Steroidomimetic Aminomethyl Spiroacetals as Novel Inhibitors of the Enzyme Δ8,7‐Sterol Isomerase in Cholesterol Biosynthesis

Abstract

Grundmann's ketone is converted to a spiroacetal containing a 5-hydroxymethyl-5-nitro-1,3-dioxane moiety whose hydroxymethyl group can be esterified or directly substituted with primary and secondary amines. Among the resulting aminomethyl spiroacetals, several ones bearing diamino residues were found to be inhibitors of the enzyme Δ8,7-isomerase in cholesterol biosynthesis. The complex bicyclic building block derived from Grundmann's ketone could be replaced by a properly substituted tetraline scaffold, without noteworthy loss in activity. This opens the opportunity to perform further structural modifications for the design of new steroidomimetic inhibitors of human Δ8,7-isomerase.

Fungal sterol C22-desaturase is not an antimycotic target as shown by selective inhibitors and testing on clinical isolates

“…Our efforts led to the discovery of new, selective cholesterol biosynthesis inhibitors targeting the enzymes oxidosqualene cyclase (OSC) [14], sterol D 8/7 -isomerase [15,16], sterol C5-desaturase as well as D 24 -desaturase (inhibited by lathosterol side chain amides depending on the size of the Nalkyl residue) [17], and 7-dehydrocholesterol reductase (7-DHCR) [18]. Furthermore, new ergosterol biosynthesis inhibitors with distinct targets like sterol D 14 -reductase [19], sterol C24-methyltransferase (24-SMT) [20], sterol D 8/7 -isomerase [19,21], but also with unidentified target(s) [22] were developed.…”