Communications
For the synthesis of a compound collection we employed
heterocycle was kept, and substituents A and C were varied
(Figure 1a).
an iterative approach and focused on the heterocycle as well
as its substituents. Initial attempts focused on immobilization
of an N-carboxyalkyl-substituted rhodanine core on a poly-
meric resin by means of an ester bond, and subsequent
Knoevenagel reaction with aromatic aldehydes equipped with
a suitable functional group to allow formation of the biaryl
bond by means of a Pd0-catalyzed aryl coupling reaction.
However, these attempts failed because the Pd0-catalyzed
reaction was inhibited by the rhodanine heterocycle. Thus, the
solution-phase synthesis sequence shown in Scheme 1 was
We investigated the importance of the carboxylic acid (A,
Figure 1a) and the influence of the substitution and length of
the linker connecting the central core (B, Figure 1a) to the
carboxylic acid (Figure 2). Replacement of the carboxylic
acid with an imidazole or a benzimidazole as well as
esterification led to reduced disassembly activity (Table 1,
entries 1–4). Furthermore, the length of the linker between
the carboxylic acid and the rhodanine core (B, Figure 1a) was
varied. These experiments revealed that increasing the
distance up to two carbon
bonds resulted in an appre-
ciable increase in the com-
poundꢀs inhibitory potency
without markedly affecting
the disassembly activity
(Table 1, entries 1, 5, and
6). In subsequent experi-
ments, biaryl part C of the
compounds
(Figure 1a)
was varied. The heteroaro-
matic side chain (part C,
Figure 1a) tolerated varia-
tions, but modifications on
the furan heterocycle led
to
reduced
potency
(Table 1, entries 1, 5, and
7–9, and the Supporting
Information), probably as
a result of both electronic
and steric changes, as
replacement of the furan
ring in 16 for thiophene in
22 reduced the potency.
Very bulky substituents,
such as adamantyl or fer-
Scheme 1. Synthesis of a compoundcollection. Reagents: a) 5 mol% [PdCl 2(PPh3)2], 2m aq Na2CO3, 1,2-
dimethoxyethane, 858C, 9 h. b) Ethyl isothiocyanatoacetate, Et3N, toluene, reflux, 4 h. c) Bis(carboxymethyl)tri-
thiocarbonate, Na2CO3, iPrOH, reflux, 18 h. d) Bis(p-nitrophenyl)carbonate, Et3N, N,N-dimethylformamide,
room temperature, 12 h then HCl aq, dioxane, reflux, 2 h. e) For R2 =O, NH: NaOAc, dioxane, 908C, 2 h; for
R2 =S: piperidine, CH2Cl2, room temperature, 12 h. f) NaOH, dioxane/water, room temperature, 1 h. g) meta-
Chloroperoxybenzoic acid, NaHCO3, CH2Cl2, room temperature, 24 h.
employed; this sequence involves formation of biaryl alde-
hydes and subsequent Knoevenagel condensation with the
rhodanine core as key steps (for a solid-phase synthesis of
rhodanines by a different strategy, see reference [28]). The
aryl aldehydes necessary for the Knoevenagel condensation
(part C, Figure 1a) were obtained by Suzuki coupling
between haloaromatics and functionalized boronic acids
(Scheme 1).
rocene (Table 1, entries 10 and 11), at the end of side chain C
were generally well tolerated, reducing the overall efficiency
of the compounds only slightly. Also, introduction of a
charged group by means of a carboxylic acid did not influence
the potency considerably (Table 1, entries 12–14), underlining
the structural flexibility around this position.
Initially, we focused on the central heterocycle itself,
replacing the original rhodanine core with other heterocycles
(R1 and R2, Figure 1b). In these experiments, rhodanines
(R1 = S and R2 = S), thiohydantoin (R1 = S and R2 = N),
thioxooxazolidine (R1 = S and R2 = O), oxazolidinedione
(R1 = O and R2 = O), and hydantoin (R1 = O and R2 = N)
were employed (see the Supporting Information) and the
following trend in inhibition of tau aggregation was observed:
rhodanine (1) > thiohydantoin (3) @ oxazolidinedione (7) >
thioxooxazolidinone (9) > hydantoin (10). The rhodanine
heterocycle appeared to be the most potent. The thioxo
group in rhodanines is known as a carboxylic acid bioisoster
by size, low electronegativity, and ability to build hydrogen
bonds.[26,27] On the basis of these observations, the rhodanine
Figure 2. Structure–activity relationship.
After completing the synthesis of our focused library, we
observed that the efficiency of the most potent derivatives are
in the nanomolar range for both inhibition and disaggregation
(19, IC50 = 0.17 mm, DC50 = 0.13 mm, Table 1). Examples of
dose–response curves are shown in Figure 3, both for the
9216
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 9215 –9219
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