Taxonomic group: bacteria / Cyanobacteria
(Phylum: Cyanobacteria)
The structure was elucidated in this paperNCBI PubMed ID: 35673891Publication DOI: 10.1021/jacs.2c04459Journal NLM ID: 7503056Publisher: American Chemical Society
Correspondence: A. Iwasaki <a.iwasaki
chem.keio.ac.jp>; K. Suenaga <suenaga
chem.keio.ac.jp>
Institutions: Department of Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan, Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan, Faculty of Agriculture and Life Science, Hirosaki University, 3 Bunkyo-cho, Hirosaki, Aomori 036-8561, Japan
Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) is a membrane protein on the endoplasmic reticulum (ER) that transports Ca2+ from the cytosol into the ER. As its function is associated with various biological phenomena, SERCA has been recognized as a promising druggable target. Here, we report the second-strongest SERCA-inhibitory compound known to date, which we isolated from the marine cyanobacterium Leptochromothrix valpauliae and named iezoside (1). The structure of iezoside (1) is fundamentally different from that of any other SERCA inhibitor, and its potency is the strongest among marine natural products (Ki 7.1 nM). In this article, we report our comprehensive analysis of iezoside (1), which covers its isolation, structural characterization supported by density functional theory (DFT) calculations and statistical analysis, total synthesis, and clarification of the mode of action of its potent antiproliferative activity (IC50 6.7 ± 0.4 nM against HeLa cells).
total synthesis, marine cyanobacteria, SERCA inhibitor, iezoside, Leptochromothrix valpaulia
Structure type: monomer ; 690.4167 [M+H]+
C
37H
60N
3O
7S
Location inside paper: P. 11020, table 1, iezoside (compound 1)
Trivial name: iezoside
Methods: 13C NMR, 1H NMR, IR, inhibition studies, TLC, Western blotting, chemical synthesis, HPLC, UV, optical rotation measurement, CD, statistical analysis, molecular mechanics, computational methods, HR-ESI-MS, cytotoxicity assay, flash chromatography, cell proliferation assay, ECD, DFT calculations, ozonolysi
Biological activity: Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) inhibitor
Synthetic data: chemical
Comments, role: NMR temperature was not specified; peptide part of (18R,19R)-iezoside (1) to be Thz-LLeu-N-Me-D-Ala and the polyketide moiety to be unusual fatty acid moiety.
NCBI Taxonomy refs (TaxIDs): 2831759
Show glycosyltransferases
NMR conditions: in (CD3)2CO
[as TSV]
13C NMR data:
Linkage Residue C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 C14 C15 C16 C17 C18 C19 C20 C21 C22 C23 C24 C25 C26 C27 C28 C29 C30
19,2 Me 59.0
19,3 Me 57.4
19 aLRhap 94.5 77.8 82.7 72.5 69.8 18.4
Subst 143.4 119.6 174.3 50.3 45.0 25.6 22.0 23.4 - 171.4 ? ? 32.0 174.9 131.1 128.7 122.0 144.4 49.1 78.9 125.4 139.5 133.1 135.9 22.0 14.2 14.7 15.8 15.3 12.5
1H NMR data:
Linkage Residue H1 H2 H3 H4 H5 H6 H7 H8 H9 H10 H11 H12 H13 H14 H15 H16 H17 H18 H19 H20 H21 H22 H23 H24 H25 H26 H27 H28 H29 H30
19,2 Me 3.36
19,3 Me 3.40
19 aLRhap 4.82 3.56 3.37 3.44 3.60 1.19
Subst 7.70 7.48 - 5.40 1.85 1.77 0.96 0.96 7.74 - 4.99 1.35 2.86 - - 6.43 6.19 - 2.46 4.12 5.40 6.23 - 5.52 2.14 0.96 1.91 1.78 1.18 1.72
1H/13C HSQC data:
Linkage Residue C1/H1 C2/H2 C3/H3 C4/H4 C5/H5 C6/H6 C7/H7 C8/H8 C9/H9 C10/H10 C11/H11 C12/H12 C13/H13 C14/H14 C15/H15 C16/H16 C17/H17 C18/H18 C19/H19 C20/H20 C21/H21 C22/H22 C23/H23 C24/H24 C25/H25 C26/H26 C27/H27 C28/H28 C29/H29 C30/H30
19,2 Me 59.0/3.36
19,3 Me 57.4/3.40
19 aLRhap 94.5/4.82 77.8/3.56 82.7/3.37 72.5/3.44 69.8/3.60 18.4/1.19
Subst 143.4/7.70 119.6/7.48 50.3/5.40 45.0/1.85 25.6/1.77 22.0/0.96 23.4/0.96 -/7.74 ?/4.99 ?/1.35 32.0/2.86 128.7/6.43 122.0/6.19 49.1/2.46 78.9/4.12 125.4/5.40 139.5/6.23 135.9/5.52 22.0/2.14 14.2/0.96 14.7/1.91 15.8/1.78 15.3/1.18 12.5/1.72
1H NMR data:
| Linkage | Residue | H1 | H2 | H3 | H4 | H5 | H6 | H7 | H8 | H9 | H10 | H11 | H12 | H13 | H14 | H15 | H16 | H17 | H18 | H19 | H20 | H21 | H22 | H23 | H24 | H25 | H26 | H27 | H28 | H29 | H30 |
|---|
| 19,2 | Me | 3.36 | |
| 19,3 | Me | 3.40 | |
| 19 | aLRhap | 4.82 | 3.56 | 3.37 | 3.44 | 3.60 | 1.19 | |
| | Subst | 7.70 | 7.48 |
| 5.40 | 1.85 | 1.77 | 0.96 | 0.96 | 7.74 |
| 4.99 | 1.35 | 2.86 |
|
| 6.43 | 6.19 |
| 2.46 | 4.12 | 5.40 | 6.23 |
| 5.52 | 2.14 | 0.96 | 1.91 | 1.78 | 1.18 | 1.72 |
|
13C NMR data:
| Linkage | Residue | C1 | C2 | C3 | C4 | C5 | C6 | C7 | C8 | C9 | C10 | C11 | C12 | C13 | C14 | C15 | C16 | C17 | C18 | C19 | C20 | C21 | C22 | C23 | C24 | C25 | C26 | C27 | C28 | C29 | C30 |
|---|
| 19,2 | Me | 59.0 | |
| 19,3 | Me | 57.4 | |
| 19 | aLRhap | 94.5 | 77.8 | 82.7 | 72.5 | 69.8 | 18.4 | |
| | Subst | 143.4 | 119.6 | 174.3 | 50.3 | 45.0 | 25.6 | 22.0 | 23.4 |
| 171.4 | ? | ? | 32.0 | 174.9 | 131.1 | 128.7 | 122.0 | 144.4 | 49.1 | 78.9 | 125.4 | 139.5 | 133.1 | 135.9 | 22.0 | 14.2 | 14.7 | 15.8 | 15.3 | 12.5 |
|
The spectrum also has 3 signals at unknown positions (not plotted). |
There is only one chemically distinct structure:
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