Biomedical Engineering Reference
In-Depth Information
Scheme 3.5
Synthesis of 4
0
-Se nucleosides. Reagent and conditions: (
a
) Allyl alcohol, H
2
SO
4.
(
b
) 4-Methoxybenzyl chloride (PMB-Cl), NaH, THF, PdCl
2
,CHCl
3
/H
2
O. (
c
)NaBH
4
, MeOH.
(
d
) MsCl, pyridine. (
e
) LiBr, reflux. (
f
)Se,NaBH
4
, EtOH, 60
ı
.(
g
) 10% CF
3
COOH (TFA),
CH
2
Cl
2
,NaHCO
3.
(
h
) 1,1,3,3-Tetraisopropyldisiloxane-1,3-diyldichloride (TIPDS-Cl), pyridine,
0
ı
.(
i
) 2,4-Dimethoxybenzoyl-Cl. (
j
)O
3
,CH
2
Cl
2
,
78
ı
.(
k
) Uracil, TMSOTf, Et
3
N, toluene. (
l
)2,
4, 6-Triisopropylbenzenesulfonyl chloride (TPS-Cl), Et
3
N, DMAP. (
m
)Bu
4
NF, THF. (
n
)TIBS-Cl,
Et
3
N, DMAP. (
o
)NH
3
H
2
O
amplified by PCR and can direct transcription in mammalian cells [
40
]. These
investigations suggested that the 4
0
-Se-containing oligonucleotides might also have
great potentials in structure as well as biological function studies. However, the
synthesis of the 4
0
-Se nucleoside is quite challenging. Until 2007, the first successful
synthesis of the 4
0
-Se-U and 4
0
-Se-C (Scheme
3.5
) was reported by Matsuda lab
[
41
]. In their work, introducing selenium into 4
0
-position was achieved by a minor
modification on previous published 4
0
-Se-U synthesis work [
42
] via a stereoselec-
tive seleno-Pummerer reaction with a protected selenoxide and a persilylated uracil.
The synthesized 4
0
-Se-uridine can be further converted to 4
0
-Se-cytidine by a two-
step activation and aminolysis reaction. One year later, 4
0
-Se-U was successfully
introduced into ribo-oligonucleotides by standard phosphoramidite chemistry and
solid-phase synthesis; two 4
0
-Se-U-containing RNAs (5
0
-
U
4
0
-Se
UUUUU-3
0
and 5
0
-
UUUUU
U
4
0
-Se
-3
0
) were synthesized to prove that the 4
0
-selenium functionality was
stable under standard TBDMS-RNA synthesis and purification protocol [
43
].
A similar synthesis of 4
0
-Se-U and 4
0
-Se-C was also reported by Jeong lab [
44
]
including an X-ray crystal structure of the nucleoside. The X-ray crystallographic
analysis showed a significant change in sugar conformation. Typical C3
0
-endo sugar
pucker of uridine (Northern Conformation) is changed to an unusual C2
0
-endo
conformation (Southern Conformation), which may be caused by steric effect of 4
0
-
selenium atom. This phenomenon was also observed by NOE NMR experiment in
solution state. This conformational change might offer resistance against nuclease
digestion, which gives 4
0
-Se nucleoside a great potential in therapeutic develop-
ment [
44
].
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