Bioorganic & Medicinal Chemistry Letters
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.
0960-894X/Ó 2016 Elsevier Ltd. All rights reserved.