Discovery of biaryl-4-carbonitriles as antihyperglycemic agents that may act through AMPK-p38 MAPK pathway

Goel, Atul; Nag, Pankaj; Rahuja, Neha; Srivastava, Rohit; Chaurasia, Sumit; Gautam, Sudeep; Chandra, Sharat; Siddiqi, Mohammad Imran; Srivastava, Arvind K.

doi:10.1016/j.mce.2014.06.007

Cited by 8 publications

(4 citation statements)

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“…A previous study also demonstrated that p38 MAPK activation is involved in stimulating glucose uptake in response to insulin and muscle contractions [13]. We next investigated whether OHC-4p and OHC-2m stimulated glucose uptake through activation of p38 MAPK.…”

Section: Resultsmentioning

confidence: 94%

“…As AMPK activators, many natural and synthesized chemicals are also able to increase glucose uptake and improve hyperglycemia through activation of p38 MAPK in different experimental models. In db/db diabetic mice, the synthesized compound, biaryl-4-carbonitrile, increased the phosphorylation of AMPK and p38 MAPK and ameliorated glucose uptake through the AMPK/p38 MAPK pathway [13]. The natural compound, capsaicin, also stimulated the phosphorylation of AMPK and p38 MAPK and subsequently increased glucose uptake by skeletal muscle cells [14].…”

Section: Introductionmentioning

confidence: 99%

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N-Hydroxycinnamide Derivatives of Osthole Ameliorate Hyperglycemia through Activation of AMPK and p38 MAPK

Lee

Huang

et al. 2015

Molecules

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Our previous studies found that osthole markedly reduced blood glucose levels in both db/db and ob/ob mice. To improve the antidiabetic activity of osthole, a series of N-hydroxycinnamide derivatives of osthole were synthesized, and their hypoglycemia activities were examined in vitro and in vivo. Both N-hydroxycinnamide derivatives of osthole, OHC-4p and OHC-2m, had the greatest potential for activating AMPK and increasing glucose uptake by L6 skeletal muscle cells. In addition, OHC-4p and OHC-2m time-and dose-dependently increased phosphorylation levels of AMPK and p38 MAPK. The AMPK inhibitor, compound C, and the p38 MAPK inhibitor, SB203580, significantly OPEN ACCESSMolecules 2015, 20 4517 reversed activation of AMPK and p38 MAPK, respectively, in OHC-4p-and OHC-2m-treated cells. Compound C and SB203580 also inhibited glucose uptake induced by OHC-4p and OHC-2m. Next, we found that OHC-4p and OHC-2m significantly increased glucose transporter 4 (GLUT4) translocation to plasma membranes and counteracted hyperglycemia in mice with streptozotocin-induced diabetes. These results suggest that activation of AMPK and p38 MAPK by OHC-4p and OHC-2m is associated with increased glucose uptake and GLUT4 translocation and subsequently led to amelioration of hyperglycemia. Therefore, OHC-4p and OHC-2m might have potential as antidiabetic agents for treating type 2 diabetes.

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Section: Resultsmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

N-Hydroxycinnamide Derivatives of Osthole Ameliorate Hyperglycemia through Activation of AMPK and p38 MAPK

Lee

Huang

et al. 2015

Molecules

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“…In 2005, Goel and coworkers reported the synthesis of functionalized p-terphenyls by the ring transformation of 2Hpyran-2-ones with 2-methoxyacetophenone under alkaline reaction conditions. [41] Furthermore, the same research group also developed the synthetic protocol for similar cyclic [25b] and acyclic [42] p-terphenyls by carbanion induced ring transformation of α-pyranones. This is a unique protocol for the facile introduction of electronic donor-acceptor ''push-pull'' system in the aromatic system which is a prerequisite for the photophysical properties.…”

Section: Introductionmentioning

confidence: 99%

Metal‐Free Synthesis of Thermally Stable Fluorescent p‐Terphenyls by Ring Transformation of 2H‐Pyran‐2‐ones

Chandrasekar

Singh

2020

ChemistrySelect

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A metal-free approach for the synthesis of p-terphenyls 7 a-i and cyclic p-terphenyls 9 ad and 11 ad is described via carbanion induced ring transformation reaction of 6-biphenyl-2H-pyran-2-ones 5 with malononitrile 6, cyclohexanone 8 and 1,4-cyclohexanedione monoethylene ketal 10 respectively. Additionally, the base-mediated ring transformation reactions were working smoothly under mild reaction conditions and ring transformation products 7, 9 and 11 were isolated in good to excellent yields. The synthetic approach provides the flexibility of introducing of both electron-withdrawing and-donating functionalities in p-terphenyl architecture. Moreover, the photo physical properties of compounds 7, 9 and 11 were analyzed using UV-visible and Fluorescence Spectroscopy. p-Terphenyls 7 c showed cyan fluorescence in chloroform (λ max (em): 508 nm) and acetonitrile (λ max (em): 420 nm) while cyclic p-terphenyl 9 a showed blue fluorescence in chloroform and 1,4-dioxane (λ max (em): 470 nm). Similarly, compound 11 a showed blue fluorescence in chloroform (λ max (em): 468 nm) and 1,4-dioxane (λ max (em): 473 nm). Additionally, the thermal stability of synthesized cyclic p-terphenyls 11 a, 11 c and 11 d were also studied using TG and DTA techniques.

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“…Activation of p38 MAPK participates in stimulation of glucose uptake by both insulin and contraction stimuli in skeletal muscles [16]. As AMPK activators, many natural and synthesized chemicals are also able to increase glucose uptake and improve hyperglycemia through activation of p38 MAPK [17,18]. …”

Section: Introductionmentioning

confidence: 99%

Hypoglycemic Effect of Opuntia ficus-indica var. saboten Is Due to Enhanced Peripheral Glucose Uptake through Activation of AMPK/p38 MAPK Pathway

et al. 2016

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Opuntia ficus-indica var. saboten (OFS) has been used in traditional medicine for centuries to treat several illnesses, including diabetes. However, detailed mechanisms underlying hypoglycemic effects remain unclear. In this study, the mechanism underlying the hypoglycemic activity of OFS was evaluated using in vitro and in vivo systems. OFS treatment inhibited α-glucosidase activity and intestinal glucose absorption assessed by Na+-dependent glucose uptake using brush border membrane vesicles. AMP-activated protein kinase (AMPK) is widely recognized as an important regulator of glucose transport in skeletal muscle, and p38 mitogen-activated protein kinase (MAPK) has been proposed to be a component of AMPK-mediated signaling. In the present study, OFS dose-dependently increased glucose uptake in L6 muscle cells. The AMPK and p38 MAPK phosphorylations were stimulated by OFS, and inhibitors of AMPK (compound C) and p38 MAPK (SB203580) abolished the effects of OFS. Furthermore, OFS increased glucose transporter 4 (GLUT4) translocation to the plasma membrane. OFS administration (1 g/kg and 2 g/kg body weight) in db/db mice dose-dependently ameliorated hyperglycemia, hyperinsulinemia, and glucose tolerance. Insulin resistance assessed by homeostasis model assessment of insulin resistance and quantitative insulin sensitivity check index were also dose-dependently improved with OFS treatment. OFS administration improved pancreatic function through increased β-cell mass in db/db mice. These findings suggest that OFS acts by inhibiting glucose absorption from the intestine and enhancing glucose uptake from insulin-sensitive muscle cells through the AMPK/p38 MAPK signaling pathway.

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Discovery of biaryl-4-carbonitriles as antihyperglycemic agents that may act through AMPK-p38 MAPK pathway

Cited by 8 publications

References 89 publications

N-Hydroxycinnamide Derivatives of Osthole Ameliorate Hyperglycemia through Activation of AMPK and p38 MAPK

N-Hydroxycinnamide Derivatives of Osthole Ameliorate Hyperglycemia through Activation of AMPK and p38 MAPK

Metal‐Free Synthesis of Thermally Stable Fluorescent p‐Terphenyls by Ring Transformation of 2H‐Pyran‐2‐ones

Hypoglycemic Effect of Opuntia ficus-indica var. saboten Is Due to Enhanced Peripheral Glucose Uptake through Activation of AMPK/p38 MAPK Pathway

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