- Water-removable ynamide coupling reagent for racemization-free syntheses of peptides, amides, and esters
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A novel ynamide coupling reagent, the by-product of which can be removed by water, was reported. It promotes the direct coupling between carboxylic acids and amines, alcohols or thiols to provide amides, peptides, esters and thioesters, respectively. No detectable racemization was observed for all the coupling reactions of carboxylic acids containing an α-chiral center. Importantly, a simple acidic aqueous work-up removed the by-product readily to afford pure coupling products in good to excellent yields without the use of column chromatography, thus making this method more environmentally benign, user friendly and cost-effective. The robustness of the water-removable ynamide coupling reagent was further exemplified by the racemization/epimerization-free synthesis of carfilzomib, in which no column chromatography purification was involved for the entire 12-step synthesis.
- Liu, Tao,Zhang, Xue,Peng, Zejun,Zhao, Junfeng
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supporting information
p. 9916 - 9921
(2021/12/24)
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- COMPOSITIONS AND METHODS FOR SUBSTRATE-SELECTIVE INHIBITION OF ENDOCANNABINOID OXYGENATION
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Methods for selectively inhibiting endocannabinoid oxygenation but not arachidonic acid oxygenation. In some embodiments, the methods include contacting a COX-2 polypeptide with an effective amount of a substrate-selective COX-2 inhibitor. Also provided are methods for elevating a local endogenous cannabinoid concentrations; methods of reducing depletion of an endogenous cannabinoid; methods for inducing analgesia; methods of providing anxiolytic therapy; methods for providing anti-depressant therapy; and compositions for performing the disclosed methods.
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- Ester and amide derivatives of the nonsteroidal antiinflammatory drug, indomethacin, as selective cyclooxygenase-2 inhibitors
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Recent studies from our laboratory have shown that derivatization of the carboxylate moiety in substrate analogue inhibitors, such as 5,8,11,14- eicosatetraynoic acid, and in nonsteroidal antiinflammatory drugs (NSAIDs), such as indomethacin and meclofenamic acid, results in the generation of potent and selective cyclooxygenase-2 (COX-2) inhibitors (Kalgutkar et al. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 925-930). This paper summarizes details of the structure-activity studies involved in the transformation of the arylacetic acid NSAID, indomethacin, into a COX-2-selective inhibitor. Many of the structurally diverse indomethacin esters and amides inhibited purified human COX-2 with IC50 values in the low-nanomolar range but did not inhibit ovine COX-1 activity at concentrations as high as 66 μM. Primary and secondary amide analogues of indomethacin were more potent as COX-2 inhibitors than the corresponding tertiary amides. Replacement of the 4- chlorobenzoyl group in indomethacin esters or amides with the 4-bromobenzyl functionality or hydrogen afforded inactive compounds. Likewise, exchanging the 2-methyl group on the indole ring in the ester and amide series with a hydrogen also generated inactive compounds. Inhibition kinetics revealed that indomethacin amides behave as slow, tight-binding inhibitors of COX-2 and that selectivity is a function of the time-dependent step. Conversion of indomethacin into ester and amide derivatives provides a facile strategy for generating highly selective COX-2 inhibitors and eliminating the gastrointestinal side effects of the parent compound.
- Kalgutkar, Amit S.,Marnett, Alan B.,Crews, Brenda C.,Remmel, Rory P.,Marnett, Lawrence J.
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p. 2860 - 2870
(2007/10/03)
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- New class of potent ligands for the human peripheral cannabinoid receptor
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A new class of potent ligand for the human peripheral cannabinoid (hCB2) receptor is described. Two indole analogs 13 and 17 exhibited nanomolar potencies (K(i)) with good selectivity for the hCB2 receptor over the human central cannabinoid (hCB1) receptor.
- Gallant, Michel,Dufresne, Claude,Gareau, Yves,Guay, Daniel,Leblanc, Yves,Prasit, Petpiboon,Rochette, Chantal,Sawyer, Nicole,Slipetz, Deborah M.,Tremblay, Nathalie,Metters, Kathleen M.,Labelle, Marc
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p. 2263 - 2268
(2007/10/03)
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