Antidiabetic effects of trihydroxychalcone derivatives via activation of AMP-activated protein kinase

Jooseok Shin; Mi Gyeong Jang; Jin Chan Park; Young Do Koo; Ji Young Lee; Kyong Soo Park; Sung Soo Chung; Kwangyong Park

Journal of Industrial and Engineering Chemistry, Vol.60, 177-184, April, 2018

DOI10.1016/j.jiec.2017.11.003 Export Citation

Antidiabetic effects of trihydroxychalcone derivatives via activation of AMP-activated protein kinase

Jooseok Shin, Mi Gyeong Jang¹, Jin Chan Park, Young Do Koo¹, Ji Young Lee, Kyong Soo Park¹, Sung Soo Chung^{1, †}, and Kwangyong Park^†

School of Chemical Engineering and Materials Science, Chung-Ang University, Seoul, Republic of Korea
¹Department of Internal Medicine, Seoul National University, College of Medicine, Seoul, Republic of Korea

E-mail:,

In this study, trihydroxychalcone derivatives were synthesized and evaluated for their potential antidiabetic effects in a cell-culture system and a diabetic mouse model in vivo. Some of them increased fatty acid oxidation (FAO) in C2C12 myotubes without affecting the cell viability. In addition, some trihydroxychalcone derivatives, including chalcone 13, facilitated AMP-activated protein kinase (AMPK) activation. Chalcone 13 administration to high-fat diet (HFD)-induced diabetic mice improved glucose tolerance, increased muscle FAO, and reduced fat accumulation in the liver and skeletal muscles. These results suggest that some chalcone derivatives, particularly chalcone 13, might be potential therapeutic agents for the treatment of diabetes.

Keywords:Trihydroxychalcone;Insulin resistance;AMPK;Diabetes;Fatty acid oxidation

[References]

Pan DA, Lillioja S, Kriketos AD, Milner MR, Baur LA, et al., Diabetes, 46, 983 (1997)
Perseghin G, Scifo P, De Cobelli F, Pagliato E, Battezzati A, et al., Diabetes, 48, 1600 (1999)
Krssak M, Petersen KF, Dresner A, DiPietro L, Vogel SM, et al., Diabetologia, 42, 113 (1999)
Choi CS, Savage DB, Abu-Elheiga L, Liu ZX, Kim S, et al., Proc. Natl. Acad. Sci. U. S. A., 104, 16480 (2007)
Bruce CR, Hoy AJ, Turner N, Watt MJ, Allen TL, et al., Diabetes, 58, 550 (2009)
Koo YD, Choi JW, Kim M, Chae S, Ahn BY, et al., Diabetes, 64, 2420 (2015)
Ruderman N, Prentki M, Nat. Rev. Drug Discov., 3, 340 (2004)
Coughlan KA, Valentine RJ, Ruderman NB, Saha AK, Diabetes Metab. Syndr. Obes., 7, 241 (2014)
Winder WW, Hardie DG, Am. J. Physiol., 277, E1 (1999)
Abu-Elheiga L, Matzuk MM, Abo-Hashema KA, Wakil SJ, Science, 29, 2613 (2001)
Hardie DG, Pan DA, Biochem. Soc. Trans., 30, 1064 (2002)
Fryer LG, Parbu-Patel A, Carling D, J. Biol. Chem., 277, 25226 (2002)
Hawley SA, Gadalla AE, Olsen GS, Hardie DG, Diabetes, 51, 2420 (2002)
Corton JM, Gillespie JG, Hawley SA, Hardie DG, Eur. J. Biochem., 229, 558 (1995)
Fogarty S, Hardie DG, Biochim. Biophys. Acta, 1804, 581 (2010)
Vincent MF, Marangos PJ, Gruber HE, Van den Berghe G, Diabetes, 40, 1259 (1991)
Hawley SA, Fullerton MD, Ross FA, Schertzer JD, Chevtzoff C, Walker KJ, Peggie MW, Zibrova D, Green KA, Mustard KJ, Kemp BE, Sakamoto K, Steinberg GR, Hardie DG, Science, 336(6083), 918 (2012)
Steinberg GR, Kemp BE, Physiol. Rev., 89, 1025 (2009)
Mahapatra DK, Bharti SK, Asati V, Eur. J. Med. Chem., 98, 69 (2015)
Mahapatra DK, Asati V, Bharti SK, Eur. J. Med. Chem., 92, 839 (2015)
Israf DA, Khaizurin TA, Syahida A, Lajis NH, Khozirah S, Mol. Immunol., 44, 673 (2007)
Aoki N, Muko M, Ohta E, Ohta S, J. Nat. Prod., 71, 1308 (2008)
Yoon G, Lee W, Kim SN, Cheon SH, Bioorg. Med. Chem. Lett., 19, 5155 (2009)
Liu M, Yin H, Liu G, Dong J, Qian Z, et al., J. Agric. Food Chem., 62, 5548 (2014)
Jung SH, Park SY, Kim-Pak Y, Lee HK, Park KS, et al., Chem Pharm Bull, 54, 368 (2006)
Choi JW, Kim M, Song H, Lee CS, Oh WK, et al., Metabolism, 65, 533 (2016)
Zhao LM, Jin HS, Sun LP, Piao HR, Quan ZS, Bioorg. Med. Chem. Lett., 15, 5027 (2005)
Boeck P, Falcao CAB, Leal PC, Yunes RA, Filho VC, et al., Bioorg. Med. Chem. Lett., 14, 1538 (2006)
Sun LP, Gao LX, Ma WP, Nan FJ, Li J, et al., Chem. Biol. Drug Des., 20, 584 (2012)
Detsi A, Majdalani M, Kontogiorgis CA, Hadjipavlou-Litina D, Kefalas P, Bioorg. Med. Chem. Lett., 17, 8073 (2009)
Lim SS, Jung SH, Ji J, Shin JH, Keum SR, J. Pharm. Pharmacol., 53, 653 (2001)
Dao TT, Tung BT, Nguyen PH, Thuong PT, Yoo SS, et al., J. Nat. Prod., 73, 1636 (2010)

[1] Pan DA, Lillioja S, Kriketos AD, Milner MR, Baur LA, et al., Diabetes, 46, 983 (1997)

[2] Perseghin G, Scifo P, De Cobelli F, Pagliato E, Battezzati A, et al., Diabetes, 48, 1600 (1999)

[3] Krssak M, Petersen KF, Dresner A, DiPietro L, Vogel SM, et al., Diabetologia, 42, 113 (1999)

[4] Choi CS, Savage DB, Abu-Elheiga L, Liu ZX, Kim S, et al., Proc. Natl. Acad. Sci. U. S. A., 104, 16480 (2007)

[5] Bruce CR, Hoy AJ, Turner N, Watt MJ, Allen TL, et al., Diabetes, 58, 550 (2009)

[6] Koo YD, Choi JW, Kim M, Chae S, Ahn BY, et al., Diabetes, 64, 2420 (2015)

[7] Ruderman N, Prentki M, Nat. Rev. Drug Discov., 3, 340 (2004)

[8] Coughlan KA, Valentine RJ, Ruderman NB, Saha AK, Diabetes Metab. Syndr. Obes., 7, 241 (2014)

[9] Winder WW, Hardie DG, Am. J. Physiol., 277, E1 (1999)

[10] Abu-Elheiga L, Matzuk MM, Abo-Hashema KA, Wakil SJ, Science, 29, 2613 (2001)

[11] Hardie DG, Pan DA, Biochem. Soc. Trans., 30, 1064 (2002)

[12] Fryer LG, Parbu-Patel A, Carling D, J. Biol. Chem., 277, 25226 (2002)

[13] Hawley SA, Gadalla AE, Olsen GS, Hardie DG, Diabetes, 51, 2420 (2002)

[14] Corton JM, Gillespie JG, Hawley SA, Hardie DG, Eur. J. Biochem., 229, 558 (1995)

[15] Fogarty S, Hardie DG, Biochim. Biophys. Acta, 1804, 581 (2010)

[16] Vincent MF, Marangos PJ, Gruber HE, Van den Berghe G, Diabetes, 40, 1259 (1991)

[17] Hawley SA, Fullerton MD, Ross FA, Schertzer JD, Chevtzoff C, Walker KJ, Peggie MW, Zibrova D, Green KA, Mustard KJ, Kemp BE, Sakamoto K, Steinberg GR, Hardie DG, Science, 336(6083), 918 (2012)

[18] Steinberg GR, Kemp BE, Physiol. Rev., 89, 1025 (2009)

[19] Mahapatra DK, Bharti SK, Asati V, Eur. J. Med. Chem., 98, 69 (2015)

[20] Mahapatra DK, Asati V, Bharti SK, Eur. J. Med. Chem., 92, 839 (2015)

[21] Israf DA, Khaizurin TA, Syahida A, Lajis NH, Khozirah S, Mol. Immunol., 44, 673 (2007)

[22] Aoki N, Muko M, Ohta E, Ohta S, J. Nat. Prod., 71, 1308 (2008)

[23] Yoon G, Lee W, Kim SN, Cheon SH, Bioorg. Med. Chem. Lett., 19, 5155 (2009)

[24] Liu M, Yin H, Liu G, Dong J, Qian Z, et al., J. Agric. Food Chem., 62, 5548 (2014)

[25] Jung SH, Park SY, Kim-Pak Y, Lee HK, Park KS, et al., Chem Pharm Bull, 54, 368 (2006)

[26] Choi JW, Kim M, Song H, Lee CS, Oh WK, et al., Metabolism, 65, 533 (2016)

[27] Zhao LM, Jin HS, Sun LP, Piao HR, Quan ZS, Bioorg. Med. Chem. Lett., 15, 5027 (2005)

[28] Boeck P, Falcao CAB, Leal PC, Yunes RA, Filho VC, et al., Bioorg. Med. Chem. Lett., 14, 1538 (2006)

[29] Sun LP, Gao LX, Ma WP, Nan FJ, Li J, et al., Chem. Biol. Drug Des., 20, 584 (2012)

[30] Detsi A, Majdalani M, Kontogiorgis CA, Hadjipavlou-Litina D, Kefalas P, Bioorg. Med. Chem. Lett., 17, 8073 (2009)

[31] Lim SS, Jung SH, Ji J, Shin JH, Keum SR, J. Pharm. Pharmacol., 53, 653 (2001)

[32] Dao TT, Tung BT, Nguyen PH, Thuong PT, Yoo SS, et al., J. Nat. Prod., 73, 1636 (2010)