171005-85-9Relevant academic research and scientific papers
Syntheses, Structures, and Enzymatic Evaluations of Conformationally Constrained, Analogue Inhibitors of Carnitine Acetyltransferase: (2R,6R)-, (2S,6S)-, (2R,6S)-, and (2S,6R)-6-(Carboxylatomethyl)-2-(hydroxymethyl)-2,4,4-trimethylmorpholinium
Sun, Guobin,Savle, Prashant S.,Gandour, Richard D.,a'Bhaird, Noirin Nic,Ramsay, Rona R.,Fronczek, Frank R.
, p. 6688 - 6695 (1995)
The syntheses and structures of the four stereoisomers of 6-(carboxylatomethyl)-2-(hydroxymethyl)-2,4,4-trimethylmorpholinium, 1, are described.The key step in the synthetic strategy involves an intramolecular Michael addition reaction.Condensation of nonracemic 3-(methylamino)-2-methylpropane-1,2-diol, 3, with methyl 4-bromo-2-butenoate followed by intramolecular Michael addition gives a mixture of two diastereomers of methyl 2-acetate, 5.The diastereomeric ratio of the products in this reaction changes from 6:1 to 1:1 with a change in solvent from diethyl ether:methanol (35:1, v:v) to methanol.The structures and absolute configurations of 1 were determined by single crystal X-ray analyses.In crystals and solution, the morpholinium rings adopt a chair conformation with carboxylatomethyl occupying an equatorial position.All four stereoisomers inhibit pigeon breast carnitine acetyltransferase (CAT).Of this series, (2S,6R)-1 binds to CAT most strongly with a Ki of 190 +/- 20 μM and an IC 50 of 0.42 mM.The enzymatic assays of 1 confirm that CAT recognizes both configurations at C2 and C6 in the analogues.CAT has a different conformation when it binds carnitine or acetylcarnitine than when it binds 1.This latter conformation may resemble that when CAT catalyzes acetyl transfer.
