Synthesis of novel D- and L-3′-deoxy-3′-C-Hydroxymethyl nucleoside with exocyclic methylene as potential ribonucleotide reductase inhibitor

Article abstract of DOI:10.1081/NCN-100002355

D- and L-3′-Deoxy-3′-C-hydroxymethyl thymidine substituted with exocyclic methylene at 2′-position were synthesized, starting from D- and L-xylose as potential ribonucleotide reductase inhibitor, respectively, but they were found to be inactive against several tumor cell lines.

Full text of DOI:10.1081/NCN-100002355

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SYNTHESIS OF NOVEL D- AND L-3′-DEOXY-3′-C-
HYDROXYMETHYL NUCLEOSIDE WITH EXOCYCLIC
METHYLENE AS POTENTIAL RIBONUCLEOTIDE
REDUCTASE INHIBITOR
Moon Woo Chun a , Myung Jung Kim a , Un Hee Jo a , Joong Hyup Kim b , Hee-Doo Kim c &
Lak Shin Jeong d
a College of Pharmacy, Seoul National University , Seoul, 151-742, Korea
b Korea Institute of Science and Technology , Seoul, 136-791, Korea
c College of Pharmacy, Sookmyung Women's University , Seoul, 140-742, Korea
d College of Pharmacy, Ewha Womans University , Seoul, 120-750, Korea
Published online: 07 Feb 2007.
To cite this article: Moon Woo Chun , Myung Jung Kim , Un Hee Jo , Joong Hyup Kim , Hee-Doo Kim & Lak Shin Jeong
(2001) SYNTHESIS OF NOVEL D- AND L-3′-DEOXY-3′-C-HYDROXYMETHYL NUCLEOSIDE WITH EXOCYCLIC METHYLENE AS
POTENTIAL RIBONUCLEOTIDE REDUCTASE INHIBITOR, Nucleosides, Nucleotides and Nucleic Acids, 20:4-7, 703-706, DOI:
10.1081/NCN-100002355
To link to this article: http://dx.doi.org/10.1081/NCN-100002355
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(4–7), 703–706 (2001)
SYNTHESIS OF NOVEL D- AND L-3ꢀ-DEOXY-3ꢀ-C-
HYDROXYMETHYL NUCLEOSIDE
WITH EXOCYCLIC METHYLENE AS
POTENTIAL RIBONUCLEOTIDE
REDUCTASE INHIBITOR
Moon Woo Chun,1,∗ Myung Jung Kim,1 Un Hee Jo,1
Joong Hyup Kim,2 Hee-Doo Kim,3 and Lak Shin Jeong4
1College of Pharmacy, Seoul National University,
Seoul 151-742, Korea
2Korea Institute of Science and Technology, Seoul 136-791, Korea
3College of Pharmacy, Sookmyung Women’s University,
Seoul 140-742, Korea
4College of Pharmacy, Ewha Womans University,
Seoul 120-750, Korea
ABSTRACT
D- and L-3ꢀ-Deoxy-3ꢀ-C-hydroxymethyl thymidine substituted with exocyclic
methylene at 2ꢀ-position were synthesized, starting from D- and L-xylose as
potential ribonucleotide reductase inhibitor, respectively, but they were found
to be inactive against several tumor cell lines.
INTRODUCTION
Ribonucleotide reductase (1) catalyzes the conversion of ribonucleotides to
the 2ꢀ-deoxyribonucleotides and has been regarded as an attractive target for the
development of antitumor agents. Among compounds reported, 2ꢀ-deoxy-2ꢀ-vinyl-
substituted nucleoside (2) has been known to act as ribonucleotide reductase
∗ Corresponding author.
703
ꢁ
C
Copyright 2001 by Marcel Dekker, Inc.
www.dekker.com

ORDER
REPRINTS
704
CHUN ET AL.
O
N
O
N
H3C
CH3
NH
HN
O
O
HO
OH
O
O
HO
OH
1
ent-1
inhibitor and its spirocyclopropyl (3) or difluoro (4) analogue also appears to
act as the same inhibitor. Based on the biological activity of 2ꢀ-vinyl substituted
nucleoside, we were interested in designing and synthesizing the corresponding
3ꢀ-homologated derivative. We also synthesized the corresponding L-nucleoside
because L-nucleoside sometimes shows better biological activity profile than the
corresponding D-nucleoside (5).
Here, we report the synthesis of D- and L-3ꢀ-deoxy-3ꢀ-C-hydroxymethyl
nucleoside substituted with exocyclic methylene at 2ꢀ-position starting from
D- and L-xylose as potential ribonucleotide reductase inhibitor, respecti-
vely.
RESULTS AND DISCUSSION
Synthesis of D-thymidine analogue began with D-xylose. D-Xylose was con-
verted to 2 by treating with acetone and conc-sulfuric acid followed by partial
hydroysis of diacetonide with 0.2% HCl. Primary hydroxyl group of 2 was pro-
tected as TBDPS ether 3. Oxidation of 3 with PDC and acetic anhydride gave keone
4 which was subjected to the Wittig reaction to yield methylene 5. Hydroboration-
oxidation of 5 gave hydroxymethyl derivative 6 which was treated with tetra-n-
butylammonium fluoride to give diol 7. Treatment of diol 7 with benzoyl chloride
gave the dibenzoate 8 which was hydrolyzed with 85% formic acid and then suc-
cessively acetylated to give diacetate 9. Condensation of diacetate98 with silylated
thymine afforded the protected nucleoside 10. Deprotection of 10 with sodium
methoxide gave triol 11 whose primary two hydroxyl groups were silylated with
TBDPSCl to give 12. Oxidation of 12 with PDC yielded ketone 13 which was
treated with methyl triphenylphosphonium bromide and n-butyl lithium to afford
methylene derivative 14. Desilylation of 14 with tetra-n-butylammonium fluoride
produced the final D-thymidine analogue 1. The corresponding L-analogue ent-1
was synthesized starting from L-xylose according to the same procedure used in
the preparation of 1.

ORDER
REPRINTS
D- AND L-3ꢀ-DEOXY-3ꢀ-C-HYDROXYMETHYL NUCLEOSIDE
705
1) c-H2SO4
acetone
TBDPSO
HO
O
O
PDC
TBDPSCl
95%
OH
OH
D-xylose
TBDPSO
O
2) 0.2% HCl
96%
O
O
O
2
3
i) BH3
ii) H2O2
TBDPSO
Ph3P+CH3Br-
TBDPSO
O
O
5
O
n-BuLi
76%
O
78%
O
O
O
HO
O
O
O
4
6
i) 85%HCO2H
ii) Ac2O
BzO
BzO
HO
BzCl
90%
O
8
O
TBAF
96%
O
7
OAc
90%
O
O
O
BzO
BzO
OAc
O
HO
9
O
O
N
O
H3C
H3C
H3C
NH
NH
NH
N
O
O
Thymine
TMSOTf
N
O
HO
TBDPSO
BzO
TBDPSCl
93%
O
O
NaOMe
80%
O
71%
OH
HO
TBDPSO
OH
OAc
BzO
10
11
12
O
N
O
N
O
H3C
H3C
H3C
Ph3P+CH3Br-
n-BuLi
O
NH
NH
NH
TBAF
79%
PDC
O
O
N
O
HO
TBDPSO
TBDPSO
O
O
O
21%
HO
TBDPSO
TBDPSO
1
13
14
Scheme 1.
The final nucleosides 1 and ent-1 were tested against several tumor cell lines,
but they were found to be inactive in tested cell lines.
ACKNOWLEDGMENT
This research was supported by the grant of the Good Health R & D Project,
Ministry of Health and Welfare, Korea (HMP-98-D-4-0057).
REFERENCES
1. Thelander, L.; Reichard, P. Ann. Rev. Biochem. 1979, 48, 133.
2. a) Kanazawa, J.; Takahashi, T.; Akinaga, S.; Tamaoki, T.; Okabe, M. Anti-Cancwer
Drugs 1998, 9, 653. b) Sun, L. Q.; Li, Y. X.; Guillou, L.; Coucke, P. A. Cancer Res.
1998, 58, 5411.

ORDER
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706
CHUN ET AL.
3. a) Samanto, V.; Robins, M. J. Tetrahedron Lett. 1994, 35, 3445. b) Czernecki, S.;
Mulard, L.; Valery, J.-M. Can. J. Chem. 1993, 71, 413.
4. Wong, S. J.; Myette, M. S.; Wereley, J. P.; Chitambar, C. R. Clinical Cancer Res. 1999,
5, 439.
5. Hong, J. H.; Choi, Y.; Chun, B. K.; Lee, K.; Chu, C. K. Arch. Pharm. Res. 1998, 21,
89–105 and references cited therein.

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