Biomedical Engineering Reference
In-Depth Information
Scheme 3.1
Synthesis of 5
0
-Se-derivatized phosphoramidites and oligonucleotides. (
a
) CBr
4
,
Ph
3
P, diisopropylazodicarboxylate (DIAD), THF. (
b
) Ts-Cl, pyridine. (
c
)MsCl,Et
3
N, THF. (
d
)
NaSeMe. (
e
)Et
3
N
3HF. (
f
) PCl(OCH
2
CH
2
CN)N(i-Pr)
2
.(
g
) Solid-phase synthesis
Selenium-Derivatized Nucleic Acid at 2
0
-Position
3.2.2
The selenium modification at 5
0
terminal position [
24
] first demonstrated various
advantages of selenium derivatization of nucleic acids, including compatibility
with phosphoramidite chemistry and solid-phase automate DNA/RNA synthesis,
outstanding stability under various conditions, and easy handling and purification
procedures. In order to further expand the application of SeNA for phase and
structure determination, Huang laboratory first decided to chemically incorporate
the selenium functionality into the internal position (such as the 2
0
-position [
25
])
to derivatize both DNAs and RNAs. Through the collaboration between Huang
and Egli laboratories, the first nucleic acid crystal structure was determined via the
selenium MAD phasing [
25
,
26
]. This Se modification provides phase information
for the crystal structure determination while retaining the RNA-like and A-form
DNA-like sugar pucker (3
0
-endo conformation). The synthesis and application of
the 2
0
-Se-derivatized nucleic acids are briefly described here.
Synthesis and Crystallography Application of 2
0
-Se-Pyrimidine
3.2.2.1
One year after the 5
0
-Se story, the first synthesis of the Se-derivatized nucleic acids
at 2
0
-position was accomplished [
25
]. The synthesis proceeded from 5
0
-DMTr-3
0
-
O-TBDMS-uridine as the starting material; the free 2
0
-hydroxyl group was first
activated by mesylation then displaced by 2-exo-oxygen subsequently, followed by
fluoride ion treatment to give 5
0
-DMTr-2, 2
0
-anhydrouridine as the intermediate.
Selenium was introduced into nucleoside by opening the ring at 2
0
-position with a Se
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