Synthesis of MR-49, a deiodinated analog of tetraiodothyroacetic acid (tetrac), as a novel pro-angiogenesis modulator

Article abstract of DOI:10.1016/j.bmcl.2016.06.064

The tyrosine-based hormones 3,3′,5-triiodo-L-thyronine (L-T₃) and L-thyroxine (L-T₄) that are produced by the thyroid gland control metabolic functions. Iodothyronine deiodinase enzymes convert L-T₄to L-T₃, the form of thyroid hormone critical to genomic actions within cells and regulation of metabolism, and to reverse-L-T₃, a hormone isoform that is largely inactive. We used tertiary amines in a study of deiodination based on derivatives of tetraiodothyroacetic acid (tetrac)—a naturally occurring derivative of L-T₄—to mimic the action of the iodothyronine deiodinases and deiodination of the outer ring iodines. Deiodinated tetrac, MR-49, was found to be pro-angiogenic, with this activity exceeding that of L-T₃and L-T₄in a hemoglobin Matrigel plug assay of angiogenesis. Tetrac is anti-angiogenic via several nongenomic pathways, and the present studies of MR-49 reveal the critical contribution of outer ring iodines to the angiogenic properties of thyroid hormone analogues, which may have utility as pro-angiogenic pharmaceuticals.

Full text of DOI:10.1016/j.bmcl.2016.06.064

Bioorganic & Medicinal Chemistry Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of MR-49, a deiodinated analog of tetraiodothyroacetic acid
(tetrac), as a novel pro-angiogenesis modulator
Mehdi Rajabi a, Thangirala Sudha a, Noureldien H. E. Darwish a,b, Paul J. Davis a,c, Shaker A. Mousa a,
⇑
a The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, 1 Discovery Drive, Rensselaer, NY, USA
b Faculty of Medicine, Mansoura University, Mansoura, Egypt
c Department of Medicine, Albany Medical College, Albany, NY, USA
a r t i c l e i n f o
a b s t r a c t
The tyrosine-based hormones 3,30,5-triiodo-
L
-thyronine (
L-T3) and
L-thyroxine (
L-T4) that are produced by
Article history:
Received 20 April 2016
Revised 23 June 2016
Accepted 24 June 2016
Available online xxxx
the thyroid gland control metabolic functions. Iodothyronine deiodinase enzymes convert
form of thyroid hormone critical to genomic actions within cells and regulation of metabolism, and to
reverse- -T3, a hormone isoform that is largely inactive. We used tertiary amines in a study of deiodina-
tion based on derivatives of tetraiodothyroacetic acid (tetrac)—a naturally occurring derivative of -T4—to
mimic the action of the iodothyronine deiodinases and deiodination of the outer ring iodines.
Deiodinated tetrac, MR-49, was found to be pro-angiogenic, with this activity exceeding that of -T3
and -T4 in
hemoglobin MatrigelÒ plug assay of angiogenesis. Tetrac is anti-angiogenic via
several nongenomic pathways, and the present studies of MR-49 reveal the critical contribution of outer
ring iodines to the angiogenic properties of thyroid hormone analogues, which may have utility as
pro-angiogenic pharmaceuticals.
L-T4 to L-T3, the
L
L
Keywords:
L
L
-Thyroxine (
L
-T4)
L
a
3,30,5-Triiodo-
L
-thyronine (L-T3)
Tetraiodothyroacetic acid (tetrac)
Deiodination
Pro-angiogenesis
Ó 2016 Elsevier Ltd. All rights reserved.
The tyrosine-based hormone 3,30,5-triiodo-
secreted by the thyroid gland or derived in the periphery from
-thyroxine ( -T4) (Fig. 1) via outer ring deiodination. It controls a
large number of physiological processes such as normal differenti-
ation, growth, and integration of metabolic functions in most
L
-thyronine (
L
-T3) is
Angiogenesis is the process of formation and growth of new
blood vessels through relevant cell division and cell–cell adhesion
and adhesion of cells to the extracellular matrix (ECM) proteins. In
endothelial and vascular smooth muscle cells, angiogenesis is
dependent upon plasma membrane integrin expression.
L
L
cells.1–8
L
-T4 is thus a prohormone for
hormonal actions, but at a receptor on the cell surface of blood
vessel cells,
-T4 acts as hormone and is pro-angiogenic.9,10
Deiodination of the inner ring of -T4 may also occur, yielding
3,30,5-triiodo-
-thyronine (reverse- -T3, also called r -T3), a gener-
ally inactive form of the hormone. Types 1 and 2 iodothyronine
deiodinases (D1 and D2) catalyze the conversion of -T4 to -T3
(Fig. 2A). Both -T3 and r -T3 may then undergo further monodeio-
dination (outer ring 50-iodine of r
-T3, inner ring 5-iodine of -T3) to
3,30-T2, and these transformations are due either to type 3 iodothy-
ronine deiodinase (D3) ( -T3) or D1 (r
-T3).3,11–13
L
-T3 in terms of intracellular
Results of studies of thyroid hormone (L-T4, L-T3) and hormone ana-
logues such as GC-1 ([4-(4-hydroxy-3-isopropylphenoxy)-3,5-
dimethylphenoxy]acetic acid) in the chick chorioallantoic mem-
brane (CAM) model of angiogenesis led to the description of a cell
L
L
L
L
L
surface receptor for thyroid hormone on integrin avb3 by which
the hormone can stimulate angiogenesis as effectively as vascular
endothelial growth factor (VEGF) or fibroblast growth factor
(FGF)9,10 (Fig. 2B).
L
L
L
L
L
L
It was also shown that the pro-angiogenic thyroid hormone
signal at plasma membrane integrin
avb3 was transduced into
L
L
downstream intracellular actions by mitogen-activated protein
kinase, specifically, extracellular-signal-regulated kinase 1/2
(ERK1/2).1 We have described the pro-angiogenesis activity of thy-
roid hormone analogues such as L-T4, L-T3, diiodothyropropionic
Abbreviations: CAM, chick chorioallantoic membrane; FGF, fibroblast growth
acid (DITPA) and GC-1, a nuclear thyroid hormone receptor-b
(TRb)-selective agonist, in the human dermal microvascular
endothelial cell (HDMEC) tubule and CAM models.9,10,14–17 We also
extensively studied angiogenesis activity of tetraiodothyroacetic
factor; D1 and D2, types 1 and 2 iodothyronine deiodinases; ECM, extracellular
matrix; ERK1/2, extracellular-signal-regulated kinase 1/2;
L
-T4,
L-thyroxine; L-T3,
3,30,5-triiodo-
L-thyronine; rL-T3, reverse-L-T3; tetrac, tetraiodothyroacetic acid.
⇑
Corresponding author. Tel.: +1 518 694 7397; fax: +1 518 694 7567.
E-mail address: shaker.mousa@acphs.edu (S.A. Mousa).
http://dx.doi.org/10.1016/j.bmcl.2016.06.064
0960-894X/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Rajabi, M.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.06.064

2
M. Rajabi et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
O
I
O
I
via crosstalk is critical to the binding of vascular growth factors
by their specific protein receptors10,15 that are adjacent to the inte-
grin. Cellular uptake of tetrac is prevented by covalent conjugation
of its outer ring hydroxyl to 120–150 nm nanoparticles. This tet-
rac-nanoparticulate acts exclusively at the hormone receptor on
the integrin and is anti-angiogenic, confirming the role of this
receptor in the results mentioned above.10,22,23 Tetrac also has
been studied for its tumor cell-targeting properties for drug deliv-
ery. For example, Lee et al.24 synthesized tetrac-linked pegylated
liposomes that displayed heightened accumulation in integrin
OH
OH
I
I
HO
HO
NH2
NH2
O
I
O
I
I
Triiodothyronine (L-T3)
Thyroxine (L-T4)
I
OH
OH
HO
I
HO
I
O
O
O
O
I
I
I
avb3-expressing melanoma cells and increased cell uptake of a
4 (MR-49)
Tetrac 1
chemotherapeutic agent (edelfosine) compared to non-targeted
liposomes. In tumor xenografted animals, administration of tet-
rac-linked liposomes decreased tumor growth and increased ani-
mal survival compared to control (non-targeted) lipsomes. The
same group25 synthesized 64Cu-labeled tetrac-conjugated lipo-
somes for PET imaging of tumor angiogenesis. They found tetra-
c/64Cu-DOTA-liposomes had higher uptake by human aortic
endothelial cells in vitro and clear in vivo visualization of tumors
in micro PET images, compared to 64Cu-DOTA-liposomes.
Figure 1. Chemical structures of
(tetraiodothyroacetic acid), and MR-49 (deiodinated tetrac).
L-thyroxine (L-T4), triiodothyronine (L-T3), tetrac
acid (tetrac), a deaminated derivative of T4 (Figs. 1 and 2B) that,
acting alone, is anti-angiogenic at the receptor site and that also
blocks pro-angiogenic activity of thyroid hormone analogues, such
as those listed above.15,18–21 As shown in Figure 2B—in the absence
of L-T4 and L-T3—tetrac surprisingly inhibited the vascular budding
In the current study, we synthesized a new analog of tetrac that
expresses pro-angiogenic rather than anti-angiogenic activity. To
mimic the action of the three iodothyronine deiodinases, deiodina-
tion of tetrac has been explored with the use of tertiary amines.
MR-49 (Fig. 1) is the result of this approach to deiodination of
in response to VEGF and b-FGF in chick and human endothelial cell
assays. Thus, we found that its anti-angiogenic activity is
apparently related to its binding to the cell surface receptor for
thyroid hormone on integrin
avb3. The receptor is proximal to
the Arg-Gly-Asp (RGD) recognition site of the integrin, a site that
inner
ring
outer
ring
I
O
A
OH
I
HO
NH2
D1
D3
D1 D2
O
I
I
T4
O
I
O
I
OH
OH
I
I
HO
HO
NH2
NH2
O
O
I
I
rT3
T3
D3
O
I
D1
D1
D2
OH
I
HO
NH2
O
T2
B
T4
T3
T3
Tetrac
T4
X
X
VEGF-R
EGF
b-FGF
X
X
Endothelial
cells
FGF-R
EGF-R
VEGF-R
Matrix Gla
protein (MGP)
Vascular smooth muscle cells
Figure 2. (A) The metabolism of
hormone ( -T4 and -T3) on endothelial cells and vascular smooth cells that are initiated at the cell surface receptor for the hormone on the extracellular domain of integrin
vb3. A thyroid hormone analogue that is inhibitory at the integrin receptor, tetraiodothyroacetic acid (tetrac), is anti-angiogenic.
L-T3 and L-T4 into active and inactive intermediates involves the action of 3 types of deiodinases. (B) Pro-angiogenic actions of thyroid
L
L
a
Please cite this article in press as: Rajabi, M.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.06.064

M. Rajabi et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
3
tetrac, and its angiogenic activity has been found to exceed that of
-T3 and -T4 in standard angiogenesis assays.
We began by protecting the phenylacetic acid end of tetrac 1,
has wide applications in many of the same areas as basic hydro-
genation. Similar to debromination, different reducing agents such
as metal hydrides,28 catalytic hydrogenation, and acidic conditions
such as Zn/HCl, Pd/C, Zn or SnCl2/CH3CO2H, and CuCN/FeCl3 have
been used for deiodination of aromatic halides.29 Several studies
have reported deiodination by using derivatives of 2,4-diiodophe-
nol to mimic the action of the iodothyronine deiodinases.30,31 Con-
sequently, following the work of Talekar et al.,29 our plan was to
deiodinate compound 2 via initial deprotonation of the phenolic
OH group by tertiary amines like N-methylmorpholine (NMM),
and then the resulting anion abstracts a proton to form tautomeric
dienone. Subsequently, nucleophilic attack on the iodine atom by
either hydroxide ion or base results in the deiodinated product
(Scheme 2). We also tried using other tertiary bases like TEA, N-
methyl-2-pyrrolidone (NMP), and pyridine, but NMM showed
higher yield of deiodination than other bases.
L
L
employing three different methods. In method A, using a protecting
method published by Desage-El Murr et al.,26 a solution of tetrac 1
and boron trifluoride diethyl etherate (BF3ꢀEt2O) in methanol was
stirred in dry conditions at ambient temperature for 24 h. The
reaction was quenched by adding saturated NaHCO3 solution
and compound 2 (methyl-2-(4-(4-hydroxy-3,5-diiodophenoxy)-
3,5-diiodophenyl)acetate) was obtained in 62% yield. In method
B,27 protection of tetrac 1 was achieved with thionyl chloride
(SOCl2) in anhydrous methanol under 2 days reflux; compound 2
was precipitated by adding water and then was collected by vacuum
filtration, followed by recrystallization as a lipophilic ester in 62%
yield. We also tried another method (C) for synthesis of ester tetrac
2, suspending the tetrac in anhydrous methanol and adding triethy-
lamine (TEA), followed by adding benzylchloroformate and stirring
for 30 min. Compound 2 was obtained with a 73% yield by filtering,
removing the solvent, and recrystallization. Fourier transform infra-
red spectroscopy (FTIR) and 1H and 13C NMR spectroscopy were
used to confirm the synthesized compounds. The carbonyl (C@O)
Results from 1H NMR showed that tertiary base catalyzed
removal of two iodines from the ortho position of the phenol
ring of 2 (outer-ring) without any effect on iodines of the inner
ring. After hydrodehalogenation,
a new peak appeared at
6.67 ppm, which is assigned to hydrogen at the ortho position
and was associated with disappearance of the hydrogen peak
assigned to the meta position at 7.12 ppm that shifted to
6.76 ppm (Fig. 3).
Finally, the compound MR-49 was obtained by deprotection of
compound 3 using KOH in THF/methanol (1:1). Organic solvent
was evaporated completely and the mixture was neutralized by
1 M HCl. The precipitate was then collected by vacuum filtration
and dried to give a white powder of [4-(4-hydroxyphenoxy)-3,5-
diiodophenyl]acetic acid MR-49 in 73% yield.
of the acid group of tetrac, which had an FTIR peak at 1693 cmꢁ1
,
shifted to 1719 cmꢁ1 after protection of acid to ester. 1H NMR data
showed a 3-proton peak at 3.74 ppm and 13CNMR data showed a
peak at 52.1 ppm, which is assigned to the methyl group of ester tet-
rac 2 (Scheme 1).
Our efforts continued with dehalogenation of compound 2 by
selectively removing the iodines from the outer ring. Dehalogena-
tion of aromatic halides and, particularly hydrodehalogenation,
refers to efficient replacement of a halogen with hydrogen and that
Scheme 1. Synthesis of deiodinated tetrac (MR-49) from tetraiodothyroacetic acid (tetrac).
B-
I
I
I
I
I
O-
H+
O
H3CO
I
H3CO
I
H
H
I
H3CO
H3CO
O
I
H+
O
O
O
O
O
O
B-
O
I
O
I
O
H
I
I
I
I
2
B-
O
H+
O-
B-
I
H
O
I
H3CO
I
H3CO
I
H+
O
O
O
I
I
H3CO
I
OH
O
O
I
3
Scheme 2. Possible mechanism for deiodination of protected tetrac 1, using base.
Please cite this article in press as: Rajabi, M.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.06.064

4
M. Rajabi et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
Figure 3. NMR analysis of deiodination of protected tetrac 2.
To confirm that our deiodination method has an effect only on
Supplementary information). Compound 5 was reacted with 7 in
the presence of trimethylamine, copper bromide, and absolute
methanol stirred overnight at room temperature. Copper was
removed through a short aluminum hydroxide column, followed
by washing with benzene, DCM, and methanol. The collected sol-
vent was removed, and the resulting crude methyl [3,5-diiodo-4-
the outer-ring of 2 and also to study the role of the hydroxyl group
in deiodination, we protected the hydroxyl group of ester tetrac 2
with 1-bromo-3-phenylpropane to synthesize the compound 4
(methyl {4-[3,5-diiodo-4-(3-phenylpropoxy)phenoxy]-3,5-diiodo-
phenyl}acetate) in the presence of potassium carbonate and ace-
tone with 76% yield. Compound 4 was subsequently used in
reaction with tertiary bases, but we didn’t observe any conversion.
This confirmed that the presence of the phenolic OH group is key
for initial deprotonation of the phenolic OH group by tertiary ami-
nes to cause the anion to form a tautomeric dienone, which under-
goes nucleophilic attack (Scheme 3).
We also tried using an alternative method for synthesis of MR-
49, similar to the published method of Ziegler and Marr,32 but
instead of using dianisyliodonium bromide, we started from bis
(4-methoxyphenyl)iodonium tetrafluoroborate 5 in reaction with
[4-hydroxy-3,5-diiodophenyl]acetic acid 7, which was obtained
from (4-hydroxy-3,5-diiodophenyl)acetic acid 6 according to the
procedure in method B and also confirmed by Balyon, et al. (see
(4-methoxyphenoxy)phenyl]acetate
8 was used without any
purification and boiled in acetic acid and hydriodic acid for 3 h
for deprotection, resulting in MR-49 (Scheme 4).
To assess the potency of the pro-angiogenic activity of MR-49
versus tetrac and T3, their activities were evaluated in a MatrigelÒ
plug and a hemoglobin assay. The MatrigelÒ plug assay is an effi-
cient method to evaluate either stimulators or inhibitors of angio-
genesis in vivo.33 MatrigelÒ is derived from Engelbreth-Holm-
Swarm (EHS) mouse sarcoma and contains growth factors and
extracellular matrix components.34
We evaluated the effect of MR-49 in vivo using a mouse model
(BALB/c mice). Male BALB/c mice aged 5–6 weeks weighing
between 18 and 20 g were purchased from Envigo (Indianapolis,
I
I
OH
O
I
O
2
O
I
O
I
1-Bromo-3-phenylpr
Base
opane,
K2CO3,
Reflux,
No
Reaction
O
O
Acetone,
overnight
I
O
4
Reflux,
Overnight
I
I
Scheme 3. Synthesis of methyl {4-[3,5-diiodo-4-(3-phenylpropoxy)phenoxy]-3,5-diiodophenyl}acetate 4 and reaction with tertiary base.
-BF4
O
I
O
O
I
CuBr
O
O
O
+
O
Methanol
55%
OH
O
I
I
7
I
5
8
OH
I
HO
HO
I
O
O
OH
O
I
I
6
MR-49
Scheme 4. Alternative method for synthesis of MR-49.
Please cite this article in press as: Rajabi, M.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.06.064

M. Rajabi et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
5
extraction of a proton to form a tautomeric dienone. Subsequent
nucleophilic attack on the iodine atom by either hydroxide ion or
base resulted in a deiodinated product of tetrac, designated MR-
49. Tetrac is anti-angiogenic via several nongenomic pathways
and the present studies of MR-49 reveal the critical contribution
of outer ring iodines to the angiogenic properties of thyroid hor-
mone analogues.
Funding sources: Partial funding was from NanoPharmaceuti-
cals, LLC.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2016.06.
064. These data include MOL files and InChiKeys of the most
important compounds described in this article.
References and notes
Figure 4. MatrigelÒ plug assay of angiogenesis (pro-angiogenesis effect of MR-49,
-T3, and tetrac). Values are expressed as mean SEM versus control vehicle (CTR).
Values are expressed as mean SEM. Tetrac significantly inhibited hemoglobin
L
1. Brent, G. A. J. Clin. Invest. 2012, 122, 3035.
2. Cheng, S. Y.; Leonard, J. L.; Davis, P. J. Endocr. Rev. 2010, 31, 139.
3. Gereben, B.; Zavacki, A. M.; Ribich, S.; Kim, B. W.; Huang, S. A.; Simonides, W.
S.; Zeold, A.; Bianco, A. C. Endocr. Rev. 2008, 29, 898.
content in the Matrigel plug (index of angiogenesis) while MR-49 or
it.
L-T3 increased
4. Hollenberg, A. N.; Forrest, D. Cell Metab. 2008, 8, 10.
5. Horn, S.; Heuer, H. Mol. Cell Endocrinol. 2010, 315, 19.
6. López, M.; Alvarez, C. V.; Nogueiras, R.; Diéguez, C. Trends Mol. Med. 2013, 19,
418.
7. Warner, A.; Mittag, J. J. Mol. Endocrinol. 2012, 49, R29.
8. van der Deure, W. M.; Peeters, R. P.; Visser, T. J. J. Mol. Endocrinol. 2010, 44, 1.
9. Mousa, S. A.; Davis, F. B.; Mohamed, S.; Davis, P. J.; Feng, X. Int. Angiol. 2006, 25,
407.
10. Luidens, M. K.; Mousa, S. A.; Davis, F. B.; Lin, H. Y.; Davis, P. J. Vasc. Pharmacol.
2010, 52, 142.
11. Martínez-Sánchez, N.; Alvarez, C. V.; Fernø, J.; Nogueiras, R. C. D.; López, M. Best
Prac. Res. Clin. Endocrinol. Metab. 2014, 28, 703.
12. Dentice, M.; Marsili, A.; Zavacki, A.; Larsen, P. R.; Salvatore, D. Biochim. Biophys.
Acta 2013, 1830, 3937.
13. Drigo, R. A. E.; Fonseca, T. L.; Werneck-de-Castro, J. P. S.; Bianco, A. C. Biochim.
Biophys. Acta 2013, 1830, 3956.
14. Davis, P. J.; Davis, F. B.; Mousa, S. A. Curr. Cardiol. Rev. 2009, 5, 12.
15. Mousa, S. A.; Bergh, J. J.; Dier, E.; Rebbaa, A.; O’Connor, L. J.; Yalcin, M.; Aljada,
A.; Dyskin, E.; Davis, F. B.; Lin, H. Y.; Davis, P. J. Angiogenesis 2008, 11, 183.
16. Mousa, S. A.; O’Connor, L.; Davis, F. B.; Davis, P. J. Endocrinology 2006, 147,
1602.
IN). All animal studies were conducted at the animal facility of the
Albany College of Pharmacy and Health Sciences, Albany, NY in
accordance with and approved by institutional guidelines for
humane animal treatment and according to the current guidelines.
Mice were maintained under specific pathogen-free conditions and
housed under controlled conditions of temperature (20–24 °C),
humidity (60–70%), and 12 h light/dark cycle with ad libitum
access to water and food. Mice were allowed to acclimatize for
5 d prior to the start of study.
Mice were dived into 4 groups: control, MR-49,
L-T3, and tetrac.
Pro-angiogenic (MR-49 and
L-T3) and anti-angiogenic substances
(tetrac) were added to MatrigelÒ and injected subcutaneously in
the mice (MatrigelÒ plug assay), and the control group received
vehicle. There were 4 implants per mouse with a concentration
of 10 lg/implant and 2 mice per group. After 7–10 days, the Matri-
gel plug was removed and new blood vessel formation in the
MatrigelÒ could be visualized. Vessel formation was quantified
by measuring the hemoglobin concentration (Drabkin method35).
Drabkin’s solution consists of potassium ferricyanide, potassium
cyanide, and sodium bicarbonate. In this method, hemoglobin is
oxidized to methemoglobin by potassium ferricyanide, which in
turn reacts with potassium cyanide to form cyanmethemoglobin.36
Spectrophotometric readings were taken at 540 nm in a spec-
trophotometer. Hemoglobin values were calculated from a hemo-
globin curve prepared using a hemoglobin standard.
17. Mousa, S. A.; O’Connor, L. J.; Bergh, J. J.; Davis, F. B.; Scanlan, T. S.; Davis, P. J. J.
Cardiovas. Pharmacol. 2005, 46, 356.
18. Glinskii, A. B.; Glinsky, G. V.; Lin, H. Y.; Tang, H. Y.; Sun, M.; Davis, F. B.; Luidens,
M. K.; Mousa, S. A.; Hercbergs, A. H.; Davis, P. J. Cell Cycle 2009, 8, 3562.
19. Yoshida, T.; Gong, J.; Xu, Z.; Wei, Y.; Duh, E. J. Exp. Eye Res. 2012, 94, 41.
20. Yalcin, M.; Bharali, D. J.; Dyskin, E.; Dier, E.; Lansing, L.; Mousa, S. S.; Davis, F.
B.; Davis, P. J.; Mousa, S. A. Thyroid 2010, 20, 281.
21. Yalcin, M.; Dyskin, E.; Lansing, L.; Bharali, D. J.; Mousa, S. S.; Bridoux, A.;
Hercbergs, A. H.; Lin, H. Y.; Davis, F. B.; Glinsky, G. V.; Glinskii, A.; Ma, J.; Davis,
P. J.; Mousa, S. A. J. Clin. Endocrinol. Metab. 2010, 95, 1972.
22. Rajabi, M.; Srinivasan, M.; Mousa, S. A. Nanobiomaterials in Drug Delivery In
Nanobiomaterials in Drug Delivery: Applications of Nanobiomaterials;
Grumezescu, A., Ed.; Elsevier: Amsterdam, 2016; Vol. 9, p 1.
23. Srinivasan, M.; Rajabi, M.; Mousa, S. A. Nanobiomaterials in Cancer Therapy In
Nanobiomaterials in Cancer Therapy: Applications of Nanobiomaterials;
Grumezescu, A., Ed.; Elsevier: Amsterdam, 2016; Vol. 7, p 57.
24. Lee, S.; Kim, J.; Shim, G.; Kim, S.; Han, S. E.; Kim, K.; Kwon, I. C.; Choi, Y.; Kim, Y.
B.; Kim, C. W.; Oh, Y. K. J. Control. Rel. 2012, 164, 213.
We found that MR-49 and L-T3 were associated with increased
hemoglobin concentration, consistent with new blood vessels’ for-
mation. MR-49 increased hemoglobin concentration by 1.6-fold in
comparison to the control group, while L-T3 increased hemoglobin
25. Kang, C. M.; Koo, H. J.; Lee, S.; Lee, K. C.; Oh, Y. K.; Choe, Y. S. Nucl. Med. Biol.
2013, 40, 1018.
26. Desage-El Murr, M.; Nowaczyk, S.; Le Gall, T.; Mioskowski, C. Eur. J. Org. Chem.
2006, 1489.
concentration to a lesser extent (1.4-fold). On the other hand, tet-
rac was associated with decreased hemoglobin concentration by
about 50% (Fig. 4).
27. Bridoux, A.; Cui, H. D.; Dyskin, E.; Yalcin, M.; Mousa, S. A. Bioorg. Med. Chem.
Lett. 2009, 19, 3259.
28. Czaplik, W. M.; Grupe, S.; Mayer, M.; Jacobi von Wangelin, A. Chem. Commun.
2010, 6350.
29. Talekar, R. S.; Chen, G. S.; Lai, S. Y.; Chern, J. W. J. Org. Chem. 2005, 70, 8590.
30. Beck, C.; Jensen, S. B.; Reglinski, J. Bioorg. Med. Chem. Lett. 1994, 4, 1353.
31. Vasil’ev, A. A.; Engman, L. J. Org. Chem. 1998, 63, 3911.
32. Ziegler, H.; Marr, C. J. Org. Chem. 1962, 27, 3335.
In conclusion, we used tertiary amines in a study of deiodina-
tion based on derivatives of tetrac—a naturally occurring derivative
of T4—to mimic the action of the iodothyronine deiodinases and
deiodination of the ortho-iodohydroxylated arenes of thyroid
hormone analogs. Iodothyronine deiodinase enzymes convert T4
to
L-T3, the form of thyroid hormone critical to genomic actions
within cells and to regulation of metabolism, and to reverse
L-T3,
33. Malinda, K. M. Methods Mol. Biol. 2009, 467, 287.
34. Lee, K. H.; Choi, H. R.; Kim, C. H. J. Ethnopharmacol. 2005, 97, 509.
35. Nuti, E.; Cantelmo, A. R.; Gallo, C.; Bruno, A.; Bassani, B.; Camodeca, C.;
Tuccinardi, T.; Vera, L.; Orlandini, E.; Nencetti, S.; Stura, E. A.; Martinelli, A.;
Dive, V.; Albini, A.; Rossello, A. J. Med. Chem. 2015, 58, 7224.
36. Balasubramaniam, P.; Malathi, A. J. Postgrad. Med. 1992, 38, 8.
a hormone isoform that is largely inactive. T4, itself, initiates a
number of nongenomic actions of thyroid hormone at the cell sur-
face. Deiodination was obtained via initial deprotonation of the
phenolic OH group by tertiary amines and consequent anion
Please cite this article in press as: Rajabi, M.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.06.064