104871-99-0Relevant articles and documents
The total synthesis of (-)-tetrahydrolipstatin
Bodkin, Jennifer A.,Humphries, Edward J.,McLeod, Malcolm D.
, p. 2869 - 2872 (2003)
Careful control during the bromolactonisation of β,γ-unsaturated acid 3 was required to afford regioselectively the trans-β-lactone 4 as the major diastereomer. Radical debromination of 4 followed by a three-step sequence of reactions afforded the lipase inhibitor (-)-tetrahydrolipstatin.
Diastereoselective allylations and crotylations under phase-transfer conditions using trifluoroborate salts: An application to the total synthesis of (-)-tetrahydrolipstatin
Thadani, Avinash N.,Batey, Robert A.
, p. 8051 - 8055 (2003)
A mild protocol for diastereoselective allylations and crotylations of α- and β-silyloxy substituted aldehydes utilizing potassium allyl/crotyltrifluoroborates is described. The reactions proceed to completion within 30 min at room temperature in biphasic or aqueous media in the presence of a phase transfer catalyst. The resulting homoallylic alcohols are obtained in high yields and moderate to excellent diastereoselectivities. The method was applied to the asymmetric total synthesis of the antiobesity agent tetrahydrolipstatin (orlistat).
Total synthesis and comparative analysis of orlistat, valilactone, and a transposed orlistat derivative: Inhibitors of fatty acid synthase
Ma, Gil,Zancanella, Manuel,Oyola, Yatsandra,Richardson, Robyn D.,Smith, Jeffrey W.,Romo, Daniel
, p. 4497 - 4500 (2006)
Concise syntheses of orlistat (Xenical), a two-carbon transposed orlistat derivative, and valilactone are described that employ the tandem Mukaiyama aldol-lactonization (TMAL) process as a key step. This process allows facile modification of the α-side chain. Versatile strategies for modifying the δ-side chain are described, involving cuprate addition and olefin metathesis. Comparative antagonistic activity of these derivatives toward a recombinant form of the thioesterase domain of fatty acid synthase is reported along with comparative activity-based profiling.
Asymmetric syntheses of the lactone core of tetrahydrolipstatin and tetrahydroesterastin and of the oriental hornet Vespa Orientalis pheromone
Mineeva
, p. 842 - 848 (2015)
Abstract 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-2H-pyran-2-one (metabolite of a fungus separated from mangrove seeds) has been proposed.
One-step modification to identify dual-inhibitors targeting both pancreatic triglyceride lipase and Niemann-Pick C1-like 1
Zhang, Renshuai,Song, Zhengming,Wang, Xueting,Xue, Jiao,Xing, Dongming
, (2021/03/16)
Pancreatic triglyceride lipase (PTL) and Niemann-Pick C1-like 1 (NPC1L1) have been identified as attractive therapeutic targets for obesity and hypercholesteremia, respectively. Obesity and hypercholesteremia usually co-exist, however no dual-inhibitors against PTL and NPC1L1 were reported for the treatment of obesity patients with hypercholesteremia so far. In this work, molecular hybridization-based one-step modification screening identified a potent dual-inhibitor against PTL and NPC1L1. Compound P1-11 has IC50 values of 2.1 μM against PTL through covalent binding, as well as significantly reduces cholesterol absorption in a non-competitive inhibitory manner. Molecule docking and molecular dynamics studies revealed the reason of its activity to both PTL and NPC1L1. Moreover, the gene and protein expression levels of PTL and NPC1L1 were also determined respectively after the treatment of P1-11. Development of dual-inhibitors against PTL and NPC1L1 could provide novel treatment options for obesity patients with hypercholesteremia. The results of current research would great support the development of dual-inhibitors against PTL and NPC1L1.
Total Synthesis of Tetrahydrolipstatin, Its Derivatives, and Evaluation of Their Ability to Potentiate Multiple Antibiotic Classes against Mycobacterium Species
Khan, Saniya S.,Landgraf, Alexander D.,Ronning, Donald R.,Sucheck, Steven J.,Sudasinghe, Thanuja D.
, (2021/09/27)
Tetrahydrolipstatin (THL, 1a) has been shown to inhibit both mammalian and bacterial α/β hydrolases. In the case of bacterial systems, THL is a known inhibitor of several Mycobacterium tuberculosis hydrolases involved in mycomembrane biosynthesis. Herein we report a highly efficient eight-step asymmetric synthesis of THL using a route that allows modification of the THL α-chain substituent to afford compounds 1a through 1e. The key transformation in the synthesis was use of a (TPP)CrCl/Co2(CO)8-catalyzed regioselective and stereospecific carbonylation on an advanced epoxide intermediate to yield a trans-β-lactone. These compounds are modest inhibitors of Ag85A and Ag85C, two α/β hydrolases of M. tuberculosis involved in the biosynthesis of the mycomembrane. Among these compounds, 10d showed the highest inhibitory effect on Ag85A (34 ± 22 μM) and Ag85C (66 ± 8 μM), and its X-ray structure was solved in complex with Ag85C to 2.5 ? resolution. In contrast, compound 1e exhibited the best-in-class MICs of 50 μM (25 μg/mL) and 16 μM (8.4 μg/mL) against M. smegmatis and M. tuberculosis H37Ra, respectively, using a microtiter assay plate. Combination of 1e with 13 well-established antibiotics synergistically enhanced the potency of few of these antibiotics in M. smegmatis and M. tuberculosis H37Ra. Compound 1e applied at concentrations 4-fold lower than its MIC enhanced the MIC of the synergistic antibiotic by 2-256-fold. In addition to observing synergy with first-line drugs, rifamycin and isoniazid, the MIC of vancomycin against M. tuberculosis H37Ra was 65 μg/mL; however, the MIC was lowered to 0.25 μg/mL in the presence of 2.1 μg/mL 1e demonstrating the potential of targeting mycobacterial hydrolases involved in mycomembrane and peptidoglycan biosynthesis.
Refining method for key intermediate of orlistat
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Paragraph 0020; 0039-0041, (2021/04/10)
The invention discloses a refining method for a key intermediate of orlistat as well as key intermediate impurities and a preparation method thereof. The refining method comprises the step that a compound I is recrystallized in an organic solvent or a mixed organic solvent to remove impurities 1-5 which are difficult to remove in a process. The method has good selectivity on the impurities 1-5, and is simple and convenient to operate, low in cost and suitable for industrial production. The invention also provides an impurity 3 and a preparation method thereof, and application of the impurity 3 as an impurity reference substance of an orlistat key intermediate (3S,4S)-3-hexyl-4-[(R)-2-(hydroxytridecyl)]oxetan-2-one (the compound I).
Orlistat derivatives
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, (2019/07/04)
The invention relates to orlistat derivatives. In particular, the invention relates to the general formula (I) compound of formula, wherein R such as specification and defined in the claims. The general formula (I) indicated by the compounds can be used as anti-tumor and inhibit lipase activity of the drug.
COMPOUNDS FOR THE REDUCING LIPOTOXIC DAMAGE
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, (2019/01/30)
Provided herein are novel lipase inhibitors and methods for using the same to treat inflammation, multisystem organ failure, necrotic pancreatic acinar cell death, acute pancreatitis, sepsis (e.g., culture negative sepsis), burns, and acne. For example, provided herein are two novel lipase inhibitors useful in the methods described herein: (I) (II) or a pharmaceutically acceptable salt thereof.
Total synthesis of tetrahydrolipstatin and stereoisomers via a highly regio- and diastereoselective carbonylation of epoxyhomoallylic alcohols
Mulzer, Michael,Tiegs, Brandon J.,Wang, Yanping,Coates, Geoffrey W.,O'Doherty, George A.
supporting information, p. 10814 - 10820 (2014/08/18)
A concise enantioselective synthesis of tetrahydrolipstatin (THL) and seven stereoisomers has been achieved. The synthesis of THL was accomplished in 10 steps and 31% overall yield from an achiral ynone. Key to the success of the approach is the use of a bimetallic [Lewis acid]+[Co(CO)4]- catalyst for a late-stage regioselective carbonylation of an enantiomerically pure cis-epoxide to a trans-β-lactone. The success of this route to THL and its stereoisomers also demonstrated the practicality of the carbonylation catalyst for complex molecule synthesis as well as its functional group compatibility.
