| Autor: |
Romo D; Department of Chemistry, Texas A&M University, College Station 77843-3012, USA. romo@chemvx.chem.tamu.edu, Harrison PH, Jenkins SI, Riddoch RW, Park K, Yang HW, Zhao C, Wright GD |
| Jazyk: |
angličtina |
| Zdroj: |
Bioorganic & medicinal chemistry [Bioorg Med Chem] 1998 Aug; Vol. 6 (8), pp. 1255-72. |
| DOI: |
10.1016/s0968-0896(98)00114-x |
| Abstrakt: |
A homologous series of both C3-unsubstituted and C3-methyl substituted oxetan-2-ones (beta-lactones) was investigated as potential inhibitors of yeast 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) synthase. Several reported methods for racemic beta-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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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