25491-00-3Relevant academic research and scientific papers
Eudismic analysis of tricyclic sesquiterpenoid alcohols: Lead structures for the design of potent inhibitors of the human UDP-glucuronosyltransferase 2B7
Bichlmaier, Ingo,Kurkela, Mika,Siiskonen, Antti,Finel, Moshe,Yli-Kauhaluoma, Jari
, p. 386 - 400 (2007)
The epimeric tricyclic sesquiterpenoid alcohols globulol, epiglobulol, cedrol, epicedrol, longifolol, and isolongifolol were investigated in their ability to inhibit the recombinant human UDP-glucuronosyltransferase (UGT) 2B7. The stereoisomers displayed rapidly reversible competitive inhibition, which was substrate-independent. Longifolol and its stereoisomer isolongifolol displayed the lowest competitive inhibition constants (Kic) of 23 and 26 nM, respectively. The Kic values of cedrol and its epimer epicedrol were 0.15 and 0.21 μM, those of globulol and epiglobulol were 5.4 and 4.0 μM, respectively. The diastereomeric alcohols exhibited nearly identical affinities toward UGT2B7 indicating that the spatial arrangement of the hydroxy group had no influence on the dissociation of the enzyme-terpenoid complex. The high affinities stemmed presumably from mere hydrophobic interactions between the hydrocarbon scaffold of the terpenoid alcohol and the binding site of the enzyme. Glucuronidation assays revealed that there were large differences in the rates at which the epimeric alcohols were conjugated. Therefore, the spatial arrangement of the hydroxy group controlled the rate of the UGT2B7-catalyzed reaction. The introduction of a methyl group into the side chain of isolongifolol and longifolol increased the steric hindrance. As a result, the rate of the UGT2B7-catalyzed reaction was decreased by more than 88%. The findings indicated that the rate of the UGT2B7-catalyzed glucuronidation is significantly controlled by stereochemical and steric factors. Considering the high inhibition levels exerted by the tricyclic sesquiterpenoid alcohols, these compounds might serve as valuable lead structures for the design of potent inhibitors for UGT2B7.
Isoform-selective inhibition of the human UDP-glucuronosyltransferase 2B7 by isolongifolol derivatives
Bichlmaier, Ingo,Kurkela, Mika,Joshi, Tanmaya,Siiskonen, Antti,Rüffer, Tobias,Lang, Heinrich,Suchanová, Bohumila,Vahermo, Mikko,Finel, Moshe,Yli-Kauhaluoma, Jari
, p. 2655 - 2664 (2008/02/02)
A set of 48 derivatives of the tricyclic sesquiterpenol alcohol isolongifolol was synthesized. The set comprised homochiral and diastereomeric alcohols, amines, chlorohydrins, as well as carboxylic acids, phosphonic acids, and their corresponding esters. The absolute configuration of the epimeric compounds was assigned by 2D NMR experiments [gradient heteronuclear single quantum correlation (gHSQC) and gradient nuclear Overhauser enhancement spectroscopy (gNOESY)] in agreement with crystallographic data. The tricyclic derivatives were assessed as inhibitors of the human UDP-glucuronosyltransferase (UGT) 2B7. The phenyl-substituted secondary alcohol 26b was the best inhibitor in this series and its competitive inhibition constant was 18 nM. Compound 26b was not glucuronidated by UGT2B7 and other hepatic UGT enzymes, presumably due to the high steric hindrance exerted by its bulky phenyl substituent. Its inhibitory activity toward 14 other UGT isoforms of subfamily 1A and 2B was determined, and the data indicated that the tricyclic secondary alcohol 26b was highly selective for UGT2B7 (true selectivity > 1000).
The ozonolysis of longifolene: A tool for the preparation of useful chiral compounds. Configuration determination of new stereogenic centers by NMR spectroscopy and X-ray crystallography
Dimitrov, Vladimir,Rentsch, Gudrun Hopp,Linden, Anthony,Hesse, Manfred
, p. 106 - 121 (2007/10/03)
The ozonolysis of (+)-longifolene (1) in different solvents (Et2O, CH2Cl2, CHCl3, acetone) at -80° provided quantitatively longifolene epoxide (3) as a single diastereoisomer in which the O-atom is endopositioned (Scheme 2). Upon warming to room temperature, the epoxide remained stable only in acetone and was isolated as a low-melting crystalline compound. In CH2Cl2, Et2O, or CHCl3 solution, epoxide 3 rapidly rearranged to the isomeric enols 4 and 5, which underwent further rearrangement to give the exo-aldehyde 6. On standing for several weeks in CH2Cl2 solution, or in CHCl3 and Et2O as well, at room temperature, aldehyde 6 slowly rearranged into its epimer 7. The aldehydes 6 and 7 were isolated on the preparative scale for further synthetic use. The addition of methylmagnesium iodide to 6 and 7 provided the corresponding alcohols 13/14 and 15/16. respectively, which were isolated as pure diastereoisomers (Scheme 4). The configurations of the new chiral centers in 13-16 were determined by NMR methods and X-ray crystallography.
Camphor/Longicamphor and 7β-Formylnorlongifolane/7β-Acetylnorlongifolane Oximes: A Comparative Beckmann Rearrangement Study
Satyanarayana, N.,Shitole, H. R.,Nayak, U. R.
, p. 997 - 1001 (2007/10/02)
Camphor oxime (3)/longicamphor oxime (4) have been shown to undergo Beckmann fragmentation on exposure to tosyl chloride in pyridine generating olefinic nitriles: 3->5+6 and 4->7+8+9; in the case of 4 this reaction provides an entry into the bicyclononane system characteristic of the secolongifolene diol fungal metabolite (10). 7β-Formylnorlongifolane oxime (14)/7β-acetylnorlongifolane oxime (15) when treated with the same Beckmann catalyst under similar conditions, afford the nitrile (16)/amide (17); on hydrolysis with base 17 gives the amine 18.Reaction of longicamphor (2) with hydroxylamine-O-sulfonic acid, however, a ffords the nitrogen-insertion product, α-longicamphidone (24) besides the fragmented nitrile (7).
