Discovery of Isoquinolinoquinazolinones as a Novel Class of Potent PPARγ Antagonists with Anti-adipogenic Effects.
Conformational change in helix 12 can alter ligand-induced PPARγ activity; based on this reason, isoquinolinoquinazolinones, structural homologs of berberine, were designed and synthesized as PPARγ antagonists. Computational docking and mutational study indicated that isoquinolinoquinazolinones form hydrogen bonds with the Cys285 and Arg288 residues of PPARγ. Furthermore, SPR results demonstrated strong binding affinity of isoquinolinoquinazolinones towards PPARγ. Additionally, biological assays showed that this new series of PPARγ antagonists more strongly inhibit adipocyte differentiation and PPARγ2-induced transcriptional activity than GW9662.
College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Republic of Korea.
Yifeng
Y
Jin
College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Republic of Korea.
Younho
Y
Han
College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Republic of Korea.
Daulat Bikram
DB
Khadka
College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Republic of Korea.
Chao
C
Zhao
College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Republic of Korea.
Kwang Youl
KY
Lee
College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Republic of Korea.
Won-Jea
WJ
Cho
D041721:3T3-L1 Cells; D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D001120:Arginine / Q000737:chemistry / Q000378:metabolism; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D055808:Drug Discovery; D006860:Hydrogen Bonding; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D062105:Molecular Docking Simulation; D047495:PPAR gamma / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D052999:Quinazolinones / Q000737:chemistry / Q000494:pharmacology*
D007546:Isoquinolines; D047495:PPAR gamma; D052999:Quinazolinones; D001120:Arginine; D003545:Cysteine
Mol Pharmacol. 2013 Jan;83(1):1-8
22869589
Physiol Rev. 1998 Jul;78(3):783-809
9674695
J Med Chem. 2013 Apr 25;56(8):3414-8
23527816
Bioorg Med Chem Lett. 2009 May 1;19(9):2551-4
19328687
J Pharmacol Exp Ther. 2004 Nov;311(2):467-75
15273253
Expert Opin Ther Pat. 2016;26(2):229-43
26610159
Biochemistry. 2005 Feb 1;44(4):1193-209
15667213
Cell. 1995 Dec 15;83(6):835-9
8521507
Biochemistry. 2002 May 28;41(21):6640-50
12022867
PPAR Res. 2014;2014:537865
24790595
Expert Opin Ther Pat. 2015 Feb;25(2):175-91
25416646
J Mol Biol. 2000 Apr 28;298(2):187-94
10764590
Nature. 1998 Sep 10;395(6698):137-43
9744270
Nature. 2008 Nov 20;456(7220):350-6
19043829
Gene. 1995 Sep 11;162(2):297-302
7557447
Nat Med. 2004 Apr;10(4):355-61
15057233
Mol Endocrinol. 2002 Nov;16(11):2628-44
12403851
Eur J Biochem. 2004 Jan;271(2):386-97
14717706
Nutr Res Pract. 2014 Dec;8(6):613-7
25489399
Cardiovasc Radiat Med. 2004 Apr-Jun;5(2):97-103
15464947
Biochem Biophys Res Commun. 2006 Sep 22;348(2):571-8
16890192
Bioorg Med Chem. 2011 Sep 15;19(18):5311-20
21873069
Sci Rep. 2014 Dec 09;4:7375
25487878