ORGANIC
LETTERS
2010
Vol. 12, No. 23
5576-5579
Total Synthesis and Antimalarial Activity
of Symplostatin 4
Trent Conroy,† Jin T. Guo,‡ Nicholas H. Hunt,‡ and Richard J. Payne†,*
School of Chemistry, The UniVersity of Sydney, NSW 2006, Australia, and School of
Medical Sciences, Sydney Medical School, The UniVersity of Sydney, NSW 2006, Australia
Received October 12, 2010
ABSTRACT
The first total synthesis of symplostatin 4, a marine cyanobacterium-derived natural product, is described. Notable features of the route
include the efficient preparation of three key fragments and final assembly to the natural product via sequential imide and amide couplings.
Symplostatin 4 was also demonstrated to possess significant antimalarial activity (ED50 of 74 nM against Plasmodium falciparum, strain 3D7).
Symplostatin 4 (1, Figure 1) is a linear depsipeptide natural
product of cyanobacterial origin, first isolated in 2009 from
the genus Symploca sp. by Luesch and co-workers in Key
Largo, Florida Keys.1 Structurally, it comprises a peptidic
backbone bearing a dimethylated N-terminal amino acid and
C-terminal pyrrolinone moiety. Symplostatin 4 (1) has been
shown to possess the same planar structure as gallinamide
A (2) (Figure 1), isolated from the Schizothrix species of
cyanobacteria collected off the Carribean coast of Panama
in 2009,2 but it has a diastereomeric configuration at the
N-terminal amino acid (25S, 26S). In the case of gallinamide
A, assignment of the absolute configurations of C25 and C26
has, to date, remained elusive.1,2
phase II clinical trials as anticancer agents (Figure 1).8,9
Unique structural features of symplostatin 4 and gallinamide
A include the depsipeptidic linkage, which in this instance
is formed through a 2-hydroxyisocaproic acid residue and
an unusual 4(S)-amino-2(E)-pentenoic acid unit. Initial
biological screening of symplostatin 4 indicated only moder-
ate cytotoxic activity (IC50 values of 12 and 53 µM against
HeLa cervical carcinoma cells and HT-29 colon adenocar-
cinoma cells, respectively).1 However, significantly, this
natural product was also shown to synergize with another
Symploca-derived natural product, largazole,10 which may
therefore present opportunities for the use of symplostatin 4
in the development of combination anticancer therapies.
Gallinamide A has been reported to possess antimalarial
Both symplostatin 4 and gallinamide A also share struc-
tural features with dolastatin 15 (3),3,4 dolastatin 10 (4),5,6
and symplostatin 1 (5),7 analogues of which have entered
(5) Pettit, G. R.; Kamano, Y.; Herald, C. L.; Tuinman, A. A.; Boettner,
F. E.; Kizu, H.; Schmidt, J. M.; Baczynskyj, L.; Tomer, K. B.; Bontems,
R. J. J. Am. Chem. Soc. 1987, 109, 6883–6885
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(6) Pettit, G. R.; Singh, S. B.; Hogan, F.; Lloyd-Williams, P.; Herald,
† School of Chemistry.
D. L.; Burkett, D. D.; Clewlow, P. J. J. Am. Chem. Soc. 1989, 111, 5463–
‡ School of Medical Sciences.
5465.
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10.1021/ol1024663 2010 American Chemical Society
Published on Web 11/04/2010