Synthesis and inhibitory action on HMG-CoA synthase of racemic and optically active oxetan-2-ones (β-Lactones)

被引:39
作者
Romo, D
Harrison, PHM
Jenkins, SI
Riddoch, RW
Park, K
Yang, HW
Zhao, C
Wright, GD
机构
[1] Texas A&M Univ, Dept Chem, College Stn, TX 77843 USA
[2] McMaster Univ, Dept Chem, Hamilton, ON L8S 4M1, Canada
[3] McMaster Univ, Dept Biochem, Hamilton, ON L8S 4M1, Canada
基金
英国医学研究理事会; 加拿大自然科学与工程研究理事会; 美国国家科学基金会;
关键词
beta-lactones; HMG-CoA synthase; inhibition; asymmetric synthesis; chiral Lewis acid;
D O I
10.1016/S0968-0896(98)00114-X
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 (IR,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 IC(50)s that decreased monotonically with chain length up to 10 carbons and then rose rapidly for longer chains. The irans isomers of 3-methyl-4-alkyl-oxetan-2-ones showed a similar trend but had 1.3- to 5.6-fold lower IC(50)s. 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. (C) 1998 Elsevier Science Ltd. All rights reserved.
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页码:1255 / 1272
页数:18
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