title: Solid-Phase Combinatorial Synthesis and Biological Evaluation of Destruxin E Analogues.
abstract: The solid-phase combinatorial synthesis of cyclodepsipeptide destruxin E has been demonstrated. The combinatorial synthesis of cyclization precursors 8 was achieved by using a split and pool method on SynPhase Lanterns. The products were successfully macrolactonized in parallel in the solution phase by using 2-methyl-6-nitrobenzoic anhydride and 4-(dimethylamino)pyridine N-oxide to afford macrolactones 9, and the subsequent formation of an epoxide in the side chain gave 18 member destruxin E analogues 6. Biological evaluation of analogues 6 indicated that the N-MeAla residue was crucial to the induction of morphological changes in osteoclast-like multinuclear cells (OCLs). Based on structure-activity relationships, azido-containing analogues 15 were then designed for use as a molecular probe. The synthesis and biological evaluation of analogues 15 revealed that 15 b, in which the Ile residue was replaced with a Lys(N3 ) residue, induced morphological changes in OCLs at a sufficient concentration, and modification around the Ile residue would be tolerated for attachment of a chemical tag toward the target identification of destruxin E (1).
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aza-Aoba, Aramaki, Sendai 980-8578 (Japan).
authors.forename: Masahito
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aza-Aoba, Aramaki, Sendai 980-8578 (Japan).
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Ishida
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aza-Aoba, Aramaki, Sendai 980-8578 (Japan).
authors.forename: Kenta
authors.initials: K
authors.lastname: Adachi
authors.affiliation: Department of Applied Biological Chemistry, Chubu University, 1200 Matsumoto-cho, Kasugai, Aichi 487-8501 (Japan).
authors.forename: Hayato
authors.initials: H
authors.lastname: Murase
authors.affiliation: Department of Applied Biological Chemistry, Chubu University, 1200 Matsumoto-cho, Kasugai, Aichi 487-8501 (Japan).
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakagawa
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aza-Aoba, Aramaki, Sendai 980-8578 (Japan). doi_taka@mail.pharm.tohoku.ac.jp.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Doi
mesh_terms: D000812:Anhydrides / Q000737:chemistry*; D005075:Biological Evolution; D003497:Cyclic N-Oxides / Q000737:chemistry*; D003500:Cyclization; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000737:chemistry; D005656:Fungal Proteins / Q000138:chemical synthesis* / Q000737:chemistry; D009579:Nitrobenzoates / Q000737:chemistry*; D060327:Solid-Phase Synthesis Techniques; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C526944:2-methyl-6-nitrobenzoic anhydride; C526943:4-(dimethylamino)pyridine N-oxide; D000812:Anhydrides; D003497:Cyclic N-Oxides; D047630:Depsipeptides; D005656:Fungal Proteins; D009579:Nitrobenzoates; C040425:destruxin E
keywords: combinatorial chemistry; molecular probes; peptides; solid-phase synthesis; structure-activity relationships