3-Bromo-3-deazaneplanocin and 3-bromo-3-deazaaristeromycin: Synthesis and antiviral activity

Article abstract of DOI:10.1016/j.bmcl.2012.06.075

As an outgrowth of our program to explore 3-deazaadenine carbocyclic nucleosides, 3-bromo-3-deazaneplanocin (5) and 3-bromo-3-deazaaristeromycin (6) have been synthesized from a readily available cyclopentenol and cyclopentanone and either 4-amino- or 4-c

Full text of DOI:10.1016/j.bmcl.2012.06.075

Bioorganic & Medicinal Chemistry Letters 22 (2012) 5182–5184
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
3-Bromo-3-deazaneplanocin and 3-bromo-3-deazaaristeromycin: Synthesis
and antiviral activity
⇑
Chong Liu, Qi Chen, Stewart W. Schneller
Molette Laboratory for Drug Discovery, Department of Chemistry and Biochemistry, Auburn University, Auburn, AL 36849-5312, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
As an outgrowth of our program to explore 3-deazaadenine carbocyclic nucleosides, 3-bromo-3-deazane-
planocin (5) and 3-bromo-3-deazaaristeromycin (6) have been synthesized from a readily available
cyclopentenol and cyclopentanone and either 4-amino- or 4-chloro-1H-imidazo[4,5-c]pyridine
(6-amino- or 6-chloro-3-deazaadenine) in 5 steps and 7 steps, respectively. Antiviral analysis found 5
to display significant activity towards a number of (À)-ssRNA and a few dsDNA viruses. Compound 6
was less active than 5 against selected examples of those viruses affected by 5.
Received 21 May 2012
Revised 23 June 2012
Accepted 25 June 2012
Available online 1 July 2012
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
3-Deazaadenine
Carbocyclic nucleosides
Antiviral agents
Because of their unique carbocyclic nucleoside framework and
broad-spectrum antiviral activity the naturally occurring aristero-
mycin (1) and neplanocin (2) have provided a treasure trove of
leads into uniquely structured biologically useful entities.1
Within this library are the synthetic 3-deaza analogues 3 and
4.2 Particularly noteworthy has been the ability of 4 to induce a sig-
In addition to NMR data, the structure of 5 was confirmed by X-
ray crystallography (Fig. 2),11 which served to confirm the regio-
chemistry of the cyclopentenyl and bromo substituents of 5 and
the anti-conformational preference of 5.
The preparation of 6 commenced with the oxidative conversion
of the cyclopentenone 1212 to the keto-aldehyde 13 (Scheme 2).
Lithium aluminum hydride reduction of both carbonyl centers of
13 provided 14 whose primary alcohol was protected as the
t-butyldimethylsilyl derivative 15. Mitsunobu coupling9 of 15 with
nificant increase in interferon-a
in virus infected mice.3
To expand on this observation for 4, we have been focused on
the nucleobase C-3 center for target development. For that pur-
pose, we sought a versatile entry point that would be adaptable
to further synthetic conversions. The 3-bromo compound was
determined to be the most suitable because of its possible syn-
thetic adaptability to further structural variations.4 In that direc-
tion, the synthesis of 3-bromo-3-deazaneplanocin (5) is reported
herein. To achieve a preliminary indication that 3-subsituted 3-
deazaneplanocins could provide a framework for antiviral drug
discovery, 5 has also been evaluated against a number of viral can-
didates. For comparative purposes, 3-bromo-3-deazaaristeromycin
(6) has also been prepared and evaluated against a limited number
of viruses (Fig. 1).
6-chloro-3-deazapurine
(4-chloro-1H-imidazo[4,5-c]pyridine)13
(to 16) was followed by hydrazinolysis/Raney Ni reduction9 (to
17). Subsequent bromination4 of 17 to the 3-bromo-3-deaza pre-
cursor 18 was followed by deprotection to 6.14
An antiviral analysis15 of 5 and 6 is given in Tables 1 and 2. From
that it is apparent that 5 shows promising broad spectrum activity
with its greatest effects toward the (À)-ssRNA viruses: the influ-
enza viruses, Rift Valley fever, Punto Toro, Tacaribe, Pichinde,
The synthesis of 5 (Scheme 1) began with protecting5 the 6-
amino group of 3-deazaadenine (7)6 as its diBoc derivative 9 (to
promote N-9 cyclopentenylation in the subsequent step). This
necessitated passing through the triBoc precursor 8 that gave 9
upon treatment with tetrabutylammonium fluoride.7,8 Bromina-
tion4 of 9–10 followed by Mitsunobu coupling9 with the cyclopen-
tenol i9 produced the desired N-9 product 11 in good yield.
Deprotection of 11 led to the desired 5.10
⇑
Corresponding author. Tel.: +1 334 844 6947; fax: +1 334 844 0239.
E-mail address: schnest@auburn.edu (S.W. Schneller).
Figure 1. Relevant carbocyclic nucleosides.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.06.075

C. Liu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5182–5184
5183
Scheme 1. Reagents and conditions: (a) (Boc)2O, THF, 86%; (b) TBAF, THF, 86%; (c) NBS, MeCN, 77%; (d) i, DIAD, PPh3, 70%; (e) HCl/MeOH, 67%.
Table 1
In vitro activities of 5 and 6 against the influenza viruses (in l .
M)a,b,c
Virus
Cell line
5
6
EC50
CC50
SI
EC50
CC50
SI
Flu A (H1N1)
Flu A (H3N2)
Flu A (H5N1)
Influenza B
MDCK
MDCK
MDCK
MDCK
<0.094
1.55
0.94
220
>2345
>190
>310
<7
>290
>290
1.14
0.84
>290
>290
>290
>290
0
0
>290
>290
1.1
>260
>340
>0.16
a
b
c
EC50: compound concentration that reduces viral replication by 50%.
CC50: compound concentration that reduces cell viability by 50%.
SI: CC50/EC50
.
opment of these results in pursuing the effect of interferon
enhancement by 3-deazaneplanocin-based molecules are
continuing.
Acknowledgements
Figure 2. X-ray structure for 5.
This research has been supported by funds from the Depart-
ment of Health and Human Services (Al 56540), which is appre-
ciated. Also, support from the Molette Fund and Auburn
University is appreciated. We are grateful for the assistance of
Dr. Minmin Yang and Dr. John Gorden at Auburn University.
We are also indebted to the following individuals for providing
the antiviral data following their standard protocols: Dr. Donald
Smee, Utah State University; Dr. Brent Korba, Georgetown Uni-
versity; Dr. Mark Prichard, University of Alabama at Birmingham;
and, other laboratories who are part of the non-clinical evalua-
tion program funded by the National Institute of Allergy and
Infectious Diseases.
Junin, vesicular stomatitis, and parainfluenza-3. More limited ef-
fects are seen with a few dsDNA viruses (vaccinia, Epstein Barr, fe-
line herpes—but not HSV-1, HSV-2, and varicella zoster) and one
(+)-ssRNA (dengue).16 Compound 6 was less active than 5 in all as-
says where direct comparisons are available.17 In the cytomegalo-
virus assay, 5 was toxic to the host cell (HEL).
The in vitro antiviral results reported offers 5 as a compound
with potential against a collection of viruses for which the number
of therapeutic candidates is limited. Studies in this area and devel-
Scheme 2. Reagents and conditions: (a) NaIO4, OsO4, MeOH/H2O, rt, 87%; (b) LiAlH4, THF, rt, 92%; (c) TBSCl, imidazole, CH2Cl2, 0 °C, 76%, (d) 4-chloro-1H-imidazo[4,5-
c]pyridine (6-chloro-3-deazapurine),13 DIAD, PPh3, THF, 67%; (e) (i) N2H4; (ii) RaNi, MeOH/H2O, 61%; (f) NBS, CH2Cl2, 0 °C, 79%; (g) HCl/MeOH, 71%.

5184
C. Liu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5182–5184
Table 2
Positive in vitro activity of 5 and 6 against other viruses (in
l .
M)a,b,c,d
Virus
Cell line
5
6
EC50
CC50b/MCCd
SI
EC50
58.3
CC50
>290
SI
Rift Valley Fever
Punto Toro
Tacaribe
Vero 76
Vero 76
Vero 76
Vero
<0.094
0.25
<0.094
1.2
0.094
2.9
0.5
0.4
>0.03
0.5
0.2
23.2b
35b
250
140
>2000
24
160
57
>5
188b
27.5b
15.2b
167b
>100d
100d
0.13b
>100d
94b
9.9
79
7.9
Pichinde
Junin
Vero
Dengue
Vero
93
230
184
>300
2
>1.3
Vaccinia
HeLa
Vesicular stomatitis
Epstein Barr
Parainfluenza-3
Feline herpes
HeLa
Akata
Vero
<4.3
470
CRFK
a
b
c
EC50: compound concentration that reduces viral replication by 50%.
CC50: compound concentration that reduces cell viability by 50%.
SI: CC50/EC50
.
d
MCC: minimum compound concentration that causes a microscopically detectable alternation of normal cell morphology.
charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax:
+44 1223 336033 or e mail: deposit@ccdc.cam.ac.uk)
References and notes
12. Yang, M.; Ye, W.; Schneller, S. W. J. Org. Chem. 2004, 69, 3993.
13. Tseng, C. K. H.; Marquez, V. E.; Fuller, R. W.; Goldstein, B. M.; Haines, D. R.;
McPherson, H.; Parsons, J. L.; Shannon, W. M.; Arnett, G.; Hollingshead, M.;
Driscoll, J. S. J. Med. Chem. 1989, 32, 1442.
1. De Clercq, E. Nucleosides Nucleotides Nucleic Acids 2005, 24, 1395.
2. Vittori, S.; Dal Ben, D.; Lambertucci, C.; Marucci, G.; Volpini, R.; Cristalli, G. Curr.
Med. Chem. 2006, 13, 3529.
3. Bray, M.; Raymond, J. L.; Geisbert, T.; Baker, R. O. Antiviral Res. 2002, 55, 151.
4. Minakawa, N.; Kojima, N.; Matusda, A. J. Org. Chem. 1999, 64, 7158.
5. Yin, X.; Li, W.; Schneller, S. W. Tetrahedron Lett. 2006, 47, 9187.
6. Crey-Desbiolles, C.; Kotera, M. Tetrahedron Lett. 1935, 2006, 14.
7. Jacquemard, U.; Bénéteau, V.; Lefoix, M.; Routie, S.; Mérour, J-Y.; Couder, G.
Tetrahedron 2004, 60, 10039.
8. Tetrabutylammonium fluoride is our preferred agent for removing
heteroaromatic Boc groups as the standard conditions Dey, S.; Garner, P. J.
Org. Chem. 2000, 65, 7697. of aqueous sodium bicarbonate eliminated one of
the C-6 N-Boc groups.
9. Yang, M.; Zhou, J.; Schneller, S. W. Tetrahedron 2006, 62, 1295.
10. Selected data for 5: white solid. 1H NMR (400 MHz, DMSO-d6): 8.08 (s, 1H),
7.73 (s, 1H), 6.40 (s, 2H), 6.02 (s, 1H), 5.74 (s, 1H), 5.10 (d, J = 6.8 Hz, 1H), 5.03
(d, J = 5.6 Hz, 1H), 4.91 (t, J = 5.6 Hz, 1H), 4.46 (t, J = 5.6 Hz, 1H), 4.22 (m, 1H),
4.13 (m, 2H); 13C NMR (100.6 MHz, DMSO-d6): 152.1, 150.9, 142.3, 140.3,
134.8, 128.4, 123.5, 88.2, 77.6, 72.3, 64.9, 58.5; HRMS calcd for C12H13BrN4O3
[M+H]+ 341.0249, found 341.0245.
14. Selected data for 6: white solid. 1H NMR (400 MHz, MeOD): 8.39 (s, 1H), 7.75
(s, 1H), 5.60 (dd, J = 9.6, 19.2 Hz, 1H), 4.47 (dd, J = 5.2, 9.6 Hz, 1H), 4.03 (dd,
J = 5.2, 8.0 Hz, 1H), 3.65 (m, 2H), 2.60 (m, 1H), 2.21 (m, 1H), 1.56 (m, 1H); 13C
NMR (100.6 MHz, MeOD): 153.2, 143.4, 141.9, 137.5, 129.5, 90.9, 77.0, 73.71,
64.4, 61.4, 46.5, 33.4; HRMS calcd for C12H15BrN4O3 [M+H]+ 343.0406, found
343.0407.
15. For leading references on the procedures used for the assays see (a) Roy, A.;
Serbessa, T.; Schneller, S. W. Bioorg. Med. Chem. 2006, 14, 4980; (b) http://
www.usu.edu/iar/people.html
(May
17,
2012).;
(c)
http://
www.southernresearch.org/life-sciences/infectious-diseases/virology (May 5,
2012).
16. Compound 5 was inactive towards West Nile (vero), cowpox (HFF), hepatitis B
(2.2.15), Venezuelan equine encephalitis (vero), reovirus-1 (vero), coxsackie B4
(vero), sindbis (vero), HSV-1 (HEL), HSV-2 (HEL), and feline coronavirus.
17. Compound 6 was also active towards (in
lM) yellow fever (vero, EC50 = 19,
CC50 = 183, SI = 9.7), measles (vero, EC50 = 16, CC50 = 70, SI = 4.3) and
cytomegalovirus (HEL, EC50 = 3.5, CC50 = 80, SI = 23) but inactive versus West
Nile (vero), vaccinia (HeLa), hepatitis C (AVA5), Venezuelan equine encephalitis
(vero), respiratory syncytial (MA-104), and SARS (vero).
11. The crystallographic data (excluding structure factors) for 5 has been deposited
with the Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 876026. Copies of the data can be obtained, free of