Journal
ORGANIC & BIOMOLECULAR CHEMISTRY
Volume 11, Issue 38, Pages 6642-6649Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c3ob41398e
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Funding
- JSPS [24651258, 20310130]
- Ministry of Education, Culture, Sports, Science and Technology, Japan [23105013]
- JSPS Predoctoral Fellowships for Young Scientists
- Grants-in-Aid for Scientific Research [20310130, 24651258] Funding Source: KAKEN
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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 (Na(v)Ch) suggested that the C13 carbamoyl group of STX interacts with residue E403 in the pore region of Na(v)Ch. In a cell-based assay with Neuro-2a cells, the Na(v)Ch-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 Na(v)Ch-inhibitory activity of these derivatives is influenced by both the hydrophilicity and the charge balance of the substituent at C13.
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