Synthesis and biological evaluation of triazole analogues of antillatoxin

Antillatoxin 1, a cyclic lipopeptide, is known as an activator of voltage-gated sodium channels and exhibits potent neurotoxicity toward Neuro 2a mouse neuroblastoma cells. To investigate the biological effects of the side-chain structures at C5 and C5′ in detail, we planned SAR studies of C5- and C5′-modified antillatoxin analogues. To diversify the structures at the last step of the synthesis, two key intermediates 4 and 6 possessing terminal alkynes at the C5- and C5′-positions were designed and synthesized using two distinct strategies. Sixteen side-chain derivatives were then prepared from 4 and 6 by coupling with a wide variety of azides via click chemistry, and subjected to the cytotoxicity assay. Although almost all of the C5-substituted analogues exhibited no cytotoxicity, the C5′-substituted analogues showed modest cytotoxicity. These results showed that C5′ is more tolerant than C5 to structural modifications. The present SAR study will provide valuable information for designing new antillatoxin-based molecular probes for neuroscience research.