title: New Atglistatin closely related analogues: Synthesis and structure-activity relationship towards adipose triglyceride lipase inhibition.
abstract: Adipose Triglyceride Lipase (ATGL) performs the first and rate-limiting step in lipolysis by hydrolyzing triacylglycerols stored in lipid droplets to diacylglycerols. By mediating lipolysis in adipose and non-adipose tissues, ATGL is a major regulator of overall energy metabolism and plasma lipid levels. Since chronically high levels of plasma lipids are linked to metabolic disorders including insulin resistance and type 2 diabetes, ATGL is an interesting therapeutic target. In the present study, fourteen closely related analogues of Atglistatin (1), a newly discovered ATGL inhibitor, were synthesized, and their ATGL inhibitory activity was evaluated. The effect of these analogues on lipolysis in 3T3-L1 adipocytes clearly shows that inhibition of the enzyme by Atglistatin (1) is due to the presence of the carbamate and N,N-dimethyl moieties on the biaryl central core at meta and para position, respectively. Mono carbamate-substituted analogue C2, in which the carbamate group was in the meta position as in Atglistatin (1), showed slight inhibition. Low dipole moment of Atglistatin (1) compared to the synthesized analogues possibly explains the lower inhibitory activities.
authors.affiliation: Department of Chemistry and Biochemistry, Université de Moncton, Moncton, NB E1A 3E9, Canada.
authors.forename: Pierre-Philippe
authors.initials: PP
authors.lastname: Roy
authors.affiliation: Department of Biochemistry and Molecular Biology, Dalhousie University, Saint John, NB E2L 4L5, Canada.
authors.forename: Kenneth
authors.initials: K
authors.lastname: D'Souza
authors.affiliation: National Research Council of Canada, 1200 Montreal Road, Ottawa, ON, Canada.
authors.forename: Miroslava
authors.initials: M
authors.lastname: Cuperlovic-Culf
authors.affiliation: Department of Biochemistry and Molecular Biology, Dalhousie University, Saint John, NB E2L 4L5, Canada.
authors.forename: Petra C
authors.initials: PC
authors.lastname: Kienesberger
authors.affiliation: Department of Chemistry and Biochemistry, Université de Moncton, Moncton, NB E1A 3E9, Canada. Electronic address: mohamed.touaibia@umoncton.ca.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Touaibia
mesh_terms: D041721:3T3-L1 Cells; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D060326:Chemistry Techniques, Synthetic; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007545:Isoproterenol / Q000494:pharmacology; D008049:Lipase / Q000037:antagonists & inhibitors*; D008066:Lipolysis / Q000187:drug effects; D051379:Mice; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000217:Acyltransferases
chemical_list: D004791:Enzyme Inhibitors; D007545:Isoproterenol; D008049:Lipase; D010671:Phenylurea Compounds; C585749:atglistatin; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases
keywords: Adipocytes; Adipose triglyceride lipase (ATGL); Atglistatin; Inhibitors; Lipolysis; Structure–activity relationship