Tetrahydrolipstatin: Thermal and Hydrolytic Degradation

Stalder, Henri; Schneider, Pierre R.; Oesterhelt, G.

doi:10.1002/hlca.19900730427

Cited by 21 publications

(19 citation statements)

References 16 publications

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“…as esters 2b and 3b, respectively, if the primary metabolite(s) are to be identified [7]. The resulting esters are accessible to GC/MS and HPLC analysis [7].…”

Section: Introduction -Tetrahydrolipstatin (Thl = ( S ) -1 -{ [(2s3mentioning

confidence: 99%

“…With both lipases, SerI5, attacks the 8-lactone ring exclusively at the carbonyl C-atom forming a serine ester. Products occurring by nucleophilic attack at C(8) (formation of a serine ether), as observed, e.g., with H,O [7], were not found. Therefore, in a reversible system like HCEL incubated with 1 in which 1 is consumed by the enzyme, we expected, after recovery of HCEL activity, to find 8-hydroxy acid 2a as product of hydrolysis.…”

mentioning

confidence: 99%

“…As hydroxy acids 2a and 3a are reactive and form more stable compounds by isomerization and lactonization, they have to be quenched, e.g. as esters 2b and 3b, respectively, if the primary metabolite(s) are to be identified [7]. The resulting esters are accessible to GC/MS and HPLC analysis [7].…”

mentioning

confidence: 99%

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Tetrahydrolipstatin: Degradation products produced by human carboxyl‐ester lipase

Stalder¹,

Oesterhelt²,

Borgström³

1992

Helvetica Chimica Acta

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The fate of tetrahydrolipstatin (1) incubated with human carboxyl-ester lipase (HCEL) was investigated. The primary metabolite was identified as 6-(N-formyl-~-leucyloxy)-P-hydroxy acid 2a with conserved configuration. It is formed by attack of the active-site serine of HCEL at the carbonyl C-atom of the /I-lactone ring of 1 followed by hydrolysis of the intermediate serine ester. Further products isolated were identified and a complete degradation scheme is proposed.

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“…as esters 2b and 3b, respectively, if the primary metabolite(s) are to be identified [7]. The resulting esters are accessible to GC/MS and HPLC analysis [7].…”

Section: Introduction -Tetrahydrolipstatin (Thl = ( S ) -1 -{ [(2s3mentioning

confidence: 99%

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confidence: 99%

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Tetrahydrolipstatin: Degradation products produced by human carboxyl‐ester lipase

Stalder¹,

Oesterhelt²,

Borgström³

1992

Helvetica Chimica Acta

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“…Lactones interact with the serine residues of pancreatic lipase via irreversible formation of ester bond [10,15], so that fatty acids are conserved in the form of triglycerides and are not assimilated, which leads to weight loss [16][17][18][19][20]. Modern studies have also shown prospects in using tetrahydrolipstatin as a potential antitumor agent active against breast, prostate, and ovarian cancer cells and melanoma [21][22][23][24][25].…”

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confidence: 99%

Asymmetric syntheses of the lactone core of tetrahydrolipstatin and tetrahydroesterastin and of the oriental hornet Vespa Orientalis pheromone

Минеева

2015

Russ J Org Chem

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A synthetic approach to the lactone core of the anti-obesity drugs tetrahydrolipstatin and tetrahydroesterastin has been developed starting from readily accessible methyl (5S)-5-{[tert-butyl(dimethyl)silyl]-oxy}-3-oxohexadecanoate. (6S)-6-Undecyltetrahydro-2H-pyran-2-one, the oriental hornet Vespa Orientalis pheromone, has also been synthesized. A formal synthesis of (3S,4R,6S)-dihydroxy-6-undecyltetrahydro-2Hpyran-2-one (metabolite of a fungus separated from mangrove seeds) has been proposed.

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“…1 The biological activity inherent to this family of molecules is based on the reactivity of the β -lactone moiety which is readily acylated by the pancreatic lipase enzyme. This process ultimately inhibits the enzyme reactivity aimed at hydrolyzing triglycerides to produce free fatty acids which are then readily absorbed into the dietary system 1b,2…”

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A Concise, Phosphate-Mediated Approach to the Total Synthesis of (−)-Tetrahydrolipstatin

et al. 2010

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An efficient synthesis of (−)-tetrahydrolipstatin (THL) is reported. This method takes advantage of a phosphate tether-mediated, one-pot, sequential RCM/CM/hydrogenation protocol to deliver THL in 8 total steps from a readily prepared (S,S)-triene. The strategy incorporates selective cross metathesis, regio-selective hydrogenation, regio-and diastereoselective cuprate addition and Mitsunobu inversion for installation of the C5 formamide ester subunit.(−)-Tetrahydrolipstatin (THL, 1) is an anti-obesity drug marketed under generic name Orlistat ® and is a stable saturated form of the naturally occuring lipstatin (2) (Figure 1). Lipstatin is a protein-reactive natural product and an irreversible pancreatic lipase inhibitor which was first isolated in 1987 from Streptomyces toxytricini. 1 The biological activity inherent to this family of molecules is based on the reactivity of the β-lactone moiety which is readily acylated by the pancreatic lipase enzyme. This process ultimately inhibits the enzyme reactivity aimed at hydrolyzing triglycerides to produce free fatty acids which are then readily absorbed into the dietary system. 1b,2 Recently, the discovery of selective inhibition of thioesterase activity of fatty acid synthase (FAS) in cancer cells has elevated the potential of Orlistat ® as an anticancer drug. 3,4 The inhibition of FAS stops both endothelial cell proliferation and angiogenesis and ultimately delays tumor progression in a variety of cancer cells. This promising activity highlights the broad and interesting biological profile of Orlistat ® and has prompted renewed synthetic efforts and corresponding biology of THL, lipstatin and analogs thereof.4 ,5 Herein we report a concise total synthesis of (−)-tetrahydrolipstatin via a strategy utilizing a phosphate-tether-mediated, one-pot, sequential RCM/CM/hydrogenation pathway of triene (S,S)-7. 6 Overall, the reported phanson@ku.edu. Supporting Information Available Experimental details and spectroscopic data of new compounds. This material is available free of charge via the Internet at http://pubs.acs.org. NIH Public Access Author ManuscriptOrg Lett. Author manuscript; available in PMC 2011 April 2. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript synthetic route comprises 9 total steps from the readily prepared diene diol-(S,S)-8 and highlights the utility of phosphate tethered processes and one-pot, multi-step operations.The first total synthesis of THL was achieved in 1987 by Schneider and coworkers utilizing Wittig olefination and an aldol condensation as key steps in a non-stereoselective process.7 Numerous total syntheses,8 formal syntheses 9 and synthetic analogues have followed this initial report, with the majority of synthetic pathways comprised of 14-25 steps. The shortest routes to THL reported to-date range from 10-12 steps using an array of synthetic strategies, including, (i) a 12-step anti-aldol approach,8i (ii) a 12-step diastereoselective allylation and crotylation sequence utilizing allyl/crotyltri...

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Tetrahydrolipstatin: Thermal and Hydrolytic Degradation

Cited by 21 publications

References 16 publications

Tetrahydrolipstatin: Degradation products produced by human carboxyl‐ester lipase

Tetrahydrolipstatin: Degradation products produced by human carboxyl‐ester lipase

Asymmetric syntheses of the lactone core of tetrahydrolipstatin and tetrahydroesterastin and of the oriental hornet Vespa Orientalis pheromone

A Concise, Phosphate-Mediated Approach to the Total Synthesis of (−)-Tetrahydrolipstatin

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