Steric structure–activity relationship of cyproheptadine derivatives as inhibitors of histone methyltransferase Set7/9. Issue 18 (15th September 2016)

• Record Type: Journal Article
• Authors: Fujiwara, Takashi; Ohira, Kasumi; Urushibara, Ko; Ito, Akihiro; Yoshida, Minoru; Kanai, Misae; Tanatani, Aya; Kagechika, Hiroyuki; Hirano, Tomoya
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 18(2016)
• Page Start: 4318
• Page End: 4323
• Publication Date: 2016-09-15
• Subjects: Set7/9 -- Inhibitor -- Histone methyltransferase -- Cyproheptadine -- Epigenetics; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.07.024
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Set7/9 is a histone lysine methyltransferase, but it is also thought to be involved in a wide variety of pathophysiological functions. We previously identified cyproheptadine, which has a characteristic butterfly-like molecular conformation with bent tricyclic dibenzosuberene and chair-form N -methylpiperidine moieties, as a Set7/9 inhibitor. In this work, we synthesized several derivatives in order to examine the steric structure–inhibitory activity relationship. We found that even a small change of molecular shape due to reduction or replacement of the 10, 11-olefinic bond of the tricyclic ring generally resulted in a drastic decrease of the inhibitory activity. Our results should be useful not only for development of more potent and selective inhibitors, but also for the construction of novel inhibitor scaffolds.