title: Novel Tranylcypromine/Hydroxylcinnamic Acid Hybrids as Lysine-Specific Demethylase 1 Inhibitors with Potent Antitumor Activity.
abstract: Novel tranylcypromine/hydroxylcinnamic acid hybrids 15a, b, and 19a-l were designed and synthesized by connecting tranylcypromine with hydroxylcinnamic acid, and their biological activities were evaluated. The in vitro assay of their inhibitory activities against lysine-specific demethylase 1 (LSD1) showed that most of the target compounds displayed high potency with IC50 values ranging from submicromolar to single-digit micromolar levels. In particular, compound 19l had robust, selective LSD1 inhibitory activity, which was obviously higher than the inhibitory activity against homologues monoamine oxidase-A (MAO-A) and MAO-B, respectively. Furthermore, the most potent compound 19l selectively inhibited cancer cell but not nontumor colon cell proliferation in vitro. In addition, compound 19l also dose-dependently increased the expression of H3K4me2 at the cellular level. Our findings suggest that tranylcypromine/hydroxylcinnamic acid hybrids as LSD1 inhibitors may hold great promise as therapeutic agents for the treatment of human cancers.
authors.affiliation: Department of Orthopedics, The First Affiliated Hospital, Wenzhou Medical University.
authors.forename: Yan
authors.initials: Y
authors.lastname: Han
authors.forename: Chunlei
authors.initials: C
authors.lastname: Wu
authors.forename: Haifeng
authors.initials: H
authors.lastname: Lv
authors.forename: Na
authors.initials: N
authors.lastname: Liu
authors.forename: Huaying
authors.initials: H
authors.lastname: Deng
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003373:Coumaric Acids / Q000737:chemistry / Q000494:pharmacology; D056466:Histone Demethylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D013329:Structure-Activity Relationship; D014191:Tranylcypromine / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D003373:Coumaric Acids; D008996:Monoamine Oxidase Inhibitors; D014191:Tranylcypromine; D056466:Histone Demethylases; C495195:KDM1A protein, human