Electrophilic aromatic selenylation: New OPRT inhibitors

Article abstract of DOI:10.1021/ol1010032

2-Ethoxyethaneseleninic acid reacts with electron-rich aromatic substrates to deliver, by way of the selenoxides, the (2-ethoxyethyl)seleno ethers, which can in turn be transformed into a diverse set of aryl-selenylated products. Among these, a family of 5-uridinyl derivatives shows submicromolar inhibition of human and malarial orotate phosphoribosyltransferase.

Full text of DOI:10.1021/ol1010032

ORGANIC
LETTERS
2010
Vol. 12, No. 13
2982-2985
Electrophilic Aromatic Selenylation: New
OPRT Inhibitors
Mohannad Abdo,† Yong Zhang,‡ Vern L. Schramm,‡ and Spencer Knapp*,†
Department of Chemistry & Chemical Biology, Rutgers, The State UniVersity of New
Jersey, 610 Taylor Road, Piscataway, New Jersey 08854, and Albert Einstein College
of Medicine, 1300 Morris Park AVenue, Bronx, New York 10461
spencer.knapp@rutgers.edu
Received May 1, 2010
ABSTRACT
2-Ethoxyethaneseleninic acid reacts with electron-rich aromatic substrates to deliver, by way of the selenoxides, the (2-ethoxyethyl)seleno
ethers, which can in turn be transformed into a diverse set of aryl-selenylated products. Among these, a family of 5-uridinyl derivatives shows
submicromolar inhibition of human and malarial orotate phosphoribosyltransferase.
A wide assortment of selenium-based reagents allows the
introduction of Se into organic structures by both nucleophilic
and electrophilic pathways, and the resulting organoselenium
products can be oxidized, reduced, or otherwise converted
to useful targets that may or may not retain Se.1 Despite the
toxic nature of organoselenium derivatives in general, many
of these have shown marked biological and enzyme inhibi-
tory activities that may find important applications.2 Elec-
trophilic introduction of Se is commonly performed by using
selenenyl chlorides and their relatives, and is mostly limited
to ArSe-X examples. We recently demonstrated that alkane-
seleninic acids (RSeO2H) react as electrophiles toward
electron-rich aromatic rings such as phenols and indoles.3,4
We have now modified this reaction to allow the incorpora-
tion of the versatile 2-ethoxyethaneselenenyl substituent, and
show that tranformations of the latter can, in the case of
5-selenylated uridine, produce products that are inhibitory
to malarial and human orotate phosphoribosyltransferase.
2-Ethoxyethaneseleninic acid (1, Scheme 1), prepared from
bromoethyl ethyl ether, reacts with uridine triacetate 2 under
acidic conditions (catalytic trifluoroacetic acid) to give as
the major product the 5-selenylated nucleoside 3.5 The
5-selenylated pyrimidines 4-6 were prepared analogously.
Would this selenylation reaction work in aqueous solution?
Water-soluble nucleosides did indeed give the 5-selenylated
† Rutgers-The State University of New Jersey.
‡ Albert Einstein College of Medicine.
(3) Abdo, M.; Knapp, S. J. Am. Chem. Soc. 2008, 130, 9234–9235.
(1) Iwaoka, M.; Tomoda, S. Top. Curr. Chem. 2000, 208, 55–80. Wirth,
T. Top. Curr. Chem. 2000, 208, 1–5. Back, T. G. Organoselenium
ChemistrysA Practical Approach; Oxford Press: New York, 2000.
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2008, 130, 13196–13197. Desai, D.; Madhunapantula, S. V.; Gowdahalli,
K.; Sharma, A.; Chandagaludoreswamy, R.; El-Bayoumy, K.; Robertson,
G. P.; Amin, S. Bioorg. Med. Chem. Lett. 2010, 20, 2038–2043, and
references cited therein.
(4) Electrophilic aryl selenylations;Phenols: Oddershede, J.; Henriksen,
L.; Larsen, S. Org. Biomol. Chem. 2003, 1, 1053–1060, and references cited
therein. Indoles: Crich, D.; Davies, J. W. Tetrahedron Lett. 1989, 30, 4307–
4308, and references cited therein
.
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T.; Prusoff, W. J. Med. Chem. 1986, 29, 1293–1295. Lee, C. H.; Kim,
Y. H. Tetrahedron Lett. 1991, 32, 2401–2404. Goudgaon, N. M.; Naguib,
F. N. M.; el Kouni, M. H.; Schinazi, R. F. J. Med. Chem. 1993, 36, 4250–
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10.1021/ol1010032  2010 American Chemical Society
Published on Web 06/03/2010

Scheme 1
.
Electrophilic Selenylation with EtOCH2CH2SeO2H
Scheme 4. Oxidation of 5-Selenylated Nucleosides
Scheme 2. Selenylation in Aqueous Solution
(Scheme 4) led cleanly to the stable selenoxide 14 (two
diasteriomers at Se) or, with additional reagent, the selenone
18. Retro-ene elimination of ArSeOH,6 normally spontaneous
at 23 °C, is suppressed by the ꢀ heteroatom in the ethoxyethyl
chain.7 Nucleophilic dealkylation of 18 with sodium azide8
gave the uridine 5-seleninic acid 20. Respective deacetylation
of 14 and 20 gave the triols 16 and 22, and, in the analogous
2′-deoxy series, 15 and 21 gave diols 17 and 23.
Scheme 3. Selenylation of Tyrosine and Tryptophan Derivatives
Because of the susceptibility of phenols to oxidation,
comparable transformations of 12 could only be accom-
plished following protection of the phenolic -OH (Scheme
5). The selenoxide 25 and selenone 26 were prepared as
before, and dealkylation gave the seleninate 27. Analogous
oxidation of 13 was unsuccessful.
Careful purification of product mixtures and identification
of minor products allowed some insight into the mechanism
of selenylation (Scheme 6). Reaction of 2 gave, in addition
to 3, the diselenides 28, 29, and 30. By subjecting selenoxide
14 to the same conditions, we were able to isolate selenoether
3 and a different mix of 28, 29, and 30. Diselenide 28 results
from reductive coupling9 of ArSeOH, the product of retro-
ene elimination from 14, and 29 and 30 result from reductive
products 8, 9, and 10, and cytosine gave 6, when the reaction
was performed in the presence of heptafluorobutanoic acid
(bp 120 °C), Scheme 2. Deacetylation of the nucleoside
triacetates from Scheme 1 confirmed their structures.
More reactive aromatic rings, such as those contained in
tyrosine and tryptophan, selenylated more easily, even
without added acid catalyst (Scheme 3). Less reactive rings,
such as those in phenylalanine derivatives, did not selenylate.
(6) Sharpless, K. B.; Lauer, R. F. J. Am. Chem. Soc. 1973, 95, 2697–
2699.
(7) Tiecco, M.; Testaferri, L.; Tingoli, M.; Marini, F. J. Org. Chem.
1993, 58, 1349–1354, and references cited therein.
By altering the oxidation state and substitution at Se,
selenoethers can be transformed to a variety of related
organoselenium species. Thus, DMDO oxidation of 3
(8) Tiecco, M.; Testaferri, L.; Bagnoli, L.; Scarponi, C.; Temperini, A.;
Marini, F.; Santi, C. Tetrahedron: Asymmetry 2007, 18, 2758–2767.
Org. Lett., Vol. 12, No. 13, 2010
2983

Scheme 5
.
Oxidation of Selenylated Tyrosine Derivative
Scheme 7. Control Reactions for the Selenylation Mechanism
Scheme 6. Full Product Analysis of Selenylation Reactions
Scheme 8. Transformations of ArSeOH
coupling of 1 and diselenide scrambling,10 respectively.
These results strongly implicate selenoxide 14 as an inter-
mediate in the selenylation of 2. Formation of 14 could arise
+
from initial addition of electrophilic EtOCH2CH2Se(OH)2 ,
followed by loss of water. Reduction of 14 to 3 evidently
occurs in part by co-oxidation of seleninate 1 to 2-ethoxy-
ethaneselenonic acid, which then decomposes to 2-ethoxy-
ethanol and SeO2. The latter was isolated in both reactions,
and identified unambiguously by 77Se NMR.
Several control reactions (Scheme 7) provide further
support for the intermediacy of 14. Purposeful oxidation of
seleninate 1 with DMDO gave SeO2, as expected. Redox
reaction of 14 with didodecyl disulfide (31) led to sulfoxide
32 along with 3 (catalytic TFA was required for this
reaction), illustrating the ease with which O may be
transferred from the selenoxide. However, adding 31 to the
reaction of 1 and 2 did not improve the yield, but rather
blocked the selenylation by reducing 1. Finally, thermolysis
of 14 in the absence of acid or a reducing agent gave the
aldehyde 35, presumably by way of the retro-ene reaction,
followed by efficient readdition of the selenenic acid 33 to
alkene 34.11 Reduction of 35 and then deacetylation gave
the tetrol 36.
The thermolytic formation of 33 under mild conditions
allowed its interception by i-Pr2NH (Scheme 8), providing
not the selenenamide,12 but rather the diselenide 28. Alter-
natively, 33 was trapped by dimethylaniline13 to give the
(mixed) diarylselenide 38, and 28 was oxidatively cleaved
and then coupled to N-trimethylsilylimidazole14 to provide
38. Respective deacetylation gave 5-selenylated uridines 37,
39, and 41.
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2984
Org. Lett., Vol. 12, No. 13, 2010

Orotate phosphoribosyltransferase (OPRT) is an essential
enzyme for the de novo biosynthesis of pyrimidine nucle-
otides, promoting the attachment of orotic acid to phospho-
ribosylpyrophosphate.15 This is the only pathway for pyri-
midine nucleotide production in Plasmodium falciparum, the
major causative agent of malaria.16 Furthermore, new ways
of interrupting nucleotide synthesis in rapidly proliferating
human cancer cells may offer alternative therapy options for
this disease. The 5-selenated nucleosides were evaluated as
competitive inhibitors of malarial and human OPRTs. Six
of the relatively nonpolar uridine derivatives (8, 10, 36, 37,
39, and 41) reached submicromolar Ki values for human
OPRT (HsOPRT), and three of these (37, 39, and 41) were
also submicromolar inhibitors of P. falciparum OPRT
(PfOPRT) (Table 1). The most active nucleoside, diselenide
37, is particularly interesting as it may represent a prototype
for OPRT inhibitiors that can bind to both subunits of a
homodimeric active site. Synthetic access to the selenylated
nucleosides also provides new opportunities for investigating
the inhibition of additional nucleoside processing enzymes,
including pyrimidine nucleoside kinases, thymidine kinase,
Table 1. Inhibition of OPRTs by Selenylated Nucleosides
compd
Ki, µM (PfOPRT)
Ki, µM (HsOPRT)
6
8
2.15 ( 0.75
1.30 ( 0.33
1.44 ( 0.44
6.10 ( 1.60
10.82 ( 1.98
1.54 ( 0.47
0.16 ( 0.02
0.75 ( 0.21
0.92 ( 0.28
1.14 ( 0.48
0.26 ( 0.03
0.44 ( 0.10
2.40 ( 0.39
5.89 ( 1.31
0.72 ( 0.21
0.16 ( 0.03
0.24 ( 0.10
0.91 ( 0.27
10
16
22
36
37
39
41
thymidylate synthetase, thymidine phosphorylase, and oro-
tidine monophosphate decarboxylase.
Acknowledgment. The authors are grateful to the Prusoff
Foundation for financial support at Rutgers, and to the Rohm
and Haas Company for a graduate assistantship to M.A.
Support at the Albert Einstein College of Medicine was
provided by NIH research grants GM41916 and AI049512.
Supporting Information Available: Details of the en-
zymatic evaluation, and the preparation and spectroscopic
characterization for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(15) Zhang, Y.; Luo, M.; Schramm, V. L. J. Am. Chem. Soc. 2009, 131,
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T.; Krungkrai, J.; Horii, T. Mol. Biochem. Parasitol. 2004, 134, 245–255.
Bello, A. M.; Poduch, E.; Liu, Y.; Wei, L.; Crandall, I.; Wang, X.; Dyanand,
C.; Kain, K. C.; Pai, E. F.; Kotra, L. P. J. Med. Chem. 2008, 51, 439–448.
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