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

Naomi Rozentul, Yosef Avrahami, Moran Shubely, Laura Levy, Anna Munder, Guy Cohen, Erol Cerasi, Shlomo Sasson, Arie Gruzman

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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.

Original languageEnglish
Pages (from-to)2873-2890
Number of pages18
JournalPharmaceutical Research
Volume34
Issue number12
DOIs
StatePublished - 1 Dec 2017

Bibliographical note

Publisher Copyright:
© 2017, Springer Science+Business Media, LLC.

Funding

We thank Dr. Rachel Hertz, Department of Human Nutrition and Metabolism, The Hebrew University Faculty of Medicine, Jerusalem, Israel, for providing us the lentivirus shRNA-AMPK construct. We thank Ms. Duha Fahham for her technical help. This study was supported partly by a Bar-Ilan University new faculty grant (A.G), by Diab R&D (France) for (E.C., A.G. and S.S.) and grants from the Applied Research Program A of the Hebrew University, and the Israel Science Foundation of The Israel Academy of Sciences and Humanities (to S.S). S. Sasson is member of the David R. Bloom Center for Pharmacy and in Chair Dr. Adolf and Klara Brettler Center for Research in Molecular Pharmacology and Therapeutics. S.S. is the Adolf D. and Horty Storch Chair in Pharmaceutical Sciences, Faculty of Medicine, The Hebrew University of Jerusalem.

FundersFunder number
E.C.
Bar-Ilan University
Hebrew University of Jerusalem
Israel Academy of Sciences and Humanities

    Keywords

    • AMPK activation
    • LKB1 activation
    • glucose uptake
    • insulin secretion
    • phenylchromane scaffold

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