Synthesis of 5-Azacytidine nucleosides with rigid sugar moiety as potential antitumor agents

Article abstract of DOI:10.1081/NCN-120022685

The bicyclic 3′-O,5′-C-methylene-linked and 2′-O,5′-C-methylene-linked 5-azacytidine derivatives were readily synthesized from 1,2;5,6-di-O-isopropylidene-D-glucose and evaluated against several cancer cell lines.

Full text of DOI:10.1081/NCN-120022685

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Synthesis of 5-Azacytidine Nucleosides with Rigid Sugar
Moiety as Potential Antitumor Agents
Moon Woo Chun a f , Myong Jung Kim a , Hea Ok Kim b , Hee-Doo Kim c , Joong Hyup Kim d
Hyung Ryong Moon e & Lak Shin Jeong e
,
a College of Pharmacy, Seoul National University, Seoul, Korea
b Division of Chemistry and Molecular Engineering, Seoul National University, Seoul, Korea
c College of Pharmacy, Sookmyung Women’s University, Seoul, Korea
d Korea Institute of Science and Technology, Seoul, Korea
e College of Pharmacy, Ewha Womans University, Seoul, Korea
f Seoul National University, 56-1 Shinrim-dong San, Kwanak-gu, 151-742, Seoul, Korea
Version of record first published: 31 Aug 2006.
To cite this article: Moon Woo Chun, Myong Jung Kim, Hea Ok Kim, Hee-Doo Kim, Joong Hyup Kim, Hyung Ryong Moon & Lak
Shin Jeong (2003): Synthesis of 5-Azacytidine Nucleosides with Rigid Sugar Moiety as Potential Antitumor Agents, Nucleosides,
Nucleotides and Nucleic Acids, 22:5-8, 915-917
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, Nos. 5–8, pp. 915–917, 2003
Synthesis of 5-Azacytidine Nucleosides with Rigid Sugar
Moiety as Potential Antitumor Agents
1
2
Moon Woo Chun,1, Myong Jung Kim, Hea Ok Kim,
*
Hee-Doo Kim,3 Joong Hyup Kim,4 Hyung Ryong Moon,5
and Lak Shin Jeong5
1College of Pharmacy and
2Division of Chemistry and Molecular Engineering,
Seoul National University, Seoul, Korea
3College of Pharmacy, Sookmyung Women’s University, Seoul, Korea
4Korea Institute of Science and Technology, Seoul, Korea
5College of Pharmacy, Ewha Womans University, Seoul, Korea
ABSTRACT
The bicyclic 30-O,50-C-methylene-linked and 20-O,50-C-methylene-linked 5-aza-
cytidine derivatives were readily synthesized from 1,2;5,6-di-O-isopropylidene-d-
glucose and evaluated against several cancer cell lines.
Key Words: 5-Azacytidine; Conformationally locked nucleosides.
Unmodified nucleosides exist in either the S-type or N-type conformation. How-
ever, due to the low energy barrier between these two dominating conformers, a fast
equilibrium between them exists in solution state.[1] Therefore, many approaches to
lock the puckering of the furanose ring into N-type or S-type have been made since it
is known that HIV-1 reverse transcriptase is able to discriminate between two
*Correspondence: Moon Woo Chun, Seoul National University, 56-1 Shinrim-dong San,
Kwanak-gu, 151-742 Seoul, Korea; Fax: +82 2 888 0649; E-mail: mwchun@snu.ac.kr.
915
DOI: 10.1081/NCN-120022685
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

916
Chun et al.

5-Azacytidine Nucleosides with Rigid Sugar Moiety
917
conformationally locked carbocyclic AZT triphosphate analogues.[2] Therefore, as
we have found antitumor activity of 30,40-tetrahydrofuran fused pyrimidine nucleo-
sides locked in the C10-exo conformation, it became interesting to study the anti-
tumor activity of analogues locked into the S-type or the N-type conformation.
For this purpose, we report the synthesis of 5-azacytidine nucleoside analogues
locked into the S-type or the N-type conformation as potential antitumor agents
because 5-azacytidine derivatives like d-5-azacytidine and 20-deoxy-d-5-azacytidine
exhibit very potent anti-leukemic activity.[3]
1,2;5,6-Di-O-isopropylidene-d-glucose (3) was oxidized with PDC to give ketone
4 (Sch. 1). Selective removal of 5,6-O-isopropylidene of 4 using 80% acetic acid
followed by acetylation afforded the tricyclic diacetate which was hydrolyzed and
acetylated to give 5. Condensation of 5 with silylated 5-azacytosine and deacetylation
of the resulting nucleoside using NH4OH=MeOH afforded the final nucleoside 1.
Ketone 4 was stereoselectively reduced using NaBH4 to give diacetone d-allofur-
anose which was benzylated to afford 5. 5,6-O-Isopropylidene of 6 was selectively
removed using 75% acetic acid to give diol 11 of which primary and secondary
hydroxyl groups were selectively protected as a benzoate and a benzyl ether, respec-
tively, to give 6. Hydrolysis of 6 and acetylation afforded diacetate 7. Condensation
of diacetate 7 with silylated 5-azauracil gave the protected nucleoside which under-
went deacetylation and debenzoylation to give 8. Selective tosylation of primary
hydroxyl group of 8 followed by treatment with aqueous sodium hydroxide fur-
nished cyclized derivative 9. Treatment of 9 with POCl3 and 1,2,4-triazole yielded
triazole derivative which was hydrolyzed with aqueous NH4OH to afford 5-aza-
cytosine derivative 10. Debenzylation of 10 using hydrogenolysis yielded the final
nucleoside 2.
The final nucleosides 1 and 2 were evaluated against several cancer cell lines, but
they did not show significant antitumor activities.
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