Total synthesis of lindbladione, a Hes1 dimerization inhibitor and neural stem cell activator isolated from Lindbladia tubulina.

Tytuł:: Total synthesis of lindbladione, a Hes1 dimerization inhibitor and neural stem cell activator isolated from Lindbladia tubulina.
Autorzy:: Arai MA; Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, 223-8522, Japan. midori_.
Makita Y; Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8675, Japan.
Yamaguchi Y; Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8675, Japan.
Kawano H; Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8675, Japan.
Suganami A; Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
Tamura Y; Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
Ishibashi M; Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8675, Japan. .
Źródło:: Scientific reports [Sci Rep] 2020 Dec 08; Vol. 10 (1), pp. 21433. Date of Electronic Publication: 2020 Dec 08.
Typ publikacji:: Journal Article; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Original Publication: London : Nature Publishing Group, copyright 2011-
MeSH Terms:: Amoeba/*chemistry
Naphthoquinones/*chemical synthesis
Neural Stem Cells/*cytology
Transcription Factor HES-1/*chemistry
Transcription Factor HES-1/*metabolism
Animals ; Cell Differentiation/drug effects ; Cell Line ; Mice ; Models, Molecular ; Molecular Docking Simulation ; Molecular Structure ; Naphthoquinones/chemistry ; Naphthoquinones/pharmacology ; Neural Stem Cells/drug effects ; Neural Stem Cells/metabolism ; Protein Conformation ; Protein Multimerization/drug effects
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Substance Nomenclature:: 0 (Hes1 protein, mouse)
0 (Naphthoquinones)
0 (Transcription Factor HES-1)
0 (lindbladione)
Entry Date(s):: Date Created: 20201209 Date Completed: 20210324 Latest Revision: 20210324
Update Code:: 20240105
PubMed Central ID:: PMC7722756
DOI:: 10.1038/s41598-020-78524-7
PMID:: 33293619
: Czasopismo naukowe

Pełny tekst

Lindbladione (1) is a neural stem cell differentiation activator isolated from Lindbladia tubulina by our group. Hes1 dimerization inhibitory activity of lindbladione (1) was discovered using our original fluorescent Hes1 dimer microplate assay. We also found that lindbladione (1) accelerates the differentiation of neural stem cells. We conducted the first total synthesis of lindbladione (1) via Heck reaction of 1-hexene-3-one 7 with iodinated naphthoquinone 12, which was provided by Friedel-Crafts acylation followed by Claisen condensation, in the presence of Pd (II) acetate. Careful deprotection of the benzyl groups of 13 successively provided lindbladione (1). Synthesized lindbladione (1) exhibited potent Hes1 dimer inhibition (IC 50 of 2.7 μM) in our previously developed fluorescent Hes1 dimer microplate assay. Synthesized lindbladione (1) also accelerated the differentiation of C17.2 mouse neural stem cells into neurons dose dependently, increasing the number of neurons by 59% (2.5 μM) and 112% (10 μM) compared to the control. These activities are comparable to those of naturally occurring lindbladione (1) isolated from L. tublina.

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