title: Brominated polyunsaturated lipids from the Chinese sponge Xestospongia testudinaria as a new class of pancreatic lipase inhibitors.
abstract: Chemical analysis of the Chinese marine sponge Xestospongia testudinaria afforded a library of brominated polyunsaturated lipids including eight new compounds, named xestonarienes A-H (3-10) and thirteen known analogues (11-23). The structures of the new compounds were elucidated by detailed spectroscopic analysis and by comparison with literature data. The isolated lipids were evaluated for their inhibitory activity against pancreatic lipase (PL), an essential enzyme for efficient fat digestion and the major metabolite, 14, exhibited a marked inhibitory activity (IC50 = 3.11 μM), similar to that of the positive control Orlistat (IC50 = 0.78 μM). The preliminary structure-activity relationships on the series of compounds clearly evidenced that a terminal (E)-enyne functionality, a diyne within the chain, and methyl ester group are all key functional groups for the activity of this class of PL inhibitors. Further biological investigation on compound 14 revealed a significant decrease in the plasma triglyceride level following an oral lipid challenge in C57BLKS/J male mice. Acute toxicology study demonstrated that compound 14 was non-toxic up to 1600 mg/kg p.o in mice. This is the first report of the PL inhibitory activity for brominated polyunsaturated lipids and the obtained results qualify compound 14 as a potent and bioavailable drug candidate for a mild and safe treatment to prevent and reduce obesity.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhang Jiang Hi-Tech Park, Shanghai 201203, PR China; College of Material Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, PR China.
authors.forename: Lin-Fu
authors.initials: LF
authors.lastname: Liang
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhang Jiang Hi-Tech Park, Shanghai 201203, PR China.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhang Jiang Hi-Tech Park, Shanghai 201203, PR China; Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and Institute of TCM & Natural Products, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, PR China.
authors.forename: You-Sheng
authors.initials: YS
authors.lastname: Cai
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhang Jiang Hi-Tech Park, Shanghai 201203, PR China.
authors.forename: Wen-Fei
authors.initials: WF
authors.lastname: He
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhang Jiang Hi-Tech Park, Shanghai 201203, PR China.
authors.forename: Peng
authors.initials: P
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhang Jiang Hi-Tech Park, Shanghai 201203, PR China.
authors.forename: Yu-Fen
authors.initials: YF
authors.lastname: Li
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhang Jiang Hi-Tech Park, Shanghai 201203, PR China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Dipartimento di Farmacia, Università di Napoli "Federico II", Via D. Montesano 49, 80131 Napoli, Italy. Electronic address: scatagli@unina.it.
authors.forename: Orazio
authors.initials: O
authors.lastname: Taglialatela-Scafati
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhang Jiang Hi-Tech Park, Shanghai 201203, PR China. Electronic address: hywang@mail.shcnc.ac.cn.
authors.forename: He-Yao
authors.initials: HY
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhang Jiang Hi-Tech Park, Shanghai 201203, PR China. Electronic address: ywguo@mail.shcnc.ac.cn.
authors.forename: Yue-Wei
authors.initials: YW
authors.lastname: Guo
mesh_terms: D000818:Animals; D002681:China; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D005260:Female; D006842:Hydrocarbons, Brominated / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D008049:Lipase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008055:Lipids / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D010179:Pancreas / Q000201:enzymology; D013329:Structure-Activity Relationship; D013552:Swine; D047131:Xestospongia / Q000737:chemistry*
chemical_list: D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D006842:Hydrocarbons, Brominated; D008055:Lipids; D008049:Lipase
keywords: Brominated polyunsaturated lipids; Marine sponge; Pancreatic lipase inhibitory activity; SAR; Xestospongia testudinaria