Mitoxantrone analogues as ligands for a stem-loop structure of tau pre-mRNA.
A series of mitoxantrone (MTX) analogues have been designed, synthesized, and evaluated for binding to and stabilizing a stem-loop structure that serves as a splicing regulatory element in the pre-mRNA of tau, which is involved in Alzheimer's and other neurodegenerative diseases. Several compounds showed significantly improved binding activity relative to the original screening hit mitoxantrone. These findings establish essential structure-activity relationships to further optimize the activity of this promising class of compounds.
Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School,H.I.M. 754, Boston, Massachusetts 02115, USA.
Yang
Y
Liu
Eleanor
E
Peacey
John
J
Dickson
Christine P
CP
Donahue
Suxin
S
Zheng
Gabriele
G
Varani
Michael S
MS
Wolfe
D000880:Anthraquinones / Q000138:chemical synthesis* / Q000737:chemistry; D001667:Binding, Competitive; D008024:Ligands; D008942:Mitoxantrone / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D011073:Polyamines / Q000138:chemical synthesis* / Q000737:chemistry; D012322:RNA Precursors / Q000737:chemistry*; D012326:RNA Splicing; D012333:RNA, Messenger / Q000737:chemistry*; D050436:Regulatory Elements, Transcriptional; D013329:Structure-Activity Relationship; D016875:tau Proteins / Q000235:genetics*
D000880:Anthraquinones; D008024:Ligands; D011073:Polyamines; D012322:RNA Precursors; D012333:RNA, Messenger; D016875:tau Proteins; D008942:Mitoxantrone