Vasilieva_2015_Bioorg.Med.Chem_23_944

Reference

Title : Rat hormone sensitive lipase inhibition by cyclipostins and their analogs - Vasilieva_2015_Bioorg.Med.Chem_23_944
Author(s) : Vasilieva E , Dutta S , Malla RK , Martin BP , Spilling CD , Dupureur CM
Ref : Bioorganic & Medicinal Chemistry , 23 :944 , 2015
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 50muM. 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.

PubMedSearch : Vasilieva_2015_Bioorg.Med.Chem_23_944
PubMedID: 25678014
Gene_locus related to this paper: ratno-hslip

Related information

Inhibitor Cyclophostin    Cyclipostin    Cyclipostin-P    CyC-17
Gene_locus Cyclophostin    Cyclipostin    Cyclipostin-P    CyC-17    ratno-hslip

Citations formats

Vasilieva E, Dutta S, Malla RK, Martin BP, Spilling CD, Dupureur CM (2015)
Rat hormone sensitive lipase inhibition by cyclipostins and their analogs
Bioorganic & Medicinal Chemistry 23 :944

Vasilieva E, Dutta S, Malla RK, Martin BP, Spilling CD, Dupureur CM (2015)
Bioorganic & Medicinal Chemistry 23 :944