title: Synthesis of saxitoxin derivatives bearing guanidine and urea groups at C13 and evaluation of their inhibitory activity on voltage-gated sodium channels.
abstract: Here, we describe the synthesis of the first C13-N-substituted STX derivatives 4, 5, and 6 bearing a guanidine, a urea group, and an acetamide, respectively, via the fully protected saxitoxinol derivative 8. These compounds are of interest because a previous docking study of saxitoxin (STX) with voltage-gated sodium channels (NaVCh) suggested that the C13 carbamoyl group of STX interacts with residue E403 in the pore region of NaVCh. In a cell-based assay with Neuro-2a cells, the NaVCh-inhibitory activities of 4 and 5 were more than 20- to 50-fold weaker than that of decarbamoyl-STX (3), which is 10-fold less potent than STX. On the other hand, 6 was 1000 times less potent than 3. The electrostatic analysis of C13 in STX and its analogs 4-6 using EON calculations suggested that the NaVCh-inhibitory activity of these derivatives is influenced by both the hydrophilicity and the charge balance of the substituent at C13.
authors.affiliation: Department of Biotechnology and Life Science, Faculty of Technology, Tokyo University of Agriculture and Technology, 2-24-16, Naka-cho, Koganei, Tokyo, 184-8588, Japan. knaga@cc.tuat.ac.jp.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Akimoto
authors.forename: Asako
authors.initials: A
authors.lastname: Masuda
authors.forename: Mari
authors.initials: M
authors.lastname: Yotsu-Yamashita
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Hirokawa
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nagasawa
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019791:Guanidine / Q000737:chemistry*; D051379:Mice; D015394:Molecular Structure; D012530:Saxitoxin / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014508:Urea / Q000737:chemistry*; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism*
chemical_list: D061566:Voltage-Gated Sodium Channels; D012530:Saxitoxin; D014508:Urea; D019791:Guanidine