Phosphonate analogues of cytosine arabinoside monophosphate

Article abstract of DOI:10.1080/10426500212248

Phosphonate derivatives of cytidine and cytosine arabinoside have been prepared from the corresponding nucleoside aldehydes and tested for their ability to serve as substrates for nucleotide monophosphate kinase and for their toxicity to K562 leukemia cells.

Full text of DOI:10.1080/10426500212248

This article was downloaded by: [University of Connecticut]
On: 11 October 2014, At: 11:27
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
Phosphorus, Sulfur, and Silicon and the Related
Elements
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/gpss20
Phosphonate Analogues of Cytosine Arabinoside
Monophosphate
Xuemei Chen a , Kang-Yeoun Jung a b , David F. Wiemer a , Andrew J. Wiemer b & Raymond J.
Hohl b
a Department of Chemistry , University of Iowa , Iowa City, IA, 52242
b Departments of Pharmacology and Internal Medicine , University of Iowa , Iowa City, IA,
52242
c Department of Industrial Chemistry , Kangnung National University , Kangnung, Korea ,
210-702
Published online: 27 Oct 2010.
To cite this article: Xuemei Chen , Kang-Yeoun Jung , David F. Wiemer , Andrew J. Wiemer & Raymond J. Hohl (2002)
Phosphonate Analogues of Cytosine Arabinoside Monophosphate, Phosphorus, Sulfur, and Silicon and the Related Elements,
177:6-7, 1783-1786, DOI: 10.1080/10426500212248
To link to this article: http://dx.doi.org/10.1080/10426500212248
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

Phosphorus, Sulfur and Silicon, 2002, Vol. 177:1783–1786
C
Copyright 2002 Taylor & Francis
1042-6507/02 $12.00 + .00
DOI: 10.1080/10426500290093315
PHOSPHONATE ANALOGUES OF CYTOSINE
ARABINOSIDE MONOPHOSPHATE
Xuemei Chen,a Kang-Yeoun Jung,a,c David F. Wiemer,a
Andrew J. Wiemer,b and Raymond J. Hohlb
Department of Chemistry, University of Iowa, Iowa City, IA
52242;a Departments of Pharmacology and Internal Medicine,
University of Iowa, Iowa City, IA 52242;b and Department of
Industrial Chemistry, Kangnung National University,
Kangnung, Korea 210-702c
(Received July 29, 2001; accepted December 25, 2001)
Phosphonate derivatives of cytidine and cytosine arabinoside have been
prepared from the corresponding nucleoside aldehydes and tested for
their ability to serve as substrates for nucleotide monophosphate kinase
and for their toxicity to K562 leukemia cells.
Keywords: Cytidine; cytosine arabinoside; phosphonate
INTRODUCTION
Resistance to the therapeutic agent cytosine arabinoside (ara-C) is be-
lieved to follow from mutational loss of the ability to convert this pro-
drug to the corresponding monophosphate.1 Phosphonate derivatives
of ara-C may offer one way to bypass this resistance, if such compounds
can function as analogs of ara-CMP. To test this hypothesis, several
new phosphonate derivatives of cytidine and ara-C have been prepared.
These new phosphonates bear an -hydroxy group so that their pKa’s
will more closely reflect those of ara-CMP itself.2 Both the 50- and 60- -
hydroxyphosphonates were of interest, given the precedent for biologi-
cal activity in both series of compounds.3
RESULTS AND DISCUSSION
The two epimeric 50- -hydroxyphosphonate derivatives of cytidine were
prepared as shown in Scheme 1. After protection of commercial cytidine
Address correspondence to David F. Wiemer, Department of Chemistry, University of
Iowa, Iowa City, IA 52242. E-mail: david-weimer@uiowa.edu
1783

1784
X. Chen et al.
(1) and oxidation4 to the corresponding aldehyde (2), Abramov addi-
tion of diethyl phosphite gave the desired phosphonates 3a and 3b.5
These diastereomers were separated by HPLC and then deprotected
to obtain phosphonic acids 4a and 4b. The 50 stereochemistry of these
compounds was assigned on the basis of NMR data obtained from their
O-methylmandelate derivatives.6
SCHEME 1 i. MeOH, Ac2O, reflux; ii. dimethoxypropane, HClO4(cat.), ace-
tone; iii. DMSO, EDC, Pyr, TFA; iv. LiHMDS, HP(O)(OEt)2, 78 C; v. TMSBr,
CH2Cl2, then MeOH.
A similar strategy was used to prepare a 50- -hydroxyphosphonate
derivative of Ara-C (Scheme 2). Formation of an acetonide was not possi-
ble in this arabinoside, but protection of the secondary hydroxyl groups
was accomplished via formation of the 20,30-bis TBS ether. After oxida-
tion to the aldehyde (6), phosphite addition gave a single phosphonate
diastereomer (7), and deprotection gave the desired phosphonic acid 8.
SCHEME 2 i. Pyr, TBDMSCI, AgNO3, Et3N, THF; ii. TFA: H2O: THF (1:1:4),
0 C; iii. Ac2O, MeOH, reflux; iv. DMSO, EDC, Pyr, TFA toluene; v. LiHMDS,
HP(O)(OEt)2, THF, 78 C; vi. TBAF, THF; vii. TMSBr CH2Cl2, then MeOH.

Analogues of Cytosine Arabinoside Monophosphate
1785
The two 60- -hydroxyphosphonates 9 and 10 were prepared from
aldehydes 2 and 6 via Horner-Wadsworth-Emmons condensation and
subsequent AD-mix oxidation, as previously described.7 Formation
of O-methylmandelate derivatives allowed assignment of the absolute
stereochemistry of the newly incorporated stereogenic centers, and this
assignment was confirmed by a diffraction analysis.
Each of these five -hydroxyphosphonates was tested for the ability
to serve as a substrate for nucleotide monophosphate kinase. This assay
involved treatment with a mixture of the enzyme and ATP and linkage
to pyruvate kinase and lactic dehydrogenase to allow determination of
the rates of reaction by measurement of NAD* conversion to NADH. All
five phosphonates proved to be poor substrates, with the rates of phos-
phorylation only about 1% of that displayed by UMP. When tested for
their effect on phosphorylation of UMP, the two -hydroxyphosphonate
epimers of cytidine showed opposite effects; compound 4b was an in-
hibitor of this process, but compound 4a appeared to be an activator
of this enzyme. These two epimers also differed in their toxicity to
the human-derived leukemia cell line K562, where the 50-R isomer 4a
showed significantly greater toxicity than the 50-S isomer 4b (IC50’s of
about 0.5 and >10 M). Further studies to determine the basis of these
effects will be reported in due course.
ACKNOWLEDGMENTS
Financial support from the Leukemia and Lymphoma Society (LSA99-
6059) is gratefully acknowledged.
REFERENCES
[1] B. A. Chabner, In Cancer Chemotherapy: Principals and Practice, 2nd ed., B. A.
Chabner and D. L. Longo (eds.), J. B. Lippincott Co, Philadelphia (1995).
[2] D. F. Wiemer, Tetrahedron, 53, 16609 (1997).
[3] For lead references, see: (a) C. U. Kim, B. Y. Luh, and J. C. Martin, J. Org. Chem.,
56, 2642 (1991); (b) H. P. Albrecht, G. H. Jones, and J. Moffatt, Tetrahedron, 40, 79
(1984).

1786
X. Chen et al.
[4] (a) D. W. Norbeck and J. B. Kramer, J. Am. Chem. Soc., 110, 7217 (1988); (b) K. E.
Pfitzer and J. G. Moffatt, J. Am. Chem. Soc., 85, 3027 (1963).
[5] (a) W. L. McEldoon and D. F. Wiemer, Tetrahedron, 51, 7131 (1995); (b) S. Kralikova,
M. Budesinsky, M. Masojidkova, and I. Rosenberg, Tetrahedron Lett., 41, 955 (2000).
[6] (a) J. K. Kazlowski, N. P. Rath, and C. D. Spilling, Tetrahedron, 51, 6385 (1995);
(b) N. P. Rath and C. D. Spilling, Tetrahedron Lett., 35, 227 (1994).
[7] K. Y. Jung, R. J. Hohl, A. J. Wiemer, and D. F. Wiemer, Bioorganic & Medicinal
Chemistry, 8, 2501 (2000).