152906-15-5Relevant academic research and scientific papers
Development of an activity-based probe and in silico design reveal highly selective inhibitors for diacylglycerol lipase-α in brain
Baggelaar, Marc P.,Janssen, Freek J.,Vanesbroeck, Annelot C. M.,Dendulk, Hans,Allara, Marco,Hoogendoorn, Sascha,McGuire, Ross,Florea, Bogdan I.,Meeuwenoord, Nico,Vandenelst, Hans,Vandermarel, Gijsbert A.,Brouwer, Jaap,Dimarzo, Vincenzo,Overkleeft, Herman S.,Vanderstelt, Mario
supporting information, p. 12081 - 12085 (2013/12/04)
A model method: A strategy that combines a knowledge-based insilico design approach and the development of novel activity-based probes (ABPs) for the detection of endogenous diacylglycerol lipase-α (DAGL-α) is presented. This approach resulted in the rapi
Activity-based proteome profiling of potential cellular targets of orlistat - An FDA-approved drug with anti-tumor activities
Yang, Peng-Yu,Liu, Kai,Ngai, Mun Hong,Lear, Martin J.,Wenk, Markus R.,Yao, Shao Q.
supporting information; experimental part, p. 656 - 666 (2010/03/25)
Orlistat, or tetrahydrolipstatin (THL), is an FDA-approved antiobesity drug with potential antitumor activities. Cellular off-targets and potential side effects of Orlistat in cancer therapies, however, have not been extensively explored thus far. In this study, we report the total of synthesis of THL-like protein-reactive probes, in which extremely conservative modifications (i.e., an alkyne handle) were introduced in the parental THL structure to maintain the native biological properties of Orlistat, while providing the necessary functionality for target identification via the bio-orthogonal click chemistry. With these natural productlike, cell-permeable probes, we were able to demonstrate, for the first time, this chemical proteomic approach is suitable for the identification of previously unknown cellular targets of Orlistat. In addition to the expected fatty acid synthase (FAS), we identified a total of eight new targets, some of which were further validated by experiments including Western blotting, recombinant protein expression, and site-directed mutagenesis. Our findings have important implications in the consideration of Orlistat as a potential anticancer drug at its early stages of development for cancer therapy. Our strategy should be broadly useful for off-target identification against quite a number of existing drugs and/or candidates, which are also covalent modifiers of their biological targets.
Total synthesis of (-)-tetrahydrolipstatin
Hanessian,Tehim,Chen
, p. 7768 - 7781 (2007/10/02)
The total synthesis of (-)-tetrahydrolipstatin utilizing two approaches is described. In the first, L-malic acid was used as a chiral template to obtain enantiomerically pure (R)-3-(benzyloxy)-tetradecanal (11) which was chain- extended using 1-(trimethylsilyl)-2-nonene and a Lewis acid. This advanced intermediate was further elaborated to the target compound in good overall yield. The second approach utilized lauraldehyde as a starting material and capitalizes on an asymmetric allylboronation (91% ee). The product could be obtained enantiomerically pure by conversion to the (R)-acetoxymandelate ester and hydrolysis. Oxidative cleavage of the terminal double bond led to 11 which was further extended using 1,3- and 1,2-asymmetric induction based on existing neighboring chirality. The synthesis of tetrahydrolipstatin using the second approach comprises seven steps from 11 and proceeds in 38% overall yield.
