Synthesis and evaluation of anti-HSV activity of new 5-alkynyl-2′- deoxyuridines

Article abstract of DOI:10.1081/NCN-200059280

Eight 5-alkynyl-2′deoxyuridines containing different bulky substituents have been prepared and tested against HSV-1 in Vero cells. The compounds show positive antiviral activity. There is no obvious correlation between activity and substituent size. The n

Full text of DOI:10.1081/NCN-200059280

This article was downloaded by: [University of Connecticut]
On: 19 June 2014, At: 00:45
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
SYNTHESIS AND EVALUATION OF ANTI-HSV ACTIVITY OF
NEW 5-ALKYNYL-2′-DEOXYURIDINES
A. A. Pchelintseva a , M. V. Skorobogatyj a , A. L. Petrunina a , V. L. Andronova b , G. A.
Galegov b , I. V. Astakhova a , A. V. Ustinov a , A. D. Malakhov a & Vladimir A. Korshun a
a Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences ,
Moscow, Russia
b Ivanovsky Institute of Virology, Russian Academy of Medical Sciences , Moscow, Russia
Published online: 15 Nov 2011.
To cite this article: A. A. Pchelintseva , M. V. Skorobogatyj , A. L. Petrunina , V. L. Andronova , G. A. Galegov , I. V.
Astakhova , A. V. Ustinov , A. D. Malakhov & Vladimir A. Korshun (2005) SYNTHESIS AND EVALUATION OF ANTI-HSV ACTIVITY
OF NEW 5-ALKYNYL-2′-DEOXYURIDINES, Nucleosides, Nucleotides and Nucleic Acids, 24:5-7, 923-926, DOI: 10.1081/
NCN-200059280
To link to this article: http://dx.doi.org/10.1081/NCN-200059280
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, and Nucleic Acids, 24 (5–7):923–926, (2005)
Copyright D Taylor & Francis, Inc.
ISSN: 1525-7770 print/ 1532-2335 online
DOI: 10.1081/NCN-200059280
SYNTHESIS AND EVALUATION OF ANTI-HSV ACTIVITY OF
NEW 5-ALKYNYL-2’-DEOXYURIDINES
5
A. A. Pchelintseva, M. V. Skorobogatyj, and A. L. Petrunina
Shemyakin-
Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow,
Russia
5
V. L. Andronova and G. A. Galegov
Ivanovsky Institute of Virology, Russian
Academy of Medical Sciences, Moscow, Russia
I. V. Astakhova, A. V. Ustinov, A. D. Malakhov, and Vladimir A. Korshun
5
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences,
Moscow, Russia
5
Eight 5-alkynyl-2’deoxyuridines containing different bulky substituents have been prepared and
tested against HSV-1 in Vero cells. The compounds show positive antiviral activity. There is no obvious
correlation between activity and substituent size. The nature of the linker between uracil and a
substituent appears to be more important for antiviral properties: nucleosides containing arylethynyl
groups show higher activity.
INTRODUCTION
More than two decades ago, 5-alkynyl-2’-deoxyuridines were prepared and
tested for anti-HSV activity.[1–4] The 5-(1-propynyl)-derivative showed highest
activity, while 5-(1-heptynyl)- and phenylethynyl-2’-deoxyuridines were completely
inactive.[4] This finding does not favor further search for antivirals among this class
This research was partially supported by RFBR grants (02-03-32376 and 03-03-32196). We thank Prof.
Vladimir A. Efimov and Igor A. Prokhorenko for their encouraging interest and Larisa V. Grusintseva for
technical assistance.
Address correspondence to Vladimir A. Korshun, Shemyakin-Ovchinnikov Institute of Bioorganic Chem-
istry, Russian Academy of Sciences, Miklukho-Maklaya 16/10, Moscow 117997, Russia; E-mail: korshun@mail.
ibch.ru
923
Order reprints of this article at www.copyright.rightslink.com

924
A. A. Pchelintseva et al.
SCHEME 1 Synthesis of 5-alkynyl-2’-deoxyuridines.
of compounds. Recently, however, we found that 5-arylethynyl-2’-deoxyuridines
with bulky substituents [where aryl is 1-pyrenyl, 3-perylenyl and 4-(2-benzoxazo-
lyl)phenyl] possess reliable activity against HSV-1.[5] This result encouraged us to
synthesize other 5-alkynyl-2’-deoxyuridines for the investigation of their structure–
activity relationship.
Modified nucleosides were prepared as depicted in Scheme 1. The starting
3’,5’-O-(tetraisopropyldisiloxane-1,3-diyl)-5-iodo-2’-deoxyuridine (1)[6] was reacted
with various terminal acetylenes under standard conditions of Sonogashira coupling
for nucleosides[3,7] to give protected nucleosides 2a--h. Markiewicz’s 3’,5’-O-silyl
group facilitates dramatically the purification of compounds 2a--h by chromatog-
raphy and can be easily removed by treatment with triethylamine trihydrofluoride
*
yielding desired 5-alkynyl-2’-deoxyuridines 3a--h.
The structures of substituents R for nucleosides 3a--h as well as their cytotoxic
and anti-HSV-1 activities are given in Table 1. Nucleosides 3 are considerably more
cytotoxic than acyclovir (ACV). Interestingly, two compounds bearing carbonyl
groups—benzophenone nucleoside 3a and estrone nucleoside 3b—showed the
lowest cytotoxicity. Arylethynyl nucleosides 3f and 3e have considerable antiviral
activity; however, these derivatives are rather toxic for Vero cells. These compounds
are active also against ACV-resistant strain of HSV-1 thus demonstrating their mode
of action differs cardinally from that of ACV.
Less lipophilic dinucleoside compounds 3g and 3h are practically inactive.
The insertion of a flexible linker between ethynyl group and aryl residue leads to
complete disappearance of therapeutic properties (compound 3c in comparison
with 5-(perylen-3-ylethynyl)-2’-deoxyuridine).[5]
Thus, 5-alkynyl-2’deoxyuridines containing bulky aromatic substituents repre-
sent a new class of anti-HSV nucleosides with moderate activity. Further inves-
tigations are needed to understand the mechanism of viral replication inhibition by
these compounds.
*
Detailed procedures and characterization of compounds will be published elsewhere.

A. A. Pchelintseva et al.
925
TABLE 1 Cytotoxic and Antiviral Properties of 5-Alkynyl-2’-Deoxyuridines 3 in Vero Cell Culture (mg/mL)a
HSV-1/ACVR
HSV-1
ID95
Nucleoside
R
CD50
ID50
ID50
ID95
3a
250
31.3
>250
31.3
62.5
>250
3b
3c
250
31.3
62.5
62.5
125
62.5
>62.5
62.5
>62.5
3d
3e
220
31.3
7.8
125
>220
>220
13.8
>7.8
7.8
3.9
>7.8
3f
38.8
3.9
>15.6
>15.6
>125
3g
220
125
>125
125
3h
53.8
>62.5
>62.5
>62.5
>400
> 62.5
> 400
ACV
–
>400
0.45
0.90
aHerpes simplex virus type 1, strain L2 (HSV-1) was from the Laboratory of Virus Museum (Ivanovsky Institute
of Virology, Moscow). ACV-resistant strains of HSV-1 were isolated as described earlier.[8] Antiviral activity was
expressed as the compound concentration required to reduce virus-inducted cytopathicity by 50% (ID50) or 95%
(ID95) compared to untreated control.

926
A. A. Pchelintseva et al.
REFERENCES
1. Perman, J.; Sharma, R.A.; Bobek, M. Synthesis of 1-(2-b-D-erythro-pentofuranosyl)-5-ethynyl-1,2,3,4-tetrahy-
dropyridine-2,4-dione (5-ethynyl-2’-deoxyuridine). Tetrahedron Lett. 1976, (28), 2427–2430.
2. De Clercq, E.; Descamps, J.; De Somer, P.; Barr, P.J.; Jones, A.S.; Walker, R.T. (E)-5-(2-bromovinyl)-2’-
deoxyuridine: a potent and selective anti-herpes agent. Proc. Natl. Acad. Sci. U. S. A. 1979, 76(6), 2947–2951.
3. Robins, M.J.; Barr, P.J. Nucleic acid related compounds. 39. Efficient conversion of 5-iodo to 5-alkynyl and
derived 5-substituted uracil bases and nucleosides. J. Org. Chem. 1983, 48(11), 1854–1862.
4. De Clercq, E.; Descamps, J.; Balzarini, J.; Giziewicz, J.; Barr, P.J.; Robins, M.J. Nucleic acid related
compounds. 40. Synthesis and biological activities of 5-alkynyluracil nucleosides. J. Med. Chem. 1983, 26(5),
661–666.
5. Andronova, V.L.; Skorobogatyi, M.V.; Manasova, E.V.; Berlin, Y.A.; Korshun, V.A.; Galegov, G.A. Antiviral
activity of some 5-arylethynyl-2’-deoxyuridines. Bioorg. Khim. 2003, 29(3), 290–295. [Engl. transl.: Russ.
J. Bioorgan. Chem. 2003, 29 (3), 262–266.]
6. Iglesias, B.; Alvarez, R.; de Lera, A.R. A general synthesis of alkylpyridines. Tetrahedron 2001, 57(15), 3125–
3130.
7. Robins, M.J.; Vinayak, R.S.; Wood, S.G. Solvent, not palladium oxidation state, is the primary determinant for
successful coupling of terminal alkynes with iodo-nucleosides. Tetrahedron Lett. 1990, 31(26), 3731–3734.
8. Galegov, G.A.; Akberova, S.I.; Andronova, V.L.; Leont’eva, N.A.; Stroeva, O.G. The potentiating effect of
p-aminobenzoic acid on the antiherpes activity of ganciclovir (9-[1,3-dihydroxy-2-propoxymethyl]guanine) in
cell culture. Dokl. Akad. Nauk 2000, 373(3), 404–407. [Engl. transl.: Dokl. Biochem. 2000, 373 ( July–
August), 135–138.]