Steroidal Triterpenes: Design of Substrate-Based Inhibitors of Ergosterol and Sitosterol Synthesis

Molecules

Jialin Liu¹ 

[1] Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas, 79409, USA

关键词: sterol C24-methyltransferase (24-SMT);    transition state analogs;    mechanismbased inactivator;    ergosterol biosynthesis inhibitors;    ergosterol;    sitosterol;    triterpenes;   

DOI  :  10.3390/molecules14114690

来源: mdpi

【 摘 要 】

This article reviews the design and study, in our own laboratory and others, of new steroidal triterpenes with a modified lanosterol or cycloartenol frame. These compounds, along with a number of known analogs with the cholestane skeleton, have been evaluated as reversible or irreversible inhibitors of sterol C24-methyltransferase (SMT) from plants, fungi and protozoa. The SMT catalyzes the C24-methylation reaction involved with the introduction of the C24-methyl group of ergosterol and the C24-ethyl group of sitosterol, cholesterol surrogates that function as essential membrane inserts in many photosynthetic and non-photosynthetic eukaryotic organisms. Sterol side chains constructed with a nitrogen, sulfur, bromine or fluorine atom, altered to possess a methylene cyclopropane group, or elongated to include terminal double or triple bonds are shown to exhibit different in vitro activities toward the SMT which are mirrored in the inhibition potencies detected in the growth response of treated cultured human and plant cells or microbes. Several of the substrate-based analogs surveyed here appear to be taxaspecific compounds acting as mechanism-based inactivators of the SMT, a crucial enzyme not synthesized by animals. Possible mechanisms for the inactivation process and generation of novel products catalyzed by the variant SMTs are discussed.

【 授权许可】

CC BY   
This is an open access article distributed under the Creative Commons Attribution License (CC BY) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.