TY - JOUR
T1 - Solid-Phase Combinatorial Synthesis and Biological Evaluation of Destruxin e Analogues
AU - Yoshida, Masahito
AU - Ishida, Yoshitaka
AU - Adachi, Kenta
AU - Murase, Hayato
AU - Nakagawa, Hiroshi
AU - Doi, Takayuki
N1 - Publisher Copyright:
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
PY - 2015/12/7
Y1 - 2015/12/7
N2 - 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). Forced to change: The 18 member analogues of destruxin E (see scheme) were successfully synthesized. Biological evaluation of these analogues indicated that the N-MeAla residue was crucial for inducing morphological changes in osteoclast-like multinuclear cells (OCLs). Molecular probes were then prepared by replacing the Ile residue with a Lys(N3) residue for target identification in OCLs.
AB - 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). Forced to change: The 18 member analogues of destruxin E (see scheme) were successfully synthesized. Biological evaluation of these analogues indicated that the N-MeAla residue was crucial for inducing morphological changes in osteoclast-like multinuclear cells (OCLs). Molecular probes were then prepared by replacing the Ile residue with a Lys(N3) residue for target identification in OCLs.
KW - combinatorial chemistry
KW - molecular probes
KW - peptides
KW - solid-phase synthesis
KW - structure-activity relationships
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U2 - 10.1002/chem.201502970
DO - 10.1002/chem.201502970
M3 - Article
C2 - 26531322
AN - SCOPUS:84949256795
VL - 21
SP - 18417
EP - 18430
JO - Chemistry - A European Journal
JF - Chemistry - A European Journal
SN - 0947-6539
IS - 50
ER -