title: TX-2152: a conformationally rigid and electron-rich diyne analogue of FTY720 with in vivo antiangiogenic activity.
abstract: We designed FTY720 analogues with conformationally rigid and electron-rich acetylenic chains as antiangiogenic agents (the monoyne 1: TX-2148, the diyne 2: TX-2152, the triyne 3: TX-2256). Molecular orbital (MO) calculations of our designed acetylenic analogues and FTY720 showed that the localization of the lowest unoccupied MO and the highest occupied MO increased from phenyl ring to acetylenic chain compared with that of FTY720. These acetylenic analogues were synthesized from p-hydroxyphenylethanol as a starting material. The construction of the acetylenic chain was carried out by an iterative strategy using a Sonogashira cross-coupling reaction and desilylative bromination in two steps. The corresponding overall yields of the monoyne 1, the diyne 2, and the triyne 3 were 27% (11 steps), 13% (13 steps), and 10% (15 steps). The in vivo antiangiogenic activities of these acetylenic analogues and FTY720 were evaluated by the chick embryo chorioallantoic membrane (CAM) assay and compared to the activities of the known antiangiogenic agent TNP-470. The diyne 2 showed more potent antiangiogenic activity (90% inhibition) than FTY720 (77% inhibition) and other acetylenic analogues (the monoyne 1: 42% inhibition, the triyne 3: 60% inhibition), and TNP-470 (82% inhibition) at a dose of 10 microg/CAM, without showing toxicity. The diyne 2 also had potent inhibitory activity at a dose of 5 and 2.5 microg/CAM. These results indicate that the flexibility of C8 alkyl chain of FTY720 is not required for its antiangiogenic activity. We suggest that the diyne 2 (TX-2152) may be a promising candidate as an antiangiogenic agent for antineoplastic drug discovery.
authors.affiliation: Department of Life System, Institute of Technology and Science, Graduate School, The University of Tokushima, Minamijosanjimacho 2, Tokushima 770-8506, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Nakayama
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Uto
authors.forename: Kanako
authors.initials: K
authors.lastname: Tanimoto
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Okuno
authors.forename: Yuki
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Hideko
authors.initials: H
authors.lastname: Nagasawa
authors.forename: Eiji
authors.initials: E
authors.lastname: Nakata
authors.forename: Ken
authors.initials: K
authors.lastname: Arai
authors.forename: Kaori
authors.initials: K
authors.lastname: Momose
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Fujita
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Asakawa
authors.forename: Satoru
authors.initials: S
authors.lastname: Goto
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hori
mesh_terms: D000480:Alkynes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000187:drug effects; D000068876:Fingolimod Hydrochloride; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D011409:Propylene Glycols / Q000737:chemistry*; D011789:Quantum Theory; D013055:Spectrophotometry, Infrared; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000480:Alkynes; D020533:Angiogenesis Inhibitors; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine