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 (Na_VCh) 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 Na_VCh-inhibitory activity of these derivatives is influenced by both the hydrophilicity and the charge balance of the substituent at C13.