Synthesis of saxitoxin derivatives bearing guanidine and urea groups at C13 and evaluation of their inhibitory activity on voltage-gated sodium channels

Takafumi Akimoto, Asako Masuda, Mari Yotsu-Yamashita, Takatsugu Hirokawa, Kazuo Nagasawa

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    15 Citations (Scopus)

    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 Na VCh. In a cell-based assay with Neuro-2a cells, the Na VCh-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.

    Original languageEnglish
    Pages (from-to)6642-6649
    Number of pages8
    JournalOrganic and Biomolecular Chemistry
    Volume11
    Issue number38
    DOIs
    Publication statusPublished - 2013 Oct 14

    ASJC Scopus subject areas

    • Biochemistry
    • Physical and Theoretical Chemistry
    • Organic Chemistry

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