title: Identification of a novel 11β-HSD1 inhibitor from a high-throughput screen of natural product extracts.
abstract: Selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) have considerable potential as a treatment for metabolic syndrome including type 2 diabetes mellitus and obesity. To identify 11β-HSD1 inhibitors, we conducted high-throughput screening (HTS) of active natural product extracts from the Korea Chemical Bank, including Tanshinone I, Tanshinone IIA, and flavanone derivatives, and 2- and 3-phenyl-4H-chromen-4-one. Then Tanshinone IIA and its derivatives were targeted for the development of a lead compound according to the HTS results. However, the mechanism for anti-adipogenic effect through 11β-HSD1 enzyme inhibition by Tanshinone IIA is not clear. Tanshinone IIA (2a) concentration-dependently inhibited 11β-HSD1 activity in human and mouse 11β-HSD1 overexpressed cells and 3T3-L1 adipocytes. Tanshinone IIA (2a) also inhibited 11β-HSD1 enzyme activities in murine liver and fats. Furthermore, Tanshinone IIA (2a)-suppressed adipocyte differentiation of cortisone-induced adipogenesis in 3T3-L1 cells was associated with the suppression of the cortisone-induced adipogenesis-specific markers mRNA and protein expression. In 3T3-L1 preadipocytes, Tanshinone IIA (2a)-inhibited cortisone induced reactive oxygen species formation in a concentration-dependent manner. Thus, these results support the therapeutic potential of Tanshinone IIA (2a) as a 11β-HSD1 inhibitor in metabolic syndrome patients.
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon 305-600, Republic of Korea; Department of Toxicology, College of Pharmacy, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 305-764, Republic of Korea.
authors.forename: Sung Bum
authors.initials: SB
authors.lastname: Park
authors.affiliation: Department of Human and Environmental Toxicology, University of Science and Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon 305-333, Republic of Korea.
authors.forename: Ji Seon
authors.initials: JS
authors.lastname: Park
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon 305-600, Republic of Korea.
authors.forename: Won Hoon
authors.initials: WH
authors.lastname: Jung
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon 305-600, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon, 305-333, Republic of Korea.
authors.forename: Areum
authors.initials: A
authors.lastname: Park
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon 305-600, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon, 305-333, Republic of Korea.
authors.forename: Sae Rom
authors.initials: SR
authors.lastname: Jo
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon 305-600, Republic of Korea.
authors.forename: Hee Youn
authors.initials: HY
authors.lastname: Kim
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon 305-600, Republic of Korea.
authors.forename: Sang
authors.initials: S
authors.lastname: Dal Rhee
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon 305-600, Republic of Korea.
authors.forename: Shi Yong
authors.initials: SY
authors.lastname: Ryu
authors.affiliation: Department of Toxicology, College of Pharmacy, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 305-764, Republic of Korea.
authors.forename: Hye Gwang
authors.initials: HG
authors.lastname: Jeong
authors.affiliation: Department of Chemistry, Center for NanoBio Applied Technology, Institute of Basic Sciences, Sungshin Women's University, 55 Dobon-ro 76ga-gil, Gangbuk-gu, Seoul 142-732, Republic of Korea.
authors.forename: Seongsoon
authors.initials: S
authors.lastname: Park
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon 305-600, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon, 305-333, Republic of Korea. Electronic address: leeh@krict.re.kr.
authors.forename: Hyuk
authors.initials: H
authors.lastname: Lee
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong-gu, Daejeon 305-600, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon, 305-333, Republic of Korea. Electronic address: kykim@krict.re.kr.
authors.forename: Ki Young
authors.initials: KY
authors.lastname: Kim
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D016475:3T3 Cells; D045784:Abietanes / Q000494:pharmacology; D017667:Adipocytes / Q000187:drug effects; D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D001688:Biological Products / Q000494:pharmacology*; D016466:CHO Cells; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D003412:Cricetulus; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D045784:Abietanes; D001688:Biological Products; D017382:Reactive Oxygen Species; C021751:tanshinone; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1
keywords: 11β-hydroxysteroid dehydrogenase type 1; Adipogenesis; Carbenoxolone (PubChem CID: 636403); Cortisone (PubChem CID: 222786); Dexamethasone (PubChem CID: 5743); Diabetes; Dimethyl sulfoxide (PubChem CID: 679); High-throughput screening; Isobutylmethylxanthine (PubChem CID: 3758); Metabolic syndrome; Tanshinone IIA; Tanshinone IIA(PubChem CID: 164676); β-Nicotinamide adenine dinucleotide 2′-phosphate reduced tetrasodium salt hydrate (PubChem CID: 16218775)