title: Rat hormone sensitive lipase inhibition by cyclipostins and their analogs.
abstract: Cyclipostins are bicyclic lipophilic phosphate natural products. We report here that synthesized individual diastereomers of cyclipostins P and R have nanomolar IC50s toward hormone sensitive lipase (HSL). The less potent diastereomers of these compounds have 10-fold weaker IC50s. The monocyclic phosphate analog of cyclipostin P is nearly as potent as the bicyclic natural product. Bicyclic phosphonate analogs of both cyclipostins exhibit IC50s similar to those of the weaker diastereomer phosphates (about 400nM). The monocyclic phosphonate analog of cyclipostin P has similar potency. A series of monocyclic phosphonate analogs in which a hydrophobic tail extends from the lactone side of the ring are considerably poorer inhibitors, with IC50s around 50μM. Finally cyclophostin, a related natural product inhibitor of acetylcholinesterase (AChE) that lacks the hydrocarbon tail of cyclipostins, is not active against HSL. These results indicate a critical SAR for these compounds, the hydrophobic tail. The smaller lactone ring is not critical to activity, a similarity shared with cyclophostin and AChE. The HSL kinetics of inhibition for the cyclipostin P trans diastereomer were examined in detail. The reaction is irreversible with a KI of 40nM and a rate constant for inactivation of 0.2min(-1). These results are similar to those observed for cyclophostin and AChE.
authors: Department of Chemistry & Biochemistry and the Center for Nanoscience, University of Missouri St. Louis, St. Louis, MO 63121, United States.
authors: Elena
authors: E
authors: Vasilieva
authors: Department of Chemistry & Biochemistry and the Center for Nanoscience, University of Missouri St. Louis, St. Louis, MO 63121, United States.
authors: Supratik
authors: S
authors: Dutta
authors: Department of Chemistry & Biochemistry and the Center for Nanoscience, University of Missouri St. Louis, St. Louis, MO 63121, United States.
authors: Raj K
authors: RK
authors: Malla
authors: Department of Chemistry & Biochemistry and the Center for Nanoscience, University of Missouri St. Louis, St. Louis, MO 63121, United States.
authors: Benjamin P
authors: BP
authors: Martin
authors: Department of Chemistry & Biochemistry and the Center for Nanoscience, University of Missouri St. Louis, St. Louis, MO 63121, United States.
authors: Christopher D
authors: CD
authors: Spilling
authors: Department of Chemistry & Biochemistry and the Center for Nanoscience, University of Missouri St. Louis, St. Louis, MO 63121, United States. Electronic address: cdup@umsl.edu.
authors: Cynthia M
authors: CM
authors: Dupureur
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D061987:Sf9 Cells; D013237:Stereoisomerism; D002787:Sterol Esterase / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D009943:Organophosphorus Compounds; C560841:cyclipostin P; C083659:cyclophostin; D002787:Sterol Esterase
keywords: Inhibition; Kinetics; Lipase; Natural products