TY - JOUR
T1 - A Novel Phenylchromane Derivative Increases the Rate of Glucose Uptake in L6 Myotubes and Augments Insulin Secretion from Pancreatic Beta-Cells by Activating AMPK
AU - Rozentul, Naomi
AU - Avrahami, Yosef
AU - Shubely, Moran
AU - Levy, Laura
AU - Munder, Anna
AU - Cohen, Guy
AU - Cerasi, Erol
AU - Sasson, Shlomo
AU - Gruzman, Arie
N1 - Publisher Copyright:
© 2017, Springer Science+Business Media, LLC.
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
KW - AMPK activation
KW - glucose uptake
KW - insulin secretion
KW - LKB1 activation
KW - phenylchromane scaffold
UR - http://www.scopus.com/inward/record.url?scp=85030673632&partnerID=8YFLogxK
U2 - 10.1007/s11095-017-2271-7
DO - 10.1007/s11095-017-2271-7
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C2 - 28983714
AN - SCOPUS:85030673632
SN - 0724-8741
VL - 34
SP - 2873
EP - 2890
JO - Pharmaceutical Research
JF - Pharmaceutical Research
IS - 12
ER -