Synthesis of 2',3',4'-trihydroxyflavone (2-D08), an inhibitor of protein sumoylation.
Protein sumoylation is a dynamic posttranslational modification involved in diverse biological processes during cellular homeostasis and development. Recently sumoylation has been shown to play a critical role in cancer, although to date there are few small molecule probes available to inhibit enzymes involved in the SUMO conjugation process. As part of a program to identify and study inhibitors of sumoylation we recently reported the discovery that 2',3',4'-trihydroxyflavone (2-D08) is a cell permeable, mechanistically unique inhibitor of protein sumoylation. The work reported herein describes an efficient synthesis of 2-D08 as well as a structurally related but inactive isomer. We also report an unanticipated Wessely-Moser rearrangement that occurs under vigorous methyl ether deprotection conditions. This rearrangement likely gave rise to 2-D08 during a deprotection step, resulting in 2-D08 appearing as a contaminant in a screening well from a commercial supplier.
Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, 376 Boyles St., Frederick, MD 21702, USA.
Yeong Sang
YS
Kim
Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, 376 Boyles St., Frederick, MD 21702, USA.
Samantha G L
SG
Keyser
Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, 376 Boyles St., Frederick, MD 21702, USA. Electronic address: schneeklothjs@mail.nih.gov.
John S
JS
Schneekloth
D047309:Flavones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D025841:Small Ubiquitin-Related Modifier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D058207:Sumoylation / Q000187:drug effects
C000592084:2',3',4'-trihydroxyflavone; D047309:Flavones; D025841:Small Ubiquitin-Related Modifier Proteins
Flavone; Inhibitor; SUMO; Synthesis