Benzene-di-N-Substituted Carbamates as Conformationally Constrained Substrate Analogs of Cholesterol Esterase

Abstract

Benzene-1,2-, 1,3-, and 1,4-di-N-substituted carbamates (1–15) are synthesized as the constrained analogs of gauche, eclipsed, and anti conformations, respectively, for the glycerol backbones of triacylglycerol. Carbamates 1–15 are characterized as the pseudo substrate inhibitors of cholesterol esterase. Long chain carbamates are more potent inhibitors than short chain ones. Comparison of different geometries for benzene-di-substituted carbamates, such as benzene-1,2-di-N-octylcarbamate (3) (ortho-3), benzene-1,3-di-N-octylcarbamate (8) (meta-8), and benzene-1,4-di-N-octylcarbamates (13) (para-13), indicates that inhibitory potencies are as followed: meta-8 > para-13 > ortho-3. Therefore, we suggest that the preferable conformation for the C(sn-1)–O/C(sn-2)–O glycerol backbone in the enzyme–triacylgycerol complex is the eclipsed conformation. Meanwhile, kinetic data indicate that among ortho, meta, and para carbamates, meta carbamates most resemble the substrate cholesterol ester.