Tetrahedron Letters
An efficient synthesis of 3-(N-piperidinemethyl)-2,2,5,5-tetramethyl-
1-oxy-3-pyrroline, a promising radioprotector for cancer
radiotherapy
a,
⇑
a
a
a
b
b
Haitao Wu , Vincent Coble , Olga Vasalatiy , Rolf E. Swenson , Murali C. Krishna , James B. Mitchell
a
Imaging Probe Development Center, National Heart, Lung, and Blood Institute, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States
Radiation Biology Branch, Center for Cancer Research, National Cancer Institute. National Institutes of Health, 9000 Rockville Pike, Bethesda, Maryland 20892, United States
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Nitroxides can ameliorate the toxic effects of radiation during cancer therapy. Nitroxides are paramag-
netic and can be used in magnetic resonance imaging (MRI) and electron paramagnetic resonance
imaging (EPRI) to monitor in vivo oxidative stress status. Compound 5 (3-(N-piperidinemethyl)-
Received 22 July 2014
Revised 5 August 2014
Accepted 8 August 2014
Available online 14 August 2014
2,2,5,5-tetramethyl-1-oxy-3-pyrroline) was found to be the most effective nitroxide radioprotector. An
efficient synthesis for this promising radioprotector was developed.
Published by Elsevier Ltd.
Keywords:
Nitroxide
Redox
Radioprotector
MRI
EPRI
Protection from radiation exposure is important for radiation
cancer treatment or a nuclear accident. Cancer is the second lead-
ing cause of death in the United States, exceeded only by heart dis-
ease. The estimated number of new cancer cases is 1.66 million and
about 580,350 people are expected to die in the US alone in 2013.
The death rates of cancer did not change much over the past
results in signal loss in T1-weighted MRI scan which can provide
an imaging-based assay of tissue redox status. Based on the initial
findings on the radioprotective effects of the model compound
7
4
,8,9
Tempol
and a systematic in vitro survey of a variety of nitrox-
1
10
ide-related radioprotectors, compound 3-(N-piperidinemethyl)-
2,2,5,5-tetramethyl-1-oxy-3-pyrroline, 5 was found to be the most
effective radioprotector against lethal doses of radiation in mice.11
In addition, the compound readily passes the blood–brain barrier
(BBB). A previous synthesis of compound 5 produced about 5%
8
0 years except for lung and bronchus cancers. It is well known
that cancer can be treated with ionizing radiation, but the inevita-
ble normal tissue exposure during cancer radiotherapy or a nuclear
2
,3
10
accident can promote carcinogenesis and a variety of toxicities.
overall yield over a 6-step synthesis (Scheme 1). Following this
Pre-exposure administration of a radiation protective drug can
reduce radiation damage by ameliorating the toxic effects of
radiation. Preclinical studies in mice have shown that administra-
tion of Tempol (1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine)
decreases the severity of xerostomia (dry mouth) after salivary
gland irradiation and increases the LD50/30 after whole-body irra-
diation.4 Nitroxides are paramagnetic and their pharmacokinet-
ics can therefore be monitored with magnetic resonance imaging
procedure we noticed a UV invisible byproduct next to product 5
on TLC plate that can be detected by I staining. The separation
2
of the two products was difficult. In addition the product purity
cannot be accurately characterized by NMR due to the paramag-
netic property of the product or by HPLC due to the weak UV
absorption of the byproduct and the similarity of their retention
times. The byproduct was found to be hydroxylamine compound
7. Contamination of the diamagnetic hydroxylamine would
adversely affect the MR and EPR imaging quality. The availability
of a more convenient and efficient synthesis method of this prom-
ising agent would be beneficial.
–6
(
MRI), electron paramagnetic resonance imaging (EPRI), and their
5,6
concentration in tissues can be quantified.
The in vivo redox
reactions among nitroxides, reactive oxygen species, and intracel-
lular antioxidants can also be used for redox imaging study. Forma-
tion of diamagnetic hydroxylamine from nitroxide redox reaction
We found that the Favorskii rearrangement of 3,5-dibromo-4-
oxo-2,2,6,6-tetramethylpiperidine 2 could be done in the presence
of piperidine to form the piperidine derivative 3 directly in 89%
1
2
yield (Scheme 2). The conversion of the amine 3 to the nitroxide
was carried out in 90% yield by stirring with the H and
⇑
4
2 2
O
040-4039/Published by Elsevier Ltd.
0