title: Combinatorial Solid-Phase Synthesis and Biological Evaluation of Cyclodepsipeptide Destruxin B as a Negative Regulator for Osteoclast Morphology.
abstract: Combinatorial synthesis and biological evaluation of cyclodepsipeptide destruxin B have been achieved. The cyclization precursors were prepared by solid-phase peptide synthesis via a split and pool method utilizing SynPhase lanterns with colored tags and cogs, followed by cleavage from the polymer-support. Macrolactonization utilizing MNBA-DMAPO in solution-phase was successfully performed in parallel to afford the desired 64-member destruxin analogues in moderate to good yields. Biological evaluation of the synthesized analogues indicated that a MeAla residue for the building block A is required to induce the desired morphological changes in osteoclast-like multinuclear cells (OCLs), and introduction of the substituent at the R(4) position of a proline moiety is tolerated by the morphology and may enable the preparation of a molecular probe for the target identification in the osteoclasts.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University , 6-3 Aza-Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan.|Mitsubishi Tanabe Pharma Corporation , 3-2-10, Dosho-machi, Chuo-ku, Osaka 541-8505, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sato
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University , 6-3 Aza-Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan.
authors.forename: Masahito
authors.initials: M
authors.lastname: Yoshida
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, Aoba-ku, Sendai 980-8578, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Doi
mesh_terms: D000818:Animals; D020650:Combinatorial Chemistry Techniques; D003500:Cyclization; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D004338:Drug Combinations; D004997:Ethinyl Estradiol / Q000737:chemistry; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009640:Norethindrone / Q000737:chemistry; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects*; D060327:Solid-Phase Synthesis Techniques / Q000379:methods; D013237:Stereoisomerism
chemical_list: D047630:Depsipeptides; D004338:Drug Combinations; C020416:norethindrone acetate, ethinyl estradiol, ferrous fumarate drug combination; D004997:Ethinyl Estradiol; C040424:destruxin B; D009640:Norethindrone
keywords: combinatorial library; cyclic peptides; cyclodepsipeptides; osteoclasts; solid-phase synthesis