Rational design and syntheis of substrate-based inhibitors of steroidogenesis
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Sterol biosynthesis is crucial to all groups of life forms. Targeted inhibition of this pathway by substrate-based analogs is currently used to probe sterol function and may have therapeutic importance. In this dissertation, a series of new steroidal triperpenes with a modified lanosterol or cycloartenol frame have been designed to inhibit steroidogenesis. These compounds, along with a number of known sterol biosynthesis inhibitors with the cholestane skeleton, have been prepared and characterized in detail using GC, MS, HPLC and NMR. Notably, a series of substrate analogs constructed with a methyl, nitrogen, sulfur, bromine or fluorine atom or altered to possess a methylene cyclopropane, or elongated to contain a terminal double or triple bonds were prepared to act as mechanism-based inactivators of the sterol 24-methyl transferase enzyme. In addition, compounds with the cholestane and lanostane structures were prepared with modifications at C-7 and C-32 to be reversible and irreversible inhibitors of the ¦¤8- ¦¤7-isomerase and 14¦Á-demethylase enzymes, respectively.