Syntheses of Tetrahydrolipstatin and Absolute Configuration of Tetrahydrolipstatin and Lipstatin

Barbier, P.; Schneider, F

doi:10.1002/hlca.19870700124

Cited by 95 publications

(49 citation statements)

References 3 publications

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“…Lipstatin features a 2,3-trans-disubstituted ␤-propiolactone with two linear alkyl chains of C 6 at the ␣-site and C 13 at the ␤-site, respectively (i.e., an ␣-branched 3,5-dihydroxy fatty acid ␤-lactone backbone), and an N-formyl-L-leucine group attached as an ester to the 5-hydroxy of the long chain of the ␣-branched fatty acid backbone (8,9) (Fig. 1, structure 1).…”

mentioning

confidence: 99%

Operon for Biosynthesis of Lipstatin, the Beta-Lactone Inhibitor of Human Pancreatic Lipase

Bai

Zhang

Lin

et al. 2014

Appl Environ Microbiol

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c Lipstatin, isolated from Streptomyces toxytricini as a potent and selective inhibitor of human pancreatic lipase, is a precursor for tetrahydrolipstatin (also known as orlistat, Xenical, and Alli), the only FDA-approved antiobesity medication for long-term use. Lipstatin features a 2-hexyl-3,5-dihydroxy-7,10-hexadecadienoic-␤-lactone structure with an N-formyl-L-leucine group attached as an ester to the 5-hydroxy group. It has been suggested that the ␣-branched 3,5-dihydroxy fatty acid ␤-lactone moiety of lipstatin in S. toxytricini is derived from Claisen condensation between two fatty acid substrates, which are derived from incomplete oxidative degradation of linoleic acid based on feeding experiments. In this study, we identified a six-gene operon (lst) that was essential for the biosynthesis of lipstatin by large-deletion, complementation, and single-gene knockout experiments. lstA, lstB, and lstC, which encode two ␤-ketoacyl-acyl carrier protein synthase III homologues and an acyl coenzyme A (acyl-CoA) synthetase homologue, were indicated to be responsible for the generation of the ␣-branched 3,5-dihydroxy fatty acid backbone. Subsequently, the nonribosomal peptide synthetase (NRPS) gene lstE and the putative formyltransferase gene lstF were involved in decoration of the ␣-branched 3,5-dihydroxy fatty acid chain with an N-formylated leucine residue. Finally, the 3␤-hydroxysteroid dehydrogenase-homologous gene lstD might be responsible for the reduction of the ␤-keto group of the biosynthetic intermediate, thereby facilitating the formation of the unique ␤-lactone ring.

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mentioning

confidence: 99%

Operon for Biosynthesis of Lipstatin, the Beta-Lactone Inhibitor of Human Pancreatic Lipase

Bai

Zhang

Lin

et al. 2014

Appl Environ Microbiol

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“…Orlistat is the saturated derivative of lipstatin, a potent natural inhibitor of pancreatic lipases isolated from the bacterium Streptomyces toxytricini. 2 However, due to simplicity and stability, orlistat rather than lipstatin was developed into an anti-obesity drug. 3 It works by inhibiting gastric and pancreatic lipases, the enzymes that break down triglycerides in the intestine.…”

Section: Introductionmentioning

confidence: 99%

A Novel Formulation of Orlistat Solid Dispersions Using Solvent Evaporation Technique

Chitra¹,

Bhimavarapu²,

Anne³

et al. 2011

Int J of Biomed & Adv Res

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Solubility is an important physicochemical factor affecting absorption of drug and there by its therapeutic effect. About 40% of newly discovered drugs are lipophilic and failed to reach market due to their poor water solubility. Solid dispersions proved to have tremendous potential for improving drug solubility. Orlistat is a poor water soluble substance possessing anti-obesity property; in the present study an attempt was made to increase the solubility of orlistat by preparing solid dispersions using solvent evaporation technique. Three different formulations were prepared using Hydroxy propyl methyl cellulose (HPMC), Polyethylene glycol (PEG) and Eudragit with varying ratios of drug and carrier viz. 1:1, 1:2, 1:3 and the corresponding physical mixtures were also prepared. These solid dispersions were evaluated for flowability, solubility characteristics and in-vitro drug release. The in-vitro release of the formulation OP-SD3 was found to be best among all the 9 formulations with a release of 87.2% at the end of 2 hours. Release was best fitted with Korsmeyer-peppas kinetics and it shows that the drug release may follow diffusion mechanism. In-vitro dissolution studies showed that the dispersion system containing orlistat, dissolution of orlistat was retarded which attributed to ionic interaction and gel forming respectively but the solid dispersion containing PEG as carrier gave faster dissolution rate than physical mixture. Thus the solid dispersion technique found to be effective in increasing aqueous solubility of orlistat.

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“…It is also known as tetrahydrolipstatin [77]. It functions by preventing absorption of fats by acting as a lipase inhibitor.…”

Section: Orlistat (Xenical®)mentioning

confidence: 99%

Prevention and Treatment of Obesity and Diabetes and their Related Complications

Song¹

2014

J Mol Genet Med

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Syntheses of Tetrahydrolipstatin and Absolute Configuration of Tetrahydrolipstatin and Lipstatin

Cited by 95 publications

References 3 publications

Operon for Biosynthesis of Lipstatin, the Beta-Lactone Inhibitor of Human Pancreatic Lipase

Operon for Biosynthesis of Lipstatin, the Beta-Lactone Inhibitor of Human Pancreatic Lipase

A Novel Formulation of Orlistat Solid Dispersions Using Solvent Evaporation Technique

Prevention and Treatment of Obesity and Diabetes and their Related Complications

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