Organic & Biomolecular Chemistry
Paper
cells, (c) parainfluenza-3 virus, reovirus, sindbis virus, cox- corresponding amines. The ensuing 29 compounds were assessed
sackie B-4 virus, and punta toro virus in green monkey kidney for their abilities to inhibit cancer cell proliferation using L1210,
(VERO) cells, (d) feline corona and feline herpes viruses in HeLa, and CEM cell lines, where some showed modest activity.
feline kidney (CRFK) cells, and (e) influenza A H1N1, influenza Antiviral assessments indicated several to possess anti-HIV-1 and
B H3N2, and influenza B viruses in canine kidney (MDCK) HIV-2 activities, and one compound showed anti-HSV-1 activity. In
cells. The activity data are summarized in Table 6.
summary, the method described herein offers a generally facile,
Several compounds showed activities against HIV-1 and broadly applicable approach for the C4 functionalization of pyri-
HIV-2 (Table 6), particularly interesting are azido derivatives midines and pyrimidine nucleosides, which can lead to the dis-
22a (compare with 20d), 22c, 22d, 25a, and 25b. In comparison covery of new pharmacologically active agents as well as for other
to diethylamino derivative 20d, presence of a 3′-azide greatly applications.
enhances activity in 22a. Piperidinyl derivative 22c was com-
parable to 22a and both showed higher activity over the pyrroli-
dinyl analogue 22b. Inclusion of an oxygen atom in the six-
membered ring in 22d increased activity by an order of magni-
Acknowledgements
tude. Ether derivatives 25a and 25b also displayed significant This work was supported by National Science Foundation
activity, with the former being higher. In these cases, release Grant CHE-1265687 to MKL. Infrastructural support at CCNY
of AZT by loss of the ether moiety may be possible.
was provided by National Institutes of Health Grant
Among the entire set of compounds tested, none of them G12MD007603 from the National Institute on Minority Health
showed activity against the other virus tested except for a and Health Disparities. Dr Padmanava Pradhan (CCNY) is
single C4 ether derivative; compound 23a displayed anti-HSV-1 thanked for assistance with some NMR experiments.
activity. This compound inhibited HSV-1 Kos strain with an
EC50 of 5.4 2.0 µM while the minimum cytotoxic concen-
tration required to cause a microscopically detectable altera-
tion of normal cell morphology was >100 µM. Removal of the
References
5-methyl unit of 23a, however, caused loss of anti-HSV-1
activity as observed with compound 24. Notably, compound
23a lacked activity against HSV-2 and an acyclovir-resistant
(thymidine-kinase deficient) HSV-1 virus.
1 J. J. Fox, D. Van Praag, I. Wempen, I. L. Doerr, L. Cheong,
J. E. Knoll, M. L. Eidinoff, A. Bendich and G. B. Brown,
J. Am. Chem. Soc., 1959, 81, 178–187.
2 I. Wempen, R. Duschinsky, L. Kaplan and J. J. Fox, J. Am.
Chem. Soc., 1961, 83, 4755–4766.
3 J.-F. Griffon, C. Mathé, A. Faraj, A.-M. Aubertin, E. De
Clercq, J. Balzarini, J.-P. Sommadossi and G. Gosselin,
Eur. J. Med. Chem., 2001, 36, 447–460.
Conclusions
Herein, we have demonstrated a procedure for the facile intro-
duction of substituents at the C4 position of pyrimidine
nucleosides. These include amines, thiols, and alcohols. The
approach involves reaction of the amide, but not the urea
moiety, with BOP and base, leading to an intermediate O4-
(benzotriazol-1-yl)pyrimidine nucleoside derivative, within a
short reaction time. With amines and thiols, two-step, one-pot,
and one-step processes have been investigated. The latter was
marginally to significantly superior to the former in every case
studied. With alcohols, only a two-step, one-pot approach is
feasible. The method is tolerant of a 3′-azido group in the
4 T. Ueda and J. J. Fox, J. Med. Chem., 1963, 6, 697–701.
5 I. Wempen, N. Miller, E. A. Falco and J. J. Fox, J. Med.
Chem., 1968, 11, 144–148.
6 M. E. Perlman, K. A. Watanabe, R. F. Schinazi and J. J. Fox,
J. Med. Chem., 1985, 28, 741–748.
7 R. Saladino, E. Mincione, C. Crestini and M. Mezzeti,
Tetrahedron, 1996, 52, 6759–6780.
8 R. Saladino, C. Crestini, R. Bernini, G. Frachey and
E. Mincione, J. Chem. Soc., Perkin Trans. 1, 1994, 3053–3054.
9 J. Žemlička and F. Šorm, Collect. Czech. Chem. Commun.,
1965, 30, 2052–2067.
nucleoside. It appears that prolonged reactions times with 10 M. J. Robins and S. R. Naik, Biochemistry, 1971, 10, 3591–
BOP and DBU lead to conversion of the O4-(benzotriazol-1-yl)
3597.
pyrimidine nucleoside to an isomeric benzotriazolyl N-oxide 11 T.-S. Lin and W. R. Mancini, J. Med. Chem., 1983, 26, 544–
form, although the latter is also expected to be reactive 548.
towards displacement by nucleophiles. The N-oxide could 12 A. Matsuda, H. Itoh, K. Takenuki, T. Sasaki and T. Ueda,
undergo reduction with PIII species in BOP, resulting in 4-(ben-
Chem. Pharm. Bull., 1988, 36, 945–953.
zotriazol-1-yl)pyrimidine nucleosides. That the byproducts 13 R. Appel, Angew. Chem., Int. Ed. Engl., 1975, 14, 775–843.
from the reactions of the amide groups in pyrimidine nucleo- 14 L. De Napoli, A. Messere, D. Montesarchio, G. Piccialli and
sides with BOP are plausibly the benzotriazolyl N-oxide and
the 4-(benzotriazol-1-yl) nucleoside derivatives was shown by 15 C. Lou, A. Dallmann, P. Marafini, R. Gao and T. Brown,
reduction of the former to the latter by B2(OH)4. Mechanism of Chem. Sci., 2014, 5, 3836–3844.
the reaction was queried by NMR experiments. All products 16 U. Hennecke, D. Kuch and T. Carell, Synthesis, 2007, 929–
C. Santacroce, Nucleosides Nucleotides, 1991, 10, 1719–1728.
were desilylated and the azido compounds were reduced to the
935.
This journal is © The Royal Society of Chemistry 2017
Org. Biomol. Chem.