96388-83-9Relevant academic research and scientific papers
Unique analogues of anandamide: Arachidonyl ethers and carbamates and norarachidonyl carbamates and ureas
Ng, Edward W.,Aung, Mie Mie,Abood, Mary E.,Martin, Billy R.,Razdan, Raj K.
, p. 1975 - 1981 (1999)
To examine the effect of changing the amide bond of anandamide (5, AN) to a less hydrolyzable moiety, analogues la-11, 2a-2c, 3a-3c, and 4a-4h were synthesized from commercially available arachidonyl alcohol or arachidonic acid and tested for their pharmacological activity. Arachidonyl ethers 1a-1k were obtained through the coupling of the arachidonyl mesylate (6) (generated from the mesylation of arachidonyl alcohol) with the appropriate alcohol in potassium hydroxide. Arachidonyl ether 11 was obtained through the phase- transfer coupling of arachidonyl alcohol with 2-(2-iodoethoxy)tetrahydropyran (which was generated from its bromide) followed by cleavage of the tetrahydropyran group with Dowex resin. Arachidonyl carbamates 2a-2c were obtained through the coupling of arachidonyl alcohol with the appropriate isocyanates. Norarachidonyl carbamates 3a-3c and ureas 4a-4h were obtained through the coupling of the norarachidonyl isocyanate (generated from arachidonic acid using diphenyl phosphorazidate and triethylamine upon heating) with the appropriate alcohols and amines, respectively. AN analogues 1-3 have shown poor binding affinities to the CB1 receptor and fail to produce significant pharmacological effect at doses up to 30 mg/kg. Several ether analogues 1 were also evaluated in the CB2 binding assay and were found to be of low affinity. However, norarachidonyl urea analogues 4 have shown generally good binding affinities to the CB1 receptor (K(i) = 55-746 nM) and pharmacological activity with AN-like profiles. The most potent analogue of this series is the 2-fluoroethyl analogue 4f which binds 2 times better than AN and was more active in several mouse behavioral assays. It was also observed that urea analogues 4a and 4g, which have weak binding affinities to the CB1 receptor (K(i)=436 and 347 nM, respectively), produced surprisingly potent pharmacological activity. These urea analogues have also shown hydrolytic stability toward the amidase enzymes, responsible for the primary degradation pathway of anandamide, in binding affinity assays in the absence of the enzyme inhibitor PMSF.
Total synthesis of furanocembranolides. 1. Stereocontrolled preparation of key heterocyclic building blocks and assembly of a complete seco-pseudopterane framework
Paquette, Leo A.,Doherty, Annette M.,Rayner, Christopher M.
, p. 3910 - 3926 (2007/10/02)
A retrosynthetic strategy for the total synthesis of pseudopterolide and allied pseudopteranes is presented. This scheme is dependent upon early elaboration of suitable 2,5-difunctionalized 3-furoate esters. To this end, the pair of useful substrates 21 and 24 was readily synthesized from 2,3-O-isopropylidene-D-glyceraldehyde and methyl 4-(phenylthio)acetoacetate. The conversion of both of these intermediates into furanolactone 27 was next studied. The best method for gaining suitable control of stereochemistry involved condensation of 24 with methyl 3-formylpropionate under conditions of boron trifluoride catalysis. Transformation of the (phenylthio)methyl substituent of 27 into the requisite isopentenyl side chain was next accomplished in five steps. Because alkylation α to the lactone carbonyl in 46 could be realized only in modest yield, this final segment of the intended macrocyclic ring was introduced earlier by more convergent means. Indeed, the coupling of 24 to 52 proved to be efficient and highly diastereoselective. Following an unsuccessful attempt to introduce the isopentenyl side chain after elaboration of the butenolide subunit, the chemical sequence was reversed. The dual selenenylation strategy for oxidation of both relevant pendant groups was notably effective for this purpose. The subsequent chemospecific attachment of the isobutenyl fragment onto bromide 62 was achieved by palladium(0)-catalyzed coupling to a vinylstannane in a process that promises considerable versatility. Further chemical manipulation gave rise to the seco-pseudopterane 71, thereby completing the intermediate stages of the total synthesis of the pseudopterane ring system.
