title: Asymmetric Total Synthesis of Heronamides A-C: Stereochemical Confirmation and Impact of Long-Range Stereochemical Communication on the Biological Activity.
abstract: Heronamides are biosynthetically related metabolites isolated from marine-derived actinomycetes. Heronamide C shows potent antifungal activity by targeting membrane phospholipids possessing saturated hydrocarbon chains with as-yet-unrevealed modes of action. In spite of their curious hypothesized biosynthesis and fascinating biological activities, there have been conflicts in regard to the reported stereochemistries of heronamides. Here, we describe the asymmetric total synthesis of the originally proposed and revised structures of heronamide C, which unambiguously confirmed the chemical structure of this molecule. We also demonstrated nonenzymatic synthesis of heronamides A and B from heronamide C, which not only proved the postulated biosynthesis, but also confirmed the correct structures of heronamides A and B. Investigation of the structure-activity relationship of synthetic and natural heronamides revealed the importance of both long-range stereochemical communication and the 20-membered macrolactam ring for the biological activity of these compounds.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aza-aoba, Aramaki, Aoba-ku, Sendai, 980-8578, Japan. nkanoh@m.tohoku.ac.jp.
authors.forename: Naoki
authors.identifier: http://orcid.org/0000-0002-4382-3715
authors.initials: N
authors.lastname: Kanoh
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aza-aoba, Aramaki, Aoba-ku, Sendai, 980-8578, Japan.
authors.forename: Shunya
authors.initials: S
authors.lastname: Itoh
authors.affiliation: Department of System Chemotherapy and Molecular Sciences, Division of Bioinformatics and Chemical Genomics, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Fujita
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aza-aoba, Aramaki, Aoba-ku, Sendai, 980-8578, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Sakanishi
authors.affiliation: Department of System Chemotherapy and Molecular Sciences, Division of Bioinformatics and Chemical Genomics, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Sugiyama
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aza-aoba, Aramaki, Aoba-ku, Sendai, 980-8578, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Terajima
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aza-aoba, Aramaki, Aoba-ku, Sendai, 980-8578, Japan.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Iwabuchi
authors.affiliation: Department of System Chemotherapy and Molecular Sciences, Division of Bioinformatics and Chemical Genomics, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Nishimura
authors.affiliation: Department of System Chemotherapy and Molecular Sciences, Division of Bioinformatics and Chemical Genomics, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan. scseigyo-hisyo@pharm.kyoto-u.ac.jp.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kakeya
mesh_terms: D039903:Actinobacteria / Q000737:chemistry / Q000378:metabolism; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002384:Catalysis; D002942:Circular Dichroism; D047029:Lactams, Macrocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008856:Microscopy, Fluorescence; D012568:Schizosaccharomyces / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000935:Antifungal Agents; D047029:Lactams, Macrocyclic; C000609105:heronamide A; C000625590:heronamide B; C555720:heronamide C
keywords: configuration determination; macrocycles; natural products; structure-activity relationships; total synthesis