title: Total synthesis and biological activity of dolastatin 16.
abstract: The total synthesis of dolastatin 16, a macrocyclic depsipeptide first isolated from the sea hare Dolabella auricularia as a potential antineoplastic metabolite by Pettit et al., was achieved in a convergent manner. Dolastatin 16 was reported by Tan to exhibit strong antifouling activity, and thus shows promise for inhibiting the attachment of marine benthic organisms such as Amphibalanus amphitrite to ships and submerged artificial structures. Therefore, dolastatin 16 is a potential compound for a new, environmentally friendly antifouling material to replace banned tributyltin-based antifouling paints. The synthesis of dolastatin 16 involved the use of prolinol to prevent formation of a diketopiperazine composed of l-proline and N-methyl-d-valine during peptide coupling. This strategy for the elongation of peptide chains allowed the efficient and scalable synthesis of one segment, which was subsequently coupled with a second segment and cyclized to form the macrocyclic framework of dolastatin 16. The synthetic dolastatin 16 exhibited potent antifouling activity similar to that of natural dolastatin 16 toward cypris larvae of Amphibalanus amphitrite.
authors.affiliation: Graduate School of Environmental Science, Hokkaido University, N10W5 Sapporo 060-0810, Japan. umezawa@ees.hokudai.ac.jp fmatsuda@ees.hokudai.ac.jp.
authors.forename: Loida O
authors.initials: LO
authors.lastname: Casalme
authors.affiliation: Graduate School of Environmental Science, Hokkaido University, N10W5 Sapporo 060-0810, Japan. umezawa@ees.hokudai.ac.jp fmatsuda@ees.hokudai.ac.jp.
authors.forename: Arisa
authors.initials: A
authors.lastname: Yamauchi
authors.affiliation: Graduate School of Environmental Science, Hokkaido University, N10W5 Sapporo 060-0810, Japan. umezawa@ees.hokudai.ac.jp fmatsuda@ees.hokudai.ac.jp.
authors.forename: Akinori
authors.initials: A
authors.lastname: Sato
authors.affiliation: Graduate School of Environmental Science, Hokkaido University, N10W5 Sapporo 060-0810, Japan. umezawa@ees.hokudai.ac.jp fmatsuda@ees.hokudai.ac.jp.
authors.forename: Julie G
authors.initials: JG
authors.lastname: Petitbois
authors.affiliation: Environmental Science Research Laboratory, Central Research Institute of Electric Power Industry, 1646 Abiko, Abiko, Chiba 270-1194, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Nogata
authors.affiliation: CERES, Inc., 1-4-5 Midori, Abiko, Chiba 270-1153, Japan.
authors.forename: Erina
authors.initials: E
authors.lastname: Yoshimura
authors.affiliation: Graduate School of Environmental Science, Hokkaido University, N10W5 Sapporo 060-0810, Japan. umezawa@ees.hokudai.ac.jp fmatsuda@ees.hokudai.ac.jp.
authors.forename: Tatsufumi
authors.identifier: http://orcid.org/0000-0002-8363-0467
authors.initials: T
authors.lastname: Okino
authors.affiliation: Graduate School of Environmental Science, Hokkaido University, N10W5 Sapporo 060-0810, Japan. umezawa@ees.hokudai.ac.jp fmatsuda@ees.hokudai.ac.jp.
authors.forename: Taiki
authors.identifier: http://orcid.org/0000-0003-4280-6574
authors.initials: T
authors.lastname: Umezawa
authors.affiliation: Graduate School of Environmental Science, Hokkaido University, N10W5 Sapporo 060-0810, Japan. umezawa@ees.hokudai.ac.jp fmatsuda@ees.hokudai.ac.jp.
authors.forename: Fuyuhiko
authors.initials: F
authors.lastname: Matsuda
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D057219:Biofouling / Q000517:prevention & control*; D049109:Cell Proliferation / Q000187:drug effects; D047630:Depsipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D061986:MCF-7 Cells; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D001468:Thoracica / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D047630:Depsipeptides; C108201:dolastatin 16