title: Synthesis of IB-01212 by multiple N-methylations of peptide bonds.
abstract: There are many natural peptides with multiple N-methylamino acids that exhibit potent attractive biological activities. N-methylation of a peptide bond(s) is also one of the standard approaches in medicinal chemistry of bioactive peptides, to improve the potency and physicochemical properties, especially membrane permeability. In this study, we investigated a facile synthesis process of N-methylated peptides via simultaneous N-methylation of several peptide bonds in the presence of peptide bonds that were not to be methylated. As a model study, we investigated the synthesis of the antiproliferative depsipeptide, IB-01212. We used a pseudoproline to protect the non-methylated peptide bond during a simultaneous N-methylation with MeI-Ag2O. Using further manipulations including a dimerization/cyclization process, IB-01212 and its derivatives were successfully synthesized. A preliminary structure-activity relationship study demonstrated that the symmetric structure contributed to the potent cytotoxic activity of IB-01212.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Nabika
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: soishi@pharm.kyoto-u.ac.jp.
authors.forename: Shinya
authors.initials: S
authors.lastname: Oishi
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Misu
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ohno
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: nfujii@pharm.kyoto-u.ac.jp.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Fujii
mesh_terms: D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008745:Methylation; D009369:Neoplasms / Q000188:drug therapy
chemical_list: D000970:Antineoplastic Agents; D047630:Depsipeptides; C519452:IB-01212
keywords: Depsipeptide; Macrolactonization; N-Methylamino acid; N-methylation