Angewandte
Chemie
and the preadipocyte cell line 3T3L1 (Table 2). Synthetic 1
displayed only weakselectivity for the cancer cell line (GI 50
49 nm) over the 3T3 cells (GI50 = 127 nm). The advanced
intermediate 13, which contains a terminal double bond, and
the analogue 1b, in which the side chain has been replaced
=
b) F. E. Koehn, G. T. Carter, Nat. Rev. Drug Discovery 2005, 4,
206 – 220.
[2] a) J. W. Blunt, B. R. Copp, W.-P. Hu, M. H. G. Munro, P. T.
b) J. W. Blunt, B. R. Copp, W.-P. Hu, M. H. G. Munro, P. T.
c) D. J. Faulkner, Nat. Prod. Rep. 2002, 19, 1 – 48.
Table 2: Antiproliferative activity of 1 and analogues 1b–g in the MTT
assay.[a]
Cell line
1
1b
1d
1e
1 f
1g[15]
[4] a) S. Carmeli, R. E. Moore, G. M. L. Patterson, T. H. Corbett,
A431
3T3L1
SI
49
127
2.6
n.d.[b]
n.d.[b]
–
n.d.[b]
n.d.[b]
–
n.d.[b]
n.d.[b]
–
n.d.[b]
n.d.[b]
–
126
1200
9.5
[5] The alkene 2a was prepared by alkylation of octanethio S-acid
(M. Toriyama, H. Kamijo, S. Motohashi, T. Takido, K. Itabashi,
with 1-bromo-3-butene (see the Supporting Information).
[6] a) S. Vrielynck, M. Vandewalle, A. M. Garcia, J. L. Mascarenas,
[7] M. Knopp, S. Koser, B. Schäfer (BASF AG), DE-19934066A1,
2001.
[a] GI50 values are given in nm. [b] n.d.=not determined; no activity was
observed up to a concentration of 5 mm.
with a C13 alkyl chain, showed no growth-inhibitory activity,
even at a concentration of 5 mm. Thus, the possibility that the
biological activity originates solely from the cyclic core
structure can be ruled out. The replacement of the thioester
functionality with an ester group in 1d also led to a complete
loss of activity.
It stood to reason that the octanoic thioester of 1 plays the
role of a protecting group, rapidly hydrolyzed under physio-
logical conditions, for the free thiol. Indeed, the free thiol 1g
(R = CH2SH)[16] displayed a strong antiproliferative activity.
Remarkably, the activity profile of 1g is not identical to that
of compound 1. The free thiol 1g showed slightly lower
potency (GI50 = 126 nm; GI50(1) = 49 nm) but a significantly
higher specificity (SI = 9.5; SI(1) = 2.6) against the wild-type
cells with respect to the thioester 1. This finding might be
explained by a reduced uptake of the free thiol by the wild-
type cells. Surprisingly, thioester derivatives 1e and 1 f, in
which the side chain is one or two carbon atoms longer than
that in 1, showed no activity at all. This result underlines how
important it is for the thio functionality to be positioned at the
right distance from the cyclic core.
In summary, we have described a short synthesis of
largazole (19% overall yield, nine steps in the longest linear
sequence), the modular nature of which enabled us to prepare
several analogues of 1. We determined the biological activ-
ities of the synthetic compounds in MTT assays and demon-
strated the necessity of the thiobutenyl group for an
antiproliferative effect. The free thiol derivative 1g displayed
improved selectivity relative to that of 1. Studies to modify
the activity of these compounds and elucidate their mode of
action on a molecular level are ongoing.[17]
[9] R. J. Bergeron, J. Wiegand, J. S. McManis, B. H. McCosar, W. R.
[11] Crystallographic data for 13: C19H24N4O4S2, M = 436.55, ortho-
rhombic, space group P212121, a = 9.6075(2), b = 10.9467(2), c =
20.3175(3) , V= 2136.80(7) 3, Z = 4, 1calcd = 1.357 Mgmꢀ3
,
T= 223 K, reflections collected: 3647, independent reflections:
3628 (Rint = 0.023), R(all) = 0.0394. wR(gt) = 0.0997, Flack
parameter ꢀ0.06(7). CCDC 686672 contains the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
[12] a) D. J. Freeman, G. Pattenden, A. F. Drake, G. Siligardi, J.
Jaspars, J. J. K. van den Bosch, K. Versluis, A. J. R. Heck, S. M.
[14] A. Michrowska, R. Bujok, S. Harutyunyan, V. Sashuk, G.
[15] All spectroscopic data of synthetic largazole (1) are in good
agreement with those of natural largazole; see the Supporting
Information.
[16] Compound 1g was synthesized by monoalkylation of bis(trime-
thylsilyl)thiol with bromide 1c.
[17] Note added in proof: For another synthesis of largazole see: Y.
Ying, K. Taori, H. Kim, J. Hong, H. Leusch, J. Am. Chem. Soc.,
2008, 130, 8455–8459.
Received: April 30, 2008
Published online: July 16, 2008
Keywords: biological activity · metathesis · natural products ·
.
structure–activity relationships · total synthesis
Angew. Chem. Int. Ed. 2008, 47, 6483 –6485
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim