glucose deprivation-like manner (20).…”

Section: Resultsmentioning

confidence: 99%

A Small-Molecule Inhibitor of Glucose Transporter 1 Downregulates Glycolysis, Induces Cell-Cycle Arrest, and Inhibits Cancer Cell Growth In Vitro and In Vivo

Liu

Cao

Zhang

et al. 2012

Molecular Cancer Therapeutics

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The functional and therapeutic importance of the Warburg effect is increasingly recognized, and glycolysis has become a target of anticancer strategies. We recently reported the identification of a group of novel small compounds that inhibit basal glucose transport and reduce cancer cell growth by a glucose deprivation-like mechanism. We hypothesized that the compounds target Glut1 and are efficacious in vivo as anticancer agents. Here, we report that a novel representative compound WZB117 not only inhibited cell growth in cancer cell lines but also inhibited cancer growth in a nude mouse model. Daily intraperitoneal injection of WZB117 at 10 mg/kg resulted in a more than 70% reduction in the size of human lung cancer of A549 cell origin. Mechanism studies showed that WZB117 inhibited glucose transport in human red blood cells (RBC), which express Glut1 as their sole glucose transporter. Cancer cell treatment with WZB117 led to decreases in levels of Glut1 protein, intracellular ATP, and glycolytic enzymes. All these changes were followed by increase in ATPsensing enzyme AMP-activated protein kinase (AMPK) and declines in cyclin E2 as well as phosphorylated retinoblastoma, resulting in cell-cycle arrest, senescence, and necrosis. Addition of extracellular ATP rescued compound-treated cancer cells, suggesting that the reduction of intracellular ATP plays an important role in the anticancer mechanism of the molecule. Senescence induction and the essential role of ATP were reported for the first time in Glut1 inhibitor-treated cancer cells. Thus, WZB117 is a prototype for further development of anticancer therapeutics targeting Glut1-mediated glucose transport and glucose metabolism.

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Section: Resultsmentioning

confidence: 99%

A Small-Molecule Inhibitor of Glucose Transporter 1 Downregulates Glycolysis, Induces Cell-Cycle Arrest, and Inhibits Cancer Cell Growth In Vitro and In Vivo

Liu

Cao

Zhang

et al. 2012

Molecular Cancer Therapeutics

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440

371

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“…In addition to inducing p53 expression and inhibiting STAT3 in prostate cancer cells, PGG suppresses the growth of prostate xenograft tumor in a nude mouse model (18). Meanwhile, PGG resembles insulin in that it activates insulin receptor to stimulate glucose transport in adipocytes and functions as an effective antidiabetic drug (21,30). This compound is also a vasorelaxant that dilates vascular smooth muscle and suppresses NO/ cGMP signaling (19).…”

mentioning

confidence: 99%

Inhibitory Effects of 1,2,3,4,6-Penta- O -Galloyl-β- d -Glucopyranose on Biofilm Formation by Staphylococcus aureus

Lin

Chang

Hua

et al. 2011

Antimicrob Agents Chemother

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1,2,3,4,6-Penta-O-galloyl-␤-D-glucopyranose (PGG)is an active ingredient in plants that are commonly used in Chinese medicine to treat inflammation. We demonstrate here that PGG, at 6.25 M, does not inhibit the growth of Staphylococcus aureus, and yet it prevents biofilm formation on polystyrene and polycarbonate surfaces. At the same concentration, PGG is not toxic to human epithelial and fibroblast cells. PGG has an IB 50 value, i.e., the PGG concentration that inhibits 50% biofilm formation, of 3.6 M. The value is substantially lower than that of N-acetylcysteine, iodoacetamide, and N-phenyl maleimide, which are known to inhibit biofilm formation by S. aureus. Biochemical and scanning electron microscopy results also reveal that PGG inhibits initial attachment of the bacteria to solid surface and the synthesis of polysaccharide intercellular adhesin, explaining how PGG inhibits biofilm formation. The results of this study demonstrate that coating PGG on polystyrene and silicon rubber surfaces with polyaniline prevents biofilm formation, indicating that PGG is highly promising for clinical use in preventing biofilm formation by S. aureus.

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“…Compounds 6Cl-TGQ and a-PGG were synthesized as described previously (Ren et al 2006). Compound solutions were prepared by dissolving the compounds in sterile ddH 2 O.…”

Section: Compounds and Cell Linesmentioning

confidence: 99%

“…The glucose transport stimulatory activity of compounds was analyzed by measuring the 3T3-L1 adipocyte uptake of 2-deoxy-D-( 3 H)-glucose (PerkinElmer Life Sciences, Waltham, MA, USA) as described previously , Ren et al 2006.…”

Section: Glucose Uptake Assaymentioning

confidence: 99%

“…Animal studies showed that a-PGG reduces blood glucose levels in diabetic and obese mice . Subsequent structureactivity relationship studies led to the synthesis and identification of an a-PGG derivative, 6-chloro-6-deoxy-1,2,3,4-tetra-O-galloyl-a-D-glucopyranose (6Cl-TGQ), which showed much enhanced glucose transport-stimulating activity in a 10-min glucose uptake assay (Ren et al 2006). But the antidiabetic activities of 6Cl-TGQ were not systematically studied.…”

Section: Introductionmentioning

confidence: 99%

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Orally efficacious novel small molecule 6-chloro-6-deoxy-1,2,3,4-tetra-O-galloyl-α-d-glucopyranose selectively and potently stimulates insulin receptor and alleviates diabetes

Cao

Kim

et al. 2013

Journal of Molecular Endocrinology

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Type 2 diabetes (T2D) has become an epidemic worldwide while T1D remains a great medical challenge. Insulin receptor (IR) signaling activators could alleviate hyperglycemia, reduce the burden on the pancreas, and contribute to prevention and treatment of both types of diabetes. Previously, we reported the synthesis and identification of a natural antidiabetic compound a-penta-galloyl-glucose (a-PGG). Subsequent studies led to the identification of an a-P6GG derivative, 6-chloro-6-deoxy-1,2,3,4-tetra-O-galloyla-D-glucopyranose (6Cl-TGQ). Here, we report that 6Cl-TGQ not only induced rapid and long-lasting glucose uptake comparable to insulin in adipocytes but also reduced high blood glucose levels to near normal and significantly decreased plasma insulin levels and improved glucose tolerance performance in high-fat diet-induced T2D mice when administered orally at 5 mg/kg once every other day. Moreover, a single gavage of 6Cl-TGQ at 10 mg/kg induced rapid and sharp decline of blood glucose in streptozotocininduced T1D mice. Our studies further indicated that 6Cl-TGQ activated IR signaling in cell models and insulin-responsive tissues of mice. 6Cl-TGQ-induced Akt phosphorylation was completely blocked by IR and PI3K inhibitors, while the induced glucose uptake was blocked by the same compounds and a Glut4 inhibitor. Receptor binding studies indicated that 6Cl-TGQ bound to IR with a higher affinity than a-PGG. Importantly, 6Cl-TGQ, unlike insulin, selectively induced phosphorylation of IR without activating IGF1R or its signaling and did not increase cancer cell proliferation. These results indicate

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Synthesis and Structure−Activity Relationship Study of Antidiabetic Penta-O-galloyl-d-glucopyranose and Its Analogues

Cited by 75 publications

References 51 publications

A Small-Molecule Inhibitor of Glucose Transporter 1 Downregulates Glycolysis, Induces Cell-Cycle Arrest, and Inhibits Cancer Cell Growth In Vitro and In Vivo

A Small-Molecule Inhibitor of Glucose Transporter 1 Downregulates Glycolysis, Induces Cell-Cycle Arrest, and Inhibits Cancer Cell Growth In Vitro and In Vivo

Inhibitory Effects of 1,2,3,4,6-Penta- O -Galloyl-β- d -Glucopyranose on Biofilm Formation by Staphylococcus aureus

Orally efficacious novel small molecule 6-chloro-6-deoxy-1,2,3,4-tetra-O-galloyl-α-d-glucopyranose selectively and potently stimulates insulin receptor and alleviates diabetes

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