Organic Letters
Letter
commercially available materials, with an overall chemical
yield of 25%. Further optimization would lead to the
development of a next-generation proteasome inhibitor that is
effective against bortezomib-resistant multiple myeloma. This
study suggests new, efficacious molecules may be designed by
subtly altering the chemical structures of natural products,
which is an approach that represents a significant synthetic
innovation within the medicinal chemistry field.
Table 1. β5 (Chymotrypsin-like) Proteasome Inhibitory
Activity
1
2
3
18
Ki (nM)
170
1190
590
1.53
that of 2 (Ki 1190 nM). The potency of 3 was between that of 1
and 2. These results indicate the importance of including the
alkene moiety in the molecular design of 3.
We have found that the chemical transformation of the
ureadipeptide moiety of 1 into the N-decanoyl L-phenylalanyl
group greatly enhanced its β5 proteasome inhibitory activity as
well as its cytotoxicity against human cancer cells.12 Compound
3 was converted into the corresponding analogue 18 by
condensation of 14 with N-decanoyl-L-phenylalanine (17) as is
shown in Scheme 2.
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge on the
Complete experimental procedure and characterization
data of all the new compounds, β5 proteasome inhibition
assay and cytotoxicity assay (PDF)
Scheme 2. Synthesis of Isosyringolin A Analogue 18
AUTHOR INFORMATION
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Corresponding Author
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We wish to thank Ms. S. Oka and Ms. A. Tokumitsu (Center
for Instrumental Analysis, Hokkaido University) for measure-
ment of the mass spectra. This research was supported by JSPS
Grant-in-Aid for Scientific Research (B) (SI, Grant Number
25293026), Scientific Research on Innovative Areas “Chemical
Biology of Natural Products” (SI, Grant Number 24102502),
and the Platform Project for Supporting Drug Discovery and
Life Science Research (Platform for Drug Discovery,
Informatics and Structural Life Science).
The analogue 18 exhibited strong β5 proteasome inhibitory
activity with a Ki value of 1.53 nM (Table 1). The cytotoxicity
of 18 was also investigated; 18 showed a strong cytotoxicity
against human myeloma OPM-2 cells with an IC50 value of 6.7
nM (Table 2). This potency is comparable to that of
Table 2. Cytotoxicity against Human Myeloma Cells
IC50 (nM)
REFERENCES
cell lines
bortezomib
18
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In conclusion, isosyringolin A, which is an isomer of the
proteasome-inhibitory natural product syringolin A, was
designed and synthesized to develop an analogue with
comparable proteasome-inhibitory activity that is step econom-
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