Structure-activity relationship of 5′-substituted fluoro-neplanocin A analogues as potent inhibitors of S-adenosylhomocysteine hydrolase

Article abstract of DOI:10.1081/NCN-200060286

Four 5′-substituted fluoro-neplanocin A analogues 1a-d were designed and synthesized, and the inhibitory activity against SAH was in the following order: NH₂ > SH > F, N₃, indicating a hydrogen bonding donor is essential for inhibito

Full text of DOI:10.1081/NCN-200060286

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STRUCTURE-ACTIVITY RELATIONSHIP OF 5′-
SUBSTITUTED FLUORO-NEPLANOCIN A ANALOGUES AS
POTENT INHIBITORS OF S-ADENOSYLHOMOCYSTEINE
HYDROLASE
Hyung Ryong Moon a , Kang Man Lee b , Hyun Joo Lee b , Sang Kook Lee b , Seung Bin Park a ,
Moon Woo Chun c & Lak Shin Jeong b
a College of Pharmacy, Pusan National University , Pusan, Korea
b College of Pharmacy, Ewha Womans University , Seoul, Korea
c College of Pharmacy, Seoul National University , Seoul, Korea
Published online: 28 Jul 2006.
To cite this article: Hyung Ryong Moon , Kang Man Lee , Hyun Joo Lee , Sang Kook Lee , Seung Bin Park , Moon Woo Chun
& Lak Shin Jeong (2005) STRUCTURE-ACTIVITY RELATIONSHIP OF 5′-SUBSTITUTED FLUORO-NEPLANOCIN A ANALOGUES AS
POTENT INHIBITORS OF S-ADENOSYLHOMOCYSTEINE HYDROLASE, Nucleosides, Nucleotides and Nucleic Acids, 24:5-7, 707-708,
DOI: 10.1081/NCN-200060286
To link to this article: http://dx.doi.org/10.1081/NCN-200060286
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Nucleosides, Nucleotides, and Nucleic Acids, 24 (5–7):707–708, (2005)
Copyright D Taylor & Francis, Inc.
ISSN: 1525-7770 print/ 1532-2335 online
DOI: 10.1081/NCN-200060286
STRUCTURE-ACTIVITY RELATIONSHIP OF 5’-SUBSTITUTED
FLUORO-NEPLANOCIN A ANALOGUES AS POTENT INHIBITORS
OF S-ADENOSYLHOMOCYSTEINE HYDROLASE
5
Hyung Ryong Moon
College of Pharmacy, Pusan National University, Pusan, Korea
5
Kang Man Lee, Hyun Joo Lee, and Sang Kook Lee
College of Pharmacy, Ewha
Womans University, Seoul, Korea
5
Seung Bin Park
Moon Woo Chun
Lak Shin Jeong
College of Pharmacy, Pusan National University, Pusan, Korea
College of Pharmacy, Seoul National University, Seoul, Korea
College of Pharmacy, Ewha Womans University, Seoul, Korea
5
5
5
Four 5’-substituted fluoro-neplanocin A analogues 1a--d were designed and synthesized, and the
inhibitory activity against SAH was in the following order: NH2 > SH > F, N3, indicating a hydrogen
bonding donor is essential for inhibitory activity.
INTRODUCTION
A number of adenosine analogues, which were known to inhibit S-
adenosylhomocysteine hydrolase (SAH) have shown antiviral activity against
DNA and RNA viruses by interfering with formation of cap structure of viral
mRNA.[1] However, they were not developed as antiviral agents due to their
cellular cytotoxicity.[2] Fluoro-neplanocin A[3] developed in our laboratory
exhibited potent inhibitory activity against SAH and significant antiviral activity
with cytotoxicity. Herein, we wish to report the structure-SAH inhibitory activity
and cytotoxicity relationships study of 5’-substituted fluoro-neplanocin A analogues
1a--d. All desired products 1a--d were synthesized via cyclopentenone 2[4] as a
key intermediate, as shown in Scheme 1. Introduction of fluorine substituent at
vinyl position was accomplished by electrophilic fluorination. Coupling of mesylate
This work was supported by the grant from the Korea Health R&D Project, Ministry of Health & Welfare,
Korea (HMP-02-PJ2-PG10-21503-0004).
Address correspondence to Lak Shin Jeong, Laboratory of Medicinal Chemistry, College of Pharmacy,
Ewha Womans University, Seoul 120-750, Korea.
707
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708
H. R. Moon et al.
SCHEME 1 Reagents and conditions: (a) I2, pyridine, CCl4, rt, 12 h; (b) NaBH4, CeCl3, MeOH, 0°C, 30 min;
(c) TBDPSCI, imidazole, DMF, 40°C, overnight; (d) N-fluorobenzene sulfonimide, n-BuLi, THF, À78°C, 1 h; (e) n-
Bu4NF, THF, rt, 2 h; (f) methanesulfonyl chloride, Et3N, CH2Cl2, 0°C, 30 min; (g) adenine, K2CO3, 18-Crown-6,
DMF, 80°C, overnight; (h) p-toluenesulfonic acid, MeOH, rt, 18 h; (i) DAST, CH2Cl2, 0°C, 30 min; (j) 33% aqueous
CF3CO2H, THF, rt, 3 d; (k) methanesulfonyl chloride, Et3N, CH2Cl2, À5°C, 20 min; (l) NaN3, DMF, 60°C, 1 h for
12; (m) KSAc, DMF, rt, 1 h for 13; (n) 33% aqueous CF3CO2H, THF, rt, 3--4 d; (o) Lindtar’s catalyst, MeOH, rt, 30
min; (p) 28% NH4OH, MeOH, rt, 20 min.
8 with adenine base in the presence of K2CO3 gave the protected nucleoside 9.
Introduction of fluorine substituent at 5’-position successfully proceeded employing
DAST. 5’-Azido- and 5’-amino-substituted analogues, 1b and 1c were synthesized
from treatment of mesylate 11 with sodium azide followed by chemoselective
reduction of azido group. 5’-Sulfhydryl-substituted fluoro-neplanocin A derivative
1d was synthesized by reaction of mesylate 11 with KSAc and then deprotection of
S-acetyl group using 28% NH4OH. The inhibitory activity for the final compounds
1a--d was assayed against SAH. 5’-Azido- and 5’-fluoro-substituted derivatives did
not exhibit inhibitory activity up to 100 mM and compound 1d with 5’-thiol group
showed very weak enzyme inhibition (IC50 = 97.27 mM), while conversion into 5’-
amino-substituted analogue restored inhibitory activity (IC50 = 12.68 mM). This
trend explained that the ability as hydrogen bonding donor at 5’-position was
essential for inhibitory activity. As expected, cytotoxicity of the synthesized
compounds 1a--d decreased, probably due to the lack of ability of phosphory-
lation at 5’-position.
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