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 IC 50 s toward hormone sensitive lipase (HSL). The less potent diastereomers of these compounds have 10-fold weaker IC 50 s. The monocyclic phosphate analog of cyclipostin P is nearly as potent as the bicyclic natural product. Bicyclic phosphonate analogs of both cyclipostins exhibit IC 50 s similar to those of the weaker diastereomer phosphates (about 400 nM). 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 IC 50 s around 50 μM. 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 K I of 40 nM and a rate constant for inactivation of 0.2 min −1 . These results are similar to those observed for cyclophostin and AChE.