Investigation of N-aryl-3-alkylidenepyrrolinones as potential Niemann-Pick type C disease therapeutics.
A five-step synthesis of an array of N-aryl-3-alkylidenepyrrolinones, which are potential Niemann-Pick type C (NPC) disease therapeutics, is described. The synthetic route allows for the production of analogues, including photoaffinity and biotinylated derivatives. Compound 1a increased esterification by acyl-coenzyme A:cholesteryl acyltransferase in NPC1 mutant cells. It also decreased LDL uptake and increased cholesterol efflux in both NPC1-deficient and normal cells.
Cosner
Casey C
CC
Department of Chemistry and Biochemistry, University of Notre Dame, 250 Nieuwland Science Hall, Notre Dame, Indiana 46556, USA.
Markiewicz
John T
JT
Bourbon
Pauline
P
Mariani
Christopher J
CJ
Wiest
Olaf
O
Rujoi
Madalina
M
Rosenbaum
Anton I
AI
Huang
Amy Y
AY
Maxfield
Frederick R
FR
Helquist
Paul
P
D000818:Animals; D016466:CHO Cells; D002784:Cholesterol / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D052556:Niemann-Pick Disease, Type C / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use
D011758:Pyrroles; C013231:pyrroline; D002784:Cholesterol