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A Novel Phenylchromane Derivative Increases the Rate of Glucose Uptake in L6 Myotubes and Augments Insulin Secretion from Pancreatic Beta-Cells by Activating AMPK

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Abstract

Purpose

A series of novel polycyclic aromatic compounds that augment the rate of glucose uptake in L6 myotubes and increase glucose-stimulated insulin secretion from beta-cells were synthesized. Designing these molecules, we have aimed at the two main pathogenic mechanisms of T2D, deficient insulin secretion and diminished glucose clearance. The ultimate purpose of this work was to create a novel antidiabetic drug candidate with bi-functional mode of action.

Methods

All presented compounds were synthesized, and characterized in house. INS-1E cells and L6 myoblasts were used for the experiments. The rate of glucose uptake, mechanism of action, level of insulin secretion and the druggability of the lead compound were studied.

Results

The lead compound (6-(1,3-dithiepan-2-yl)-2-phenylchromane), dose- and time-dependently at the low μM range increased the rate of glucose uptake in L6 myotubes and insulin secretion in INS-1E cells. The compound exerted its effects through the activation of the LKB1 (Liver Kinase B1)-AMPK pathway. In vitro metabolic parameters of this lead compound exhibited good druggability.

Conclusions

We anticipate that bi-functionality (increased rate of glucose uptake and augmented insulin secretion) will allow the lead compound to be a starting point for the development of a novel class of antidiabetic drugs.

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Abbreviations

[3H]dGlc:

1-Tritium-2-deoxyglucose

ACC:

Acetyl-CoA carboxylase

AICAR:

5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside

Akt/PKB:

Akt/Protein kinase B

AMPK:

AMP kinase

AS160 :

AMPK substrate of phosphorylation 160 kDA

BDA :

Benzaldehyde dimethyl acetal

CYP :

Cytochrome P450

DCM:

Dichloromethane

DEAD:

Diethyl azodicarboxylate

DMF:

Dimethrylformamide

GLUT4:

Glucose transporter type 4

GSIS:

Glucose-stimulated insulin secretion

hERG:

“Human ether-à-go-go”-related gene channels

HRP :

Horseradish peroxidase

LKB1:

Liver Kinase B1

mGPD:

Mitochondrial glycerophosphate dehydrogenase

OPD:

O-phenylenediamine

PCC:

Pyridinium Chlorochromate

PMSF:

Phenylmethanesulfonylfluoride

QTof:

Quadrupole time of-flight mass spectrometer

T2D:

Type 2 diabetes

THF:

Tetrahydrofuran

TMS:

Tetramethylsilane

TMSCl:

Trimethylsilyl chloride

TosCl:

Toluenesulfonyl chloride

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Author notes

  1. Naomi Rozentul and Yosef Avrahami contributed equally to this work.

Authors and Affiliations

  1. Division of Medicinal Chemistry, Department of Chemistry, Faculty of Exact Sciences, Bar-Ilan University, 52900, Ramat-Gan, Israel

    Naomi Rozentul, Moran Shubely, Laura Levy, Anna Munder & Arie Gruzman

  2. Department of Pharmacology, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 91120, Jerusalem, Israel

    Yosef Avrahami, Guy Cohen & Shlomo Sasson

  3. The Endocrinology and Metabolism Service, Department of Medicine, Hadassah-Hebrew University Medical Center, 91120, Jerusalem, Israel

    Erol Cerasi

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  1. Naomi Rozentul
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Correspondence to Shlomo Sasson or Arie Gruzman.

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Rozentul, N., Avrahami, Y., Shubely, M. et al. A Novel Phenylchromane Derivative Increases the Rate of Glucose Uptake in L6 Myotubes and Augments Insulin Secretion from Pancreatic Beta-Cells by Activating AMPK. Pharm Res 34, 2873–2890 (2017). https://doi.org/10.1007/s11095-017-2271-7

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