Identification of thiols and glutathione conjugates of depsipeptide FK228 (FR901228), a novel histone protein deacetylase inhibitor, in the blood.
Four glutathione (GSH) conjugates and two thiols were detected when depsipeptide FK228, formerly FR901228, a naturally occurring potent histone deacetylase (HDAC) inhibitor, was incubated in rat or human plasma in the presence of GSH. Their structures were elucidated by the high-performance liquid chromatography/electrospray ionization multi-stage mass spectrometry (HPLC/ESI-MS(n)) technique, and in some cases confirmed by accurate mass measurement. These products were also detected in rat and human blood homogenates following their incubation with FK228, but were not detected in GSH solution alone. A possible scheme for its formation is proposed. One of the thiols has recently been found to be more active as a histone deacetylase inhibitor than the parent compound.
Xiao
Jim J
JJ
College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
Byrd
John
J
Marcucci
Guido
G
Grever
Michael
M
Chan
Kenneth K
KK
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D047630:Depsipeptides; D004791:Enzyme Inhibitors / Q000097:blood / Q000378:metabolism; D005978:Glutathione / Q000097:blood* / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000097:blood* / Q000378:metabolism*; D010949:Plasma / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D021241:Spectrometry, Mass, Electrospray Ionization; D013438:Sulfhydryl Compounds / Q000097:blood* / Q000737:chemistry
D047630:Depsipeptides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D010456:Peptides, Cyclic; D013438:Sulfhydryl Compounds; C087123:romidepsin; D005978:Glutathione