23778-41-8Relevant academic research and scientific papers
Synthesis and inhibitory action on HMG-CoA synthase of racemic and optically active oxetan-2-ones (β-Lactones)
Romo, Daniel,Harrison, Paul H. M.,Jenkins, Stephen I.,Riddoch, R. William,Park, Kaapjoo,Yang, Hong Woon,Zhao, Cunxiang,Wright, Gerard D.
, p. 1255 - 1272 (2007/10/03)
A homologous series of both C3-unsubstituted and C3-methyl substituted oxetan-2-ones (β-lactones) was investigated as potential inhibitors of yeast 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) synthase. Several reported methods for racemic β-lactone synthesis were studied for preparation of the target series. In addition, a novel aluminum-based Lewis acid obtained by combination of Et2AlCl with (1R,2R)-2-[(diphenyl)hydroxymethyl] cyclohexan-1-ol was studied for the asymmetric [2+2] cycloaddition of aldehydes and trimethylsilylketene. This Lewis acid exhibited good reactivity but variable enantioselectivity (22-85% ee). In in vitro assays using both native and recombinant HMG-CoA synthase from Saccharomyces cerevisiae, oxetan-2-ones mono-substituted at C4 with linear alkyl chains gave IC50s that decreased monotonically with chain length up to 10 carbons and then rose rapidly for longer chains. The trans isomers of 3-methyl-4-alkyl-oxetan-2-ones showed a similar trend but had 1.3- to 5.6-fold lower IC50s. The results imply a substantial hydrophobic pocket in this enzyme that interacts with both C-3 and C-4 substituents of oxetan-2-one inhibitors. Copyright (C) 1998 Elsevier Science Ltd.
