DOI: 10.1002/cmdc.201100258
Synthesis and Structure–Activity Relationships of a Class of Sodium Iodide
Symporter Function Inhibitors
Fanny Waltz, Lucie Pillette, Elodie Verhaeghe, and Yves Ambroise*[a]
The capture of iodide is a vital process in vertebrates. It occurs
mainly in the thyroid gland and constitutes the first and limit-
ing step in the biosynthesis of iodinated hormones T3 and T4.
This transport is known to be mediated by the sodium iodide
symporter (NIS), an integral membrane glycoprotein that trans-
ports iodide against its electrochemical gradient.[1]
hibitor with a half maximal inhibi-
tory concentration (IC50) value of
40 nm. Further analysis of the
effect of ITB5 on iodide-induced
current in NIS-expressing Xenopus
oocytes showed that the inhibition
was rapid (<5 s) and reversible.[8]
Iodide capture plays a central role in many thyroid patho-
physiological conditions. Impaired iodide uptake is observed in
Grave’s and Hashimoto’s diseases, thyroiditis, adenoma and
thyroid cancers, cold nodules, goitre and hypothyroidism. Sev-
eral studies conclude that thyroid gland failure occurs in 5–7%
of populations across different countries.[2] There is also an im-
portant concern when people are accidentally exposed to radi-
oiodine species since its accumulation in the thyroid gland in-
creases the risk of cancer, especially in the youngest popula-
tion. A dramatic example of this is the Chernobyl accident in
1986 after which the World Health Organization (WHO) pre-
dicted that 9000 individuals would die from cancer as a direct
result of this disaster.[3] Iodide uptake is also at the basis of an
emerging strategy to monitor and kill cancer cells using radio-
iodide after targeted NIS gene transfer.[4] Unfortunately, this
strategy is not yet amenable to clinical applications because
transport capacities in these transformed cells is too low for ef-
ficient tumor destruction. Understanding how iodide capture is
mediated and regulated at a cellular level remains a funda-
mental area of research. The cloning of NIS in 1996[5] led to
great advances in the molecular characterization of the sym-
porter, and many studies have been conducted since then to
investigate NIS expression and NIS transcriptional regulation
mechanisms.[1a,4b,c,6] However, the molecular aspects of how
iodide is translocated inside the thyroid cells, how this capture
is up-regulated at a cellular level, and which proteins are in-
volved in post-translational regulation of NIS activity are still
unknown. It is necessary to understand the whole mechanistic
picture of iodide capture in NIS-expressing cells in order to de-
velop new therapeutic tools and improve the clinical manage-
ment of patients.
These results indicated that ITB5 acts by disrupting NIS either
directly or at a post-translational level. Consequently, this com-
pound opens new, promising perspectives to dissect the cellu-
lar regulation mechanisms of iodide capture using chemical
proteomics and affinity-based target identification ap-
proaches.[9] The discovery of ITB5 as a powerful iodide uptake
inhibitor is particularly attractive because N-benzylanilines are
small, versatile structures that can be easily synthesized. We
explored this class of compounds both to identify more potent
compounds and to elucidate the structure–activity relation-
ships (SAR) for the design of future pharmacological tools.
Here, we present the synthesis of 184 analogues of ITB5, each
having a single structural modification on the aromatic rings or
central linker. We further investigated the effects of these varia-
tions on iodide uptake in FRTL5 cells by measuring the IC50
values of the synthesized compounds.
A one-step, solution-phase combinatorial approach was
used for the preparation of a 180-membered library with varia-
tions in the substitution pattern of the chlorine and fluorine
atoms on one hand, and the nitro and hydroxy groups on the
other hand. Fifteen aniline derivatives (A1–A15) were reacted
individually with twelve aromatic aldehyde analogues (B1–
B12) using a parallel reductive amination protocol (Scheme 1).
Our synthesis strategy was developed to quickly generate a
series of compounds with high purity for biological screening.
We first tested the scope of the chemistry and optimized the
handling and purification steps. We explored the use of various
polymer-supported or nonsupported borohydrides, as well as
the use of polymer-supported scavengers, solid-phase extrac-
tion or liquid–liquid extraction procedures—for a Review on
reductive amination, see Reference [10].
Recently, a new compound, iodide transport blocker 5 (ITB5)
was discovered by high-throughput screening as a very potent
iodide uptake blocker in human embryonic kidney cells stably
expressing human NIS (hNIS-HEK293), as well as in the rat thy-
roid-derived cells FRTL5.[7] ITB5 was shown to be a powerful in-
After optimization of the chemistry, the 180-membered li-
brary was ultimately prepared as follows: aromatic amines A1–
A15 (300 mmol) were individually reacted with each aromatic
aldehyde B1–B12 (250 mmol) in the presence of polymer-sup-
ported cyanoborohydride (600 mmol) in acetic acid/tetrahydro-
furan (THF) (1:3). An excess of amine was used to prevent over
alkylation. The suspension was agitated for 16 h at room tem-
perature. Polymer-supported benzaldehyde (250 mmol) was
then added to remove unreacted amine, and this suspension
was further agitated for a period of 24 h. The mixture was then
filtered, and the filtrate was concentrated under reduced pres-
sure. Purity was assessed by analytical HPLC (C18 column) and
[a] F. Waltz, L. Pillette, Dr. E. Verhaeghe, Dr. Y. Ambroise
Department of Bioorganic Chemistry and Isotopic Labeling
Alternative Energies and Atomic Energy Commission
Institute of Biology and Technology (iBiTecS)
route de Saclay, Gif sur Yvette 91191 (France)
Supporting information for this article is available on the WWW under
ChemMedChem 2011, 6, 1775 – 1777
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1775
Waltz, Fanny
