Steroidomimetic aminomethyl spiroacetals as novel inhibitors of the enzyme Δ8,7-sterol isomerase in cholesterol biosynthesis.
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.
Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-University of Munich, Munich, Germany.
Melanie
M
Krojer
Christoph
C
Müller
Franz
F
Bracher
D000080:Acetals / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D000924:Anticholesteremic Agents / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D002470:Cell Survival; D002784:Cholesterol / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D018716:Molecular Mimicry; D015394:Molecular Structure; D013251:Steroid Isomerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000080:Acetals; D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D002784:Cholesterol; D013251:Steroid Isomerases; C022669:delta(8)-delta(7)-sterol isomerase; C090445:EBP protein, human
Acetal; Cholesterol biosynthesis; Enzyme inhibitors; Isomerase; Steroidomimetic