title: Total synthesis of syringolin A and improvement of its biological activity.
abstract: The development process for syringolin A analogues having improved proteasome inhibitory and antitumor activity is described. The strategy was to first establish a convergent synthesis of syringolin A using a rare intramolecular Ugi three-component reaction in the last stage of the synthesis, so as to gain access toa set of structure-based analogues. The inhibitory activity of chymotrypsin-like activity of 20S proteasome was largely improved by targeting the S3 subsite of the β5 subunit. Cytotoxic activity was also improved by installing the membrane-permeable substituent. These biological properties are comparable to those of bortezomib, a clinically used first-line proteasome inhibitor.
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812 (Japan).
authors.forename: Takuya
authors.initials: T
authors.lastname: Chiba
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Hosono
authors.forename: Koji
authors.initials: K
authors.lastname: Nakagawa
authors.forename: Masahiro
authors.initials: M
authors.lastname: Asaka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takeda
authors.forename: Akira
authors.initials: A
authors.lastname: Matsuda
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ichikawa
mesh_terms: D018360:Crystallography, X-Ray; D055808:Drug Discovery; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D010456:Peptides, Cyclic; C407267:syringolin A
keywords: antitumor agents; drug discovery; lactams; medicinal chemistry; natural products