Synthesis and antiviral activity of methylenedifluorocyclopropane analogues of nucleosides

Article abstract of DOI:10.1081/NCN-100002304

Synthesis and antiviral activity of methylenedifluorocyclopropane analogues 8a, 8b and 9a, 9b are described.

Full text of DOI:10.1081/NCN-100002304

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SYNTHESIS AND ANTIVIRAL ACTIVITY OF
METHYLENEDIFLUOROCYCLOPROPANE ANALOGUES
OF NUCLEOSIDES
R. Wang a , M. B. Ksebati b , J. C. Drach c & J. Zemlicka d
a Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine ,
Detroit, Michigan, 48201-1379, U.S.A.
b Central Instrumentation Facility, Department of Chemistry , Wayne State University ,
Detroit, Michigan, 48202, U.S.A.
c Department of Biologic and Materials Science , School of Dentistry, University of
Michigan , Ann Arbor, Michigan, 48019-1078, U.S.A.
d Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine ,
Detroit, Michigan, 48201-1379, U.S.A.
Published online: 07 Feb 2007.
To cite this article: R. Wang , M. B. Ksebati , J. C. Drach & J. Zemlicka (2001) SYNTHESIS AND ANTIVIRAL ACTIVITY OF
METHYLENEDIFLUOROCYCLOPROPANE ANALOGUES OF NUCLEOSIDES, Nucleosides, Nucleotides and Nucleic Acids, 20:4-7,
329-332, DOI: 10.1081/NCN-100002304
To link to this article: http://dx.doi.org/10.1081/NCN-100002304
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(4–7), 329–332 (2001)
SYNTHESIS AND ANTIVIRAL ACTIVITY OF
METHYLENEDIFLUOROCYCLOPROPANE
ANALOGUES OF NUCLEOSIDES
R. Wang,1 M. B. Ksebati,2 J. C. Drach,3 and J. Zemlicka1,∗
1Barbara Ann Karmanos Cancer Institute, Wayne State University
School of Medicine, Detroit, Michigan 48201-1379
2Central Instrumentation Facility, Department of Chemistry,
Wayne State University, Detroit, Michigan 48202
3Department of Biologic and Materials Science, School of Dentistry,
University of Michigan, Ann Arbor, Michigan 48019-1078
ABSTRACT
Synthesis and antiviral activity of methylenedifluorocyclopropane analogues
8a, 8b and 9a, 9b are described.
In the last two years we have accumulated a wealth of information
(1–11) on chemistry and antiviral activity of methylenecyclopropane analogues
1 and 2. Very recent studies of structure-activity relationships of this group of
compounds indicated that interchange of base and hydroxymethyl groups (12)
(compounds 3 and 4) or expansion of the cyclopropane ring (13) (compounds 5
and 6) abolished the antiviral activity of 1 (B = adenine). Replacement of the
remaining double bond in 1 or 2 with an additional cyclopropane ring afforded
adenine and guanine spiropentane analogues 7 (four isomers each) with a dimin-
ished antiviral potency (14). Therefore, we have focused our efforts on compounds
with a preserved methylenecyclopropane system. Because substitution of hydrogen
with fluorine led in many cases to biologically active analogues (15), we have now
synthesized methylenedifluorocyclopropanes 8a, 8b and 9a, 9b.
∗Corresponding author.
329
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Copyright 2001 by Marcel Dekker, Inc.
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WANG ET AL.
Chart 1.
The key reagent 10 for alkylation-elimination procedure (1) with nucleic acid
bases was obtained by addition of bromine (using pyridinium hydrobromide perbro-
mide) to the known (16) methylenedifluorocyclopropane 11. Reaction of 10 with
sodium salt of adenine in DMF for 16 h at room temperature afforded a mixture
of three products which were separated by column chromatography on silica gel:
Cis-isomer (17) 12a (21%), trans-isomer 13a (7%) and cyclopropene 14a (25%).
Scheme 1.

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METHYLENEDIFLUOROCYCLOPROPANE ANALOGUES
331
Deprotection of 12a and 13a using BCl3 afforded target analogues 8a and 9a in 75
and 77% yield, respectively. In a similar fashion, alkylation-elimination procedure
of 11 with 2-amino-6-chloropurine gave compounds 12c, 13c and 14c. The product
of a simple alkylation, compound 15b, was also isolated. After deprotection of 12c
and 13c, analogues 8c and 9c were obtained. Hydrolysis (1) of 8c and 9c furnished
guanine analogues 8b and 9b. Structures of all new compounds were confirmed by
1H, 13C and 19F NMR, UV and mass spectra including nuclear Overhauser effect
(NOE) data for analogues 8a and 9a.
Kineticstudiesofcyclopropene-methylenecyclopropanerearangement(19,20)
withcompounds12c, 13cand14cunderbasecatalysis/1,5-diazabicyclo[4.3.0]non-
5-ene (DBN), acetonitrile, room temperature/ by HPLC have provided a strong
evidence that composition of the products of alkylation-elimination procedure is
thermodynamically controlled.
Compound 8a inhibited the replication of human cytomegalovirus
(HCMV) in human foreskin fibroblast (HFF) culture with EC50 21 µM and it was
non-cytotoxic (IC50 > 100µM) in HFF and KB cells. Against HSV-1 in BSC-1 cells
(ELISA assay), EC50 was 70 µM. Interestingly, it was less potent than synadenol
(1) (1, B = adenine) but more effective than the corresponding saturated difluorocy-
clopropane analogue (21). Compounds 8b, 9a and 9b were without effect (EC50
>
100 µM). None of the analogues was effective against HIV-1. Other antiviral tests
are being continued.
ACKNOWLEDGMENTS
This work was supported by grants RO1-CA32779 (J. Z.) from the National
Cancer Institute and U19-AI31718 (J. C. D.) from the National Institute of Allergy
and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
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