Structure-activity relationships of apio nucleosides as potential antiviral agents

Article abstract of DOI:10.1081/NCN-100002344

Several types of novel apio nucleosides were synthesized starting from 1,3-dihydroxyacetone and evaluated for antiviral activity. Among compounds tested, amino substituted apio dideoxynucleosides exhibited anti-HBV activity, while thioapio dideoxynucleosides were found to be active against HIV-1. Apio dideoxydidehydro nucleosides showed moderate to potent anti-HCMV activity, but their bioisosteric thioapio dideoxydidehydro nucleosides did not exhibit any significant antiviral activity.

Full text of DOI:10.1081/NCN-100002344

This article was downloaded by: [The University of Manchester Library]
On: 11 October 2014, At: 01:46
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer
House, 37-41 Mortimer Street, London W1T 3JH, UK
Nucleosides, Nucleotides and Nucleic Acids
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lncn20
STRUCTURE-ACTIVITY RELATIONSHIPS OF APIO
NUCLEOSIDES AS POTENTIAL ANTIVIRAL AGENTS
Lak Shin Jeong a , Hyung Ryong Moon a , Jun Hee Hong a , Su Jeong Yoo a , Won Jun Choi
a , Hea Ok Kim b , Hee Sung Ahn a , Hye Woo Baek a , Moon Woo Chun c , Hee-Doo Kim d ,
Jeongmin Kim e & Jong-Ryoo Choi e
a College of Pharmacy, Ewha Womans University , Seoul, Korea
b College of Medicine, Yonsei University , Seoul, Korea
c College of Pharmacy, Seoul National University , Seoul, Korea
d College of Pharmacy, Sookmyung Women's University , Seoul, Korea
e LG Chem/Biotech Research Institute , Taejon, Korea
Published online: 07 Feb 2007.
To cite this article: Lak Shin Jeong , Hyung Ryong Moon , Jun Hee Hong , Su Jeong Yoo , Won Jun Choi , Hea Ok Kim , Hee
Sung Ahn , Hye Woo Baek , Moon Woo Chun , Hee-Doo Kim , Jeongmin Kim & Jong-Ryoo Choi (2001) STRUCTURE-ACTIVITY
RELATIONSHIPS OF APIO NUCLEOSIDES AS POTENTIAL ANTIVIRAL AGENTS, Nucleosides, Nucleotides and Nucleic Acids,
20:4-7, 657-660, DOI: 10.1081/NCN-100002344
To link to this article: http://dx.doi.org/10.1081/NCN-100002344
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of
the Content. Any opinions and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied
upon and should be independently verified with primary sources of information. Taylor and Francis shall
not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other
liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(4–7), 657–660 (2001)
STRUCTURE-ACTIVITY RELATIONSHIPS
OF APIO NUCLEOSIDES AS POTENTIAL
ANTIVIRAL AGENTS
Lak Shin Jeong,1,∗ Hyung Ryong Moon,1 Jun Hee Hong,1
Su Jeong Yoo,1 Won Jun Choi,1 Hea Ok Kim,2 Hee Sung Ahn,1
Hye Won Baek,1 Moon Woo Chun,3 Hee-Doo Kim,4
Jeongmin Kim,5 and Jong-Ryoo Choi 5
1College of Pharmacy, Ewha Womans University, Seoul, Korea
2College of Medicine, Yonsei University, Seoul, Korea
3College of Pharmacy, Seoul National University, Seoul, Korea
4College of Pharmacy, Sookmyung Women’s University, Seoul, Korea
5LG Chem/Biotech Research Institute, Taejon, Korea
ABSTRACT
Several types of novel apio nucleosides were synthesized starting from 1,3-
dihydroxyacetoneandevaluatedforantiviralactivity. Amongcompoundstested,
amino substituted apio dideoxynucleosides exhibited anti-HBV activity, while
thioapio dideoxynucleosides were found to be active against HIV-1. Apio
dideoxydidehydro nucleosides showed moderate to potent anti-HCMV activ-
ity, but their bioisosteric thioapio dideoxydidehydro nucleosides did not exhibit
any significant antiviral activity.
INTRODUCTION
One of the nonclassical nucleosides, apio dideoxynucleoside (1–5) in which
4ꢀ-hydroxymethyl group of the classical 2ꢀ,3ꢀ-dideoxynucleosides moves to the
3ꢀ-position has been shown anti-HIV activity (1) in MT-4 cells. In addition to
antiviral activity, these nucleosides also showed metabolic advantages such as
∗Corresponding author.
657
ꢁ
C
Copyright 2001 by Marcel Dekker, Inc.
www.dekker.com

ORDER
REPRINTS
658
JEONG ET AL.
B
B
B
HO
B
HO
HO
HO
O
O
2
S
H2N
S
1
3
4
Figure 1.
resistance to adenosine deaminase and glycosyl bond hydrolysis (3). In order to
study structure-activity relationships of apio nucleosides, we synthesized several
types of apio nucleosides such as azido or amino substituted apio dideoxynucleo-
sides (1), apio dideoxydidehydro nucleosides (2), thioapio dideoxynucleosides (3),
and thioapio dideoxydidehydro nucleosides (4) and evaluated them for antiviral
activities (Fig. 1).
Here, we report the synthesis and structure-activity relationship study of novel
apio nucleosides as antiviral agents.
RESULTS AND DISCUSSION
The amino substituted apio nucleosides (1) and apio dideoxydidehydro nucle-
osides (2a–2f) were synthesized using 1,3-dihydroxyacetone as a common starting
material via lactone 5 as the common intermediate (Scheme 1). These two classes
of nucleosides were synthesized according to the known procedure reported by our
laboratory (6,7).
Thioapio dideoxynucleosides which may act as bioisosteres of apio dideoxy-
nucleosides were synthesized starting from the lactone 5 (Scheme 2).
The lactone 5 was protected as tert-butyldiphenylsilyl ether to give 7 which
was hydrogenated under palladium on carbon to afford saturated lactone ( )-8 in
quantitative yield. Treatment of ( )-8 with 1 N NaOH followed by methylation of
the resulting acid gave the hydroxyester ( )-9 which was converted to the thioac-
etate ( )-10 in two steps. Cyclization of ( )-10 was achieved using DIBAL at
−78◦C to give lactol, which was acetylated to give the thioapio acetate ( )-11.
B
HO
H2N
B = adenine (1)
ref. 6
O
HO
HO
HO
1
O
O
B = uracil (2a)
B
O
5
thymine (2b)
HO
5-fluorouracil (2c)
5-chlorouracil (2d)
5-bromouracil (2e)
5-iodouracil (2f)
O
2
ref. 7
Scheme 1.

ORDER
REPRINTS
APIO NUCLEOSIDES AS POTENTIAL ANTIVIRAL AGENTS
659
OH
O
5
OMe
O
RCl
O
7
1) 1 N NaOH
O
Pd/C
H2
99%
O
O
O
88%
2) (CH3)2SO4
78%
HO
RO
RO
RO
S
_
_
(+)-8
(+)-9
silylated
pyrimidines
and purines
S
SAc
OMe
O
B
OAc
1) MsCl
1) DIBAL
2) Ac2O
2) KSAc
86%
TMSOTf
RO
Ph
RO
RO
75%
_
(+)-10
_
+
_
(
)-11
(+)-12
B
S
S
n-Bu4NF
+
Si C(CH3)3
Ph
R =
B
HO
(B = uracil)
(B = thymine)
HO
_
_
(B = uracil)
(+)-13a
+
(
(
(
)-13b
)-14b
)-15b
_
_
(B = thymine)
(B = 6-chloropurine)
(+)-14a
+
_
(B = 6-chloropurine)
_
+
(+)-15a
MeNH2
NH3
MeNH2
NH3
_
(+)-17a
_
+
_
_
(+)-16a
(B =adenine) (B =N-methyladenine)
HSCH2CH2OH
(+)-17b
_
+
_
(
)-15a
(+)-16b
(
)-15b
(B =N-methyladenine)
(B =adenine)
HSCH2CH2OH
_
(+)-18a
(B = hypoxanthine)
_
(+)-18b
(B = hypoxanthine)
Scheme 2.
The glycosyl donor ( )-11 was condensed with silylated uracil, thymine, and 6-
chloropurine in the presence of TMSOTf to give the inseparable anomeric mixture
of protected nucleosides to give the inseparable anomeric mixtures of protected
nucleosides ( )-12, respectively. The protected nucleosides ( )-12 was treated
with tetra-n-butylammonium fluoride to give β anomers (( )-13a, 14a, and 15a)
and α-anomers (( )-13b, 14b, and 15b), respectively. The 6-chloropurine deriva-
tives, ( )-15a and ( )-15b were converted to the adenine (( )-16a and ( )-16b),
N-methyladenine (( )-17a and ( )-17b), and hypoxanthine (( )-18a and ( )-18b)
derivatives, respectively according to the conventional methods.
SynthesisofthethioapiodideoxydidehydronucleosidesisshowninScheme3.
Treatment of ( )-10 with 1 N NaOH gave the mercapto acid which without pu-
rification, was cyclized using DCC to the thiolactone ( )-19. Treatment of ( )-19
S
S
S
i) LiHMDS
ii) TMSCl
iii) PhSeBr
O
O
1) DIBAL
2) Ac2O
OAc
SePh
1) 1 N NaOH
_
(+)-10
2) DCC
RO
RO
74%
RO
R =
SePh
99%
84%
_
(+)-19
_
(+)-20
_
(+)-21
cis/trans = 1/10
silylated
uracil and
thymine
B
B
S
S
HO
B
1) mCPBA
Ph
2) n-Bu4NF
TMSOTf
Si C(CH3)3
Ph
S
HO
RO
(B = uracil)
SePh
_
(B = uracil)
(B = thymine)
(+)-24
_
_
(+)-22
_
(+)-25
(B = thymine)
(+)-23
Scheme 3.

ORDER
REPRINTS
660
JEONG ET AL.
with LiHMDS at −78◦C followed by the trapping of the enolate with TMSCl gave
silylenol ether, which was reacted with phenyl selenenyl bromide at −78◦C to af-
ford ( )-20 (cis/trans = 10/1 as determined by 1H NMR). Reduction of ( )-20 with
DIBAL followed by acetylation gave the key intermediate ( )-21. Condensation of
( )-21 with silylated uracil and thymine gave the inseparable mixture of protected
nucleosides ( )-22 and ( )-23, respectively. Syn-elimination using mCPBA and
catalytic amounts of pyridine followed by desilylation yielded the final nucleosides
( )-24 and ( )-25, respectively.
All synthesized compounds were assayed against several viruses such as
against HIV-1, HSV-1, HSV-2, HCMV, and HBV. Among compounds tested, amino
substituted apio dideoxynucleoside (1) exhibited anti-HBV activity, while their
bioisosteric thioapio dideoxynucleosides were found to be only active against
HIV-1. Most apio dideoxydidehydro nucleosides showed moderate to potent anti-
HCMV activity without cytotoxicity, among which 5-fluorouracil derivative 2c was
found to be the most potent. However, thioapio analogues, ( )-24 and ( )-25 did
not exhibit any significant antiviral activities.
ACKNOWLEDGMENTS
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. Terao, Y.; Akamatsu, M.; Achiwa, K. Chem. Pharm. Bull. 1991, 39, 823–825.
2. Bamford, M. J.; Humber, D. C.; Storer, R. Tetrahedron Lett. 1991, 32, 271–274.
3. Nair, V.; Nuesca, Z. J. Am. Chem. Soc. 1992, 114, 7951–7952.
4. Sells, T. B.; Nair, V. Tetrahedron Lett. 1992, 33, 7639–7642.
5. Sells, T. B.; Nair, V. Tetrahedron Lett. 1993, 34, 3527–3530.
6. Jeong, L. S.; Lee, Y. A; Moon, H. R.; Chun, M. W. Nucleosides Nucleotides 1998, 17,
1473–1487.
7. Jeong, L. S.; Lee, Y. A.; Moon, H. R.; Yoo, S. J.; Kim, S. Y. Tetrahedron Lett. 1998,
39, 7517–7520.

Request Permission or Order Reprints Instantly!
Interested in copying and sharing this article? In most cases, U.S. Copyright
Law requires that you get permission from the article’s rightsholder before
using copyrighted content.
All information and materials found in this article, including but not limited
to text, trademarks, patents, logos, graphics and images (the "Materials"), are
the copyrighted works and other forms of intellectual property of Marcel
Dekker, Inc., or its licensors. All rights not expressly granted are reserved.
Get permission to lawfully reproduce and distribute the Materials or order
reprints quickly and painlessly. Simply click on the "Request
Permission/Reprints Here" link below and follow the instructions. Visit the
U.S. Copyright Office for information on Fair Use limitations of U.S.
copyright law. Please refer to The Association of American Publishers’
(AAP) website for guidelines on Fair Use in the Classroom.
The Materials are for your personal use only and cannot be reformatted,
reposted, resold or distributed by electronic means or otherwise without
permission from Marcel Dekker, Inc. Marcel Dekker, Inc. grants you the
limited right to display the Materials only on your personal computer or
personal wireless device, and to copy and download single copies of such
Materials provided that any copyright, trademark or other notice appearing
on such Materials is also retained by, displayed, copied or downloaded as
part of the Materials and is not removed or obscured, and provided you do
not edit, modify, alter or enhance the Materials. Please refer to our Website
User Agreement for more details.
Order now!
Reprints of this article can also be ordered at
http://www.dekker.com/servlet/product/DOI/101081NCN100002344