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 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 IC50s 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 KI 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.

Biochemical and Structural Characterization of TesA, a Major Thioesterase Required for Outer-Envelope Lipid Biosynthesis in Mycobacterium tuberculosis

“…In this context, we have demonstrated that the CyC analogs represent powerful and selective inhibitors of mycobacterial enzymes [14,15], with no effect on the mammalian enzymes initially targeted by natural parent molecules [14][15][16][17]. The selectivity of the CyC derivatives toward the mycobacterial but not the human enzymes, is therefore highly valuable and prompted us to consider them as potential anti-tubercular agents.…”

“…New antibiotics targeting one or more proteins involved in the synthesis of mycobacterial lipids would thus represent a promising way to fight and control TB [9,13]. In this context, monocyclic enolphosphate and phosphonate analogs (CyC) of natural Cyclipostins and Cyclophostin [14][15][16][17] represent a new family of potent and selective inhibitors against mycobacteria only [18]. These CyC analogs act as powerful antitubercular agents affecting growth of M. tuberculosis both in vitro and in infected macrophages with very low toxicity towards mammalian host cells [19].…”

Cyclipostins and cyclophostin analogs inhibit the antigen 85C from Mycobacterium tuberculosis both in vitro and in vivo

“…CyC7, CyC8 and CyC17 were synthesized as previously described (31,50). To study the inhibitory effect on DGAT activity, 30 M of either Ag85A, Ag85B, Ag85C or MPT51 were coincubated with increasing concentrations of CyC7, CyC8 and CyC17 for 1 hr at room temperature in a reaction mixture containing 50 mM potassium phosphate buffer (pH 7.6), 10% DMSO and 0.5 × the critical micelle concentration (CMC) of nDodecyl β-D-maltoside (DDM).…”

Cyclipostins and Cyclophostin Analogues as Multitarget Inhibitors That Impair Growth of Mycobacterium abscessus

“…We incremented the already available library comprising 26 CyC compounds (i.e., CyC1-18 including the cis-() and trans-() isomers), 7,10 by synthesizing 12 additional analogs (CyC19-30) from various 3-keto esters following previously described synthetic routes (Scheme 1). [3][4][5][6] The general approach previously used for the synthesis of phosphonate analogs CyC4-10 was applied (Scheme 1A) to the synthesis of cyclic phosphonates with variation in the enol alkyl substituent (CyC19-22). The palladium-catalyzed substitution reaction of methyl or ethyl acetoacetate derivatives (2) 35 with the allylic carbonate (1) gave the vinyl phosphonates (3) as an E/Z mixture in good yields (35-63%).…”

“…To explore this hypothesis, we have reported the synthesis of Cyclipostins and Cyclophostin analogs (namely the CyCs - Figure 1). [3][4][5][6] We first demonstrated that this first series of 26 CyCs (Figure 1) was able to efficiently inhibit the growth of Mycobacterium tuberculosis H37Rv, in vitro as well as in infected macrophages, with very low toxicity towards the host cells. 7 These studies also strongly support the assumption that CyC compounds are multi-target inhibitors impairing various mycobacterial Ser-or Cys-containing enzymes involved in important physiological processes via the formation of a covalent bond between the enol-phosphorous atom and the catalytic residue.…”