MedChemComm
Concise Article
Acknowledgements
This work was sponsored by the National Natural Science
Foundation of China (no. 30472074, 30873139 and 21272052),
the National Basic Research Program of China (2011CB512007
and 2012CB723501), and the Natural Science Foundation of
Hebei Province (no. B2010000836) and Hebei Province Key
Technology R&D Program (no. 10276406D6). We thank
Professor Richard B. Silverman for his encouragement and
suggested manuscript edits.
Notes and references
1 G. N. Belofsky, P. R. Jensen and W. Fenical, Sansalvamide: A
new cytotoxic cyclic depsipeptide produced by a marine
fungus of the genus Fusarium, Tetrahedron Lett., 1999, 40,
2913–2916.
2 M. B. Ujiki, B. Milam, X.-Z. Ding, A. B. Roginsky,
M. R. Salabat, M. S. Talamonti, R. H. Bell, W. Gu,
Fig. 7 Morphological changes of HeLa cells and vascular smooth
muscle cells (VSMC) by compound 10. All assays were run for 24 h with
or without compound 10 at 1.8 mg mLꢀ1 concentration. Error ¼ ꢁ5%.
DMSO was used as a control. Left panels are HeLa cells, and right are
VSMC. (a) No treatment control. (b) Treatment with compound 10.
R. B. Silverman and T. E. Adrian,
A novel peptide
sansalvamide analogue inhibits pancreatic cancer cell
growth through G0/G1 cell-cycle arrest, Biochem. Biophys.
Res. Commun., 2006, 340, 1224–1228.
3 J. B. Kunicki, M. N. Petersen, L. D. Alexander, V. C. Ardi,
J. R. McConnell and S. R. McAlpine, Synthesis and
evaluation of biotinylated sansalvamide A analogs and
their modulation of Hsp90, Bioorg. Med. Chem. Lett., 2011,
21, 14716–14719.
4 R. B. Silverman, S. Liu, W. Gu, T. Adrian and G. S. Wilmette,
Cyclic peptide antitumor agents, US Pat., 7709443, 2010.
5 R. B. Silverman, S. Liu, W. Gu, T. Adrian and G. S. Wilmette,
Cyclic peptide antitumor agents, US Pat., 8058244, 2011.
6 K. Otrubova, K. L. McGuire and S. R. McAlpine, Scaffold
targeting drug-resistant colon cancers, J. Med. Chem., 2007,
50, 1999–2002.
7 W. Gu, S. Liu and R. B. Silverman, Solid-phase, Pd-catalyzed
silicon-aryl carbon bond formation. Synthesis of
sansalvamide A peptide, Org. Lett., 2002, 4, 4171–4174.
8 S. Liu, Y. Geng, X. Tian, X. Zhen and J. Han, Total synthesis
of N-methylsansalvamide A, Chin. Chem. Lett., 2006, 17, 761–
764.
cell cycle or synthesize DNA. But 10 did not cause similar changes
in VSMC under the same conditions. These results suggest that 10
is a potent and selective inhibitor of cancer cells.
Conclusions
In summary, sansalvamide A analog 10 was synthesized and was
found to be potently cytotoxic toward MDA-MB-231, HeLa,
HT-29, HCT-15, K562, and A549 cancer cell lines. The SAR
revealed through our study is expected to be valuable in facili-
tating the rational design of new sansalvamide A analogs with
improved pharmacological properties. Further investigation
will be important to dene the role of 4-methoxyl phenylalanine
in sansalvamide A peptide. Additional assays of this compound
on other cancer cell lines are underway, and the synthesis of the
next generation of sansalvamide A analogues is also in progress.
These results will be reported in due course.
Abbreviations
9 S. Liu, X. Feng, Y. Geng, J. Yao and J. Li, Novel solid-phase
synthetic method of sansalvamide A, Chin. J. Org. Chem.,
2005, 25, 604–607.
10 S. Liu, W. Gu, D. Lo, X. Ding, M. Ujiki, T. E. Adrian, G. A. Soff
and R. B. Silverman, N-Methylsansalvamide A peptide
analogues. Potent new antitumor agents, J. Med. Chem.,
2005, 48, 3630–3638.
11 T. J. Styers, A. Kekec, R. Rodriguez, J. D. Brown, J. Cajica,
P. Pan, E. Parry, C. L. Carroll, I. Medina, R. Corral,
S. Lapera, K. Otrubova, C. Pan, K. L. McGuireb and
S. R. McAlpine, Synthesis of sansalvamide A derivatives
and their cytotoxicity in the MSS colon cancer cell line HT-
29, Bioorg. Med. Chem., 2006, 14, 5625–5631.
12 R. A. Rodriguez, P. C. Pan, S. Ravula, S. Lapera, E. K. Singh,
T. J. Styers, J. D. Brown, J. Cajica, E. Parry, K. Otrubova and
S. R. McAlpine, Synthesis of second-generation
SAR
DIPEA
THF
DCM
DMF
DMAP
Boc
Structure–activity-relationship
N,N-Diisopropylethylamine
Tetrahydrofuran
Dichloromethane
N,N-Dimethylformamide
4-Dimethylamiopryidine
tert-Butyloxycarbonyl
HBTU
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexauorophosphate
O-(7-Azabenzotriazol-1-yl)-N,N,N0,N0-
tetramethyluronium hexauorophosphate
Benzotriazol-1-yl-oxytripyrrolidinophosphonium
hexauorophosphate
HATU
PyBOP
EDC$HCl 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide
DMSO Dimethyl sulphoxide
466 | Med. Chem. Commun., 2014, 5, 463–467
This journal is © The Royal Society of Chemistry 2014