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

• Published in: Scientific reports Vol. 10; no. 1; p. 21433
• Main Authors: Arai, Midori A., Makita, Yuna, Yamaguchi, Yumi, Kawano, Haruka, Suganami, Akiko, Tamura, Yutaka, Ishibashi, Masami
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08-12-2020; Nature Publishing Group; Nature Portfolio
• Subjects: 631/92; 631/92/349; 631/92/349/977; 639/638; 639/638/92; 639/638/92/349; 639/638/92/349/977; Acetic acid; Acylation; Amoeba - chemistry; Animals; Cell differentiation; Cell Differentiation - drug effects; Cell Line; Dimerization; Humanities and Social Sciences; Mice; Models, Molecular; Molecular Docking Simulation; Molecular Structure; multidisciplinary; Naphthoquinones - chemical synthesis; Naphthoquinones - chemistry; Naphthoquinones - pharmacology; Neural stem cells; Neural Stem Cells - cytology; Neural Stem Cells - drug effects; Neural Stem Cells - metabolism; Protein Conformation; Protein Multimerization - drug effects; Science; Science (multidisciplinary); Stem cell transplantation; Stem cells; Transcription Factor HES-1 - chemistry; Transcription Factor HES-1 - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-78524-7

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
.