title: Asymmetric synthesis of crambescin A-C carboxylic acids and their inhibitory activity on voltage-gated sodium channels.
abstract: Synthesis of both enantiomers of crambescin B carboxylic acid is described. A cis-enyne starting material was epoxidized under the conditions of Katsuki asymmetric epoxidation to give 95% ee of the epoxide, which was transformed to crambescin B carboxylic acid via bromocation-triggered cascade cyclization as the key step. Enantiomerically pure crambescin A and C carboxylic acids were also synthesized from the product of the cascade reaction. Structure-activity relationship (SAR) studies against voltage-gated sodium channel (VGSC) inhibition using those synthetic compounds revealed that the natural enantiomer of crambescin B carboxylic acid was most active and comparable to tetrodotoxin, and the unalkylated cyclic guanidinium structure is indispensible, while the carboxylate moiety is not important. The absolute stereochemistry of crambescin A was determined by a comparison of the methyl ester derived from natural crambescin A with that derived from the stereochemically defined crambescin A carboxylic acid synthesized in this study.
authors.affiliation: Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8601, Japan. nisikawa@agr.nagoya-u.ac.jp.
authors.forename: Atsuo
authors.initials: A
authors.lastname: Nakazaki
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Nakane
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ishikawa
authors.forename: Mari
authors.initials: M
authors.lastname: Yotsu-Yamashita
authors.forename: Toshio
authors.initials: T
authors.lastname: Nishikawa
mesh_terms: D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D019791:Guanidine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D061567:Voltage-Gated Sodium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism*
chemical_list: D002264:Carboxylic Acids; D011743:Pyrimidines; D013141:Spiro Compounds; D061567:Voltage-Gated Sodium Channel Blockers; D061566:Voltage-Gated Sodium Channels; C492937:crambescin A; C086364:crambescin B; C086365:crambescin C1; D019791:Guanidine