Synthesis and biological activities of (Z) and (E) α-ethenyl acyclonucleosides

Article abstract of DOI:10.1081/NCN-100105239

Synthesis of Z and E ethenyl acyclonucleosides (6a-e and 7a-e) via Michael addition of nucleobases with the diethyl acetylenedicarboxylate is described. The structures of compounds have been confirmed by spectral data. New compounds were found to be inact

Full text of DOI:10.1081/NCN-100105239

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SYNTHESIS AND BIOLOGICAL ACTIVITIES OF (Z) AND (E)
α-ETHENYL ACYCLONUCLEOSIDES
N. Redwane , H. B. Lazrek , J. L. Barascut a , J. L. Imbach a , J. Balzarini b , M. Witvrouw b &
E. De Clercq b
a Université des Sciences et Techniques Montpellier II , Laboratoire de Chimie Bio-Organique,
France
b Rega Institute for Medical Research, Katholieke Universiteit Leuven , Leuven, Belgium
Published online: 17 Aug 2006.
To cite this article: N. Redwane , H. B. Lazrek , J. L. Barascut , J. L. Imbach , J. Balzarini , M. Witvrouw & E. De Clercq
(2001) SYNTHESIS AND BIOLOGICAL ACTIVITIES OF (Z) AND (E) α-ETHENYL ACYCLONUCLEOSIDES, Nucleosides, Nucleotides and
Nucleic Acids, 20:8, 1439-1447, DOI: 10.1081/NCN-100105239
To link to this article: http://dx.doi.org/10.1081/NCN-100105239
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(8), 143971447 (2001)
SYNTHESIS AND BIOLOGICAL ACTIVITIES OF
(Z ) AND (E ) a-ETHENYL ACYCLONUCLEOSIDES
N. Redwane,1 H. B. Lazrek,1,* J. L. Barascut,2 J. L. Imbach,2
J. Balzarini,3 M. Witvrouw,3 and E. De Clercq3
1Laboratoire de Chimie Bio-Organique, Faculte des Sciences
Semlalia, Marrakech, Moroccco
2Laboratoire de Chimie Bio-Organique, Universite des Sciences
et Techniques Montpellier II, France
3Rega Institute for Medical Research, Katholieke Universiteit
Leuven, Leuven, Belgium
ABSTRACT
Synthesis of Z and E ethenyl acyclonucleosides (6a-e and 7a-e) via
Michael addition of nucleobases with the diethyl acetylenedicarboxylate
is described. The structures of compounds have been con®rmed by
spectral data. New compounds were found to be inactive against DNA
and RNA viruses.
The chemical and biological properties of carbocyclic nucleoside ana-
logues have been the subject of intense research during the past decade.175
A variety of carbocyclic adenosine analogues are assumed to exert their
antiviral action through inhibition of S-adenosylhomocysteine hydrolase
(AdoHcy, SAH).6 In fact, a close correlation has been found between the
antiviral activity of various carbocyclic and acyclic adenosine analogues and
their inhibitory e€ect on the cell-free SAH hydrolase,5 and they are not
susceptible to degradation in vitro by nucleases and phosphorylases. For
instance, unsaturated analogues 173 (Figure 1) were found to be substrates
of adenosine deaminase.7
*Corresponding author.
1439
Copyright # 2001 by Marcel Dekker, Inc.
www.dekker.com

1440
REDWANE ET AL.
Figure 1.
In view of the above synthetic and biological aspects, and as a part of
continuing studies,8710 we report here the synthesis of a new group of unsa-
turated analogues, trans andcis alkenes 6a-e and 7a-e (Scheme 1), respectively.
These products are mainly characterised by a nucleobase linked to a double
bond. The strategy envisioned to reach this goal involved using a Michael
addition, which is one of the most important methods for creating carbon±
carbon11 or nitrogen7carbon3,12,13 bonds to give functionalized organic com-
pounds. The reaction of NH heterocycles (pyrazole, indazole, triazole . . .) with
acetylenic esters having electron withdrawing groups such COOR, CN and
SOOR has been studied.14716 This type of reaction proceeds initially via
nucleophilic addition to an acetylenic bond to form the Michael adduct.
We have applied this strategy to both purine and pyrimidine bases. The
nucleobase anions 5a-e were generated in situ by treatment with potassium
carbonate in 1,4-dioxane or in DMF and allowed to react with diethyl
acetylenedicarboxylate 4 to give, after hydrolytic work up, a mixture of the
geometrical isomers 6a-e and 7a-e with the N1, N3 bisalkylated compounds
as side products 8a-b (Scheme 1).
Scheme 1.
For instance, the reaction of uracil 5a at room temperature or at 70 ꢀC
with 4 led to a mixture of 6a, 7a and 8a (N1, N3 bis alkylated) ( Table 1). An
excess of K2CO3 should be avoided because it causes a retro-Michael reaction.
In order to ®nd a method for determining the con®guration of the
isomers 6a-e and 7a-e, the use of NMR spectroscopy appeared to be the
most promising. A study of the NMR spectra was made paying close
0
attention to the chemical shifts of the H3 vinylic proton, as well as solvent-
0
induced shifts (Table 2). The proton resonance values of H3 (Z) in both
solvent (CDCl3 or DMSO:d6) were considerably higher than the corre-

a-ETHENYL ACYCLONUCLEOSIDES
1441
Table 1. Reaction Conditions for N-alkylation of Purine and Pyrimidine with 4
Base
Solvent
Time (h)
T ꢀC
Yield %
E %
Z %
Uracil
1,4-dioxane
1,4-dioxane
24
1,5
18
1
1
1
25
70
25
70
25
25
25
65a
75b
65a
75b
70
45
15
70
45
60
66
50
55
85
30
55
40
34
50
Thymine
Cytosine
Adenine
NAcGuanine
DMF
DMF
DMF
65
50
1
a: bisalkylated N1N3 10%, b: bisalkylated N1N3 15%.
0
sponding H3 (E). It would be expected that the signi®cant diamagnetic
anisotropy of ester carbonyls would lead to a greater deshielding of the vinyl
proton.17719 In this respect, the spectra are quite similar to those of other
unsaturated derivatives of nucleic acid bases which contain a double bond
with the heterocyclic moiety.7
The di€erence in the ratio of the maleate-fumarate isomers obtained
under a di€erent set of time, solvent and temperature conditions (Table 1),
suggests that the maleate adduct (E) which is kinetically controlled process
isomerizes to the fumarate (Z), which is thermodynamically more stable.
When the reaction time is shorter (173 hours) the isomer E is the major
product. With longer reaction times (12 hours), the isomer Z is becoming the
major product. Some experiments were performed to try to understand these
results. When the isomer E was reacted with potassium carbonate in DMF
(Table 3) at room temperature, a mixture of E and Z was obtained
(Scheme 2). The equilibrium ratio Z=E isomers was determined by 1H NMR
after TLC and showed no further changes in isomer composition.
The results (Table 3) appear to be in agreement with some results pre-
viously reported.3,19
0
Table 2. Chemical Shift of Vinylic Proton H3 in CDCl3 and DMSO-d6
Solvent
Uracil
Thymine
Cytosine
Adenine
NacGuanine
0
H3 (Z)
CDCl3
CDCl3
7.10
6.30
7.05
6.25
6.85
6.15
7.35
7.25
8.00
7.20
0
H3 (Z)
0
H3 (Z)
DMSO-d6
DMSO-d6
6.95
6.80
6.90
6.65
6.65
6.50
7.20
7.15
7.25
7.15
0
H3 (Z)

1442
REDWANE ET AL.
Biological Activity
Compounds 6a-e and 7a-e were evaluated for their activities against
human immunode®ciency virus type 1 (HIV-1) (HTLV-IIIB=LAI) and HIV-2
(LAV-2ROD) in human T-lymphocyte (CEM) cells, and against herpes sim-
plex virus type 1 (HSV-1) (strain KOS), thymidine kinase-de®cient (TKÀ )
HSV-1 (strain B2006), herpes simplex virus type 2 (HSV-2) (strain G), vac-
cinia virus and vesicular stomatitis virus in human embryonic skin-muscle
(ESM) ®broblasts. In E6SM cells, no toxicity (as assessed by microscopically
visible alteration of normal cell morphology) and no antiviral activity were
observed at compound concentrations up to 400 mg=ml. Compounds 6a-e,
7a-e and 8a-b proved to be toxic to CEM cells at a 50% cytotoxic con-
centration (CC50) of 0.871 mg=ml. No antiviral activity was observed at
concentrations up to 0.871 mg=ml (data not shown).
These compounds were subjected to the NCI in vitro disease-oriented
human cells screening panel assay.20,21 About 60 cell lines of nine tumor
subpanels (I, leukemia; II, non-small cell lung cancer; III, colon cancer; IV,
CNS cancer, V; melonoma, VI; ovarian cancer; VII, renal cancer; VIII,
prostate cancer; IX, breast cancer) were incubated with ®ve concentrations
(0.01, 0.1, 1.0, 10 and 100 mM) for each compound and were used to create
log concentration -% growth inhibition curves. Some of the test compounds
(data not shown) showed antineoplastic activity at concentrations less than
l00 mM.
EXPERIMENTAL
All melting points were determined with a Buchi apparatus and are
uncorrected. Ultra-Violet spectra were recorded with a CARY 219 spectro-
1
photometer. The H NMR spectra were recorded with a Bruker AC 250
Spectrometer. Chemical shifts are reported in parts per million (d uppm)
Table 3. Isomerization of the E Isomers
Compounds
Solvent
Time (h)
T ꢀC
E (%)
Z (%)
7a
DMF
1,4-dioxane
DMF
1,4-dioxane
DMF
DMF
4
1
4
25
70
25
70
25
25
25
10
20
20
25
50
50
50
90
80
80
75
50
50
50
6b, 7b*
1
7c
7d
7e
48
24
48
DMF
*: starting material : mixture E=Z ˆ 70=30.

a-ETHENYL ACYCLONUCLEOSIDES
1443
Scheme 2.
using internal TMS standard. Fast-atom bombardment mass spectra (FAB-
MS) were recorded in the positive or negative ion mode on a JEOL DX 300
mass spectrometer. Elemental analyses were determined by the ``Service de
microanalyse du CNRS, Division de Vernaison, France''. Thin layer chro-
matography (T.L.C) was performed on plates of kieselgel 60 F254 (Merck).
Column chromatography was performed on silica gel (0.06370.2 mm Merck).
GENERAL PROCEDURE
A mixture of nucleobase (4.45 mmol), potassium carbonate (2.22 mmol)
in l,4-dioxane or DMF (50 ml) was stirred at room temperature for 15 min.
Diethyl acetylenedicarboxylate (4.45 mmol) was then added and the solution
was stirred at room temperature for di€erent times (Table 1). The solid was
®ltered o€ and the ®ltrate was evaporated. The residue was chromatographed
on a silica gel column.
(Z)-Diethyl 2-(Uracil-1-yl)-but-2-enedioate (6a)
mp : 1147116 ꢀC (Ether); Rf : 0.55 (CH2Cl2=MeOH:90=10); UV
(MeOH) lmax 255 nm (e ˆ 12 600); FAB-MS, 283 (M‡H); 1H NMR
0
(CDCl3): 9.10 (s, 1H, NH-3); 7.05 (d, 1H, H6; J6,5 ˆ 7.9 Hz); 7.05 (s, 1H, H3 );
5.80 (d, 1H, H5, J6,5 ˆ 7.9 Hz); 4.20 (m, 4H, CH3CH2O); l.30 (m, 6H,
CH3CH2O); Anal. Calc. for: C12H14O6N2 : C, 51.06; H, 5.00; N, 9.92; Found;
C, 51.10; H, 4.85; N, 9.90.

1444
REDWANE ET AL.
(E)-Diethyl 2-(Uracil-1-yl)-but-2-enedioate (7a)
mp : 1357137 ꢀC (Ether); Rf : 0.54 (CH2Cl2=MeOH: 90=10); UV
(MeOH) lmax 271.6 nm (e ˆ 11 000); FAB-MS, 283 (M‡H); 1H NMR
0
(CDCl3): 9.30 (s, 1H, NH-3); 7.30 (d, 1H, H6; J6,5 ˆ 8.1 Hz); 6.3 (s, 1H, H3 );
5.85 (d, 1H, H5; J6,5 ˆ 8.1 Hz); 4.30 (m, 4H, CH3CH2O); 1.30 (m, 6H,
CH3CH2O); Anal. Calc. for: C12H14O6N2; C, 51.06; H, 5.00; N, 9.92; Found;
C, 51.12; H, 5.01; N, 9.80.
(E, Z)-Diethyl 2-(Thymin-1-yl)-but-2-enedioate (6b, 7b)
mp : 1287130 ꢀC (Ether); Rf : 0.57 (CH2Cl2=MeOH: 90=10);UV
(MeOH) lmax 272 nm (e ˆ 12 500); FAB-MS, 297 (M‡H) 1H NMR (CDCl3):
0
9.40 (s, 1H, NH-3, (E, Z)); 7.05 (s, 1H, H3 , Z); 7.10 (m, 1H, H6, E); 6.95 (m,
0
1H, H6, Z); 6.25 (s, 1H, H3 , E); 4.25 (m, 8H, CH3CH2O, (E, Z)); 1.95 (s, 6H,
CH3, (E, Z)); 1.30 (m, 12H, CH3CH2O, (E, Z)); Anal. Calc. for: C13H16O6N2;
C, 52.70; H, 5.44, N, 9.45; Found; C, 52.74; H, 5.46; N, 9.51.
(Z)-Diethyl 2-(Cytosin-1-yl)-but-2-enedioate (6c)
mp 1527154 ꢀC (Ether); Rf : 0.33 (CH2Cl2=MeOH: 90=10); UV
(MeOH) lmax 288 nm (e ˆ 12 400); FAB-MS, 282 (M‡H); 1H NMR
0
(CDCl3): 8.70 (s, 2H, NH2); 7.10 (d, 1H, H6, J6,5 ˆ 7.4 Hz); 6.85 (s, 1H, H3 );
5.90 (d, 1H, H5, J6,5 ˆ 7.4 Hz); 4.25 (m, 4H, CH3CH2O); 1.25 (m, 6H,
CH3CH2O); Anal. Calc. for: C12H15O5N3; C, 51.24; H, 5.37; N, 14.93; Found;
C, 51.31; H, 5.40; N, 14.82.
(E)-Diethyl 2-(Cytosin-1-yl)-but-2-enedioate (7c)
mp : 1657167 ꢀC (Ether); Rf : 0.30 (CH2Cl2=MeOH: 90=10); UV
(MeOH) lmax 284 nm (e ˆ 10 800); FAB-MS, 282 (M‡H); 1H NMR
0
(CDCl3): 8.70 (s, 2H, NH2); 7.25 (d, 1H, H6, J6,5 ˆ 7.5 HZ); 6.15 (s, 1H, H3 );
6.00 (d, 1H, H5, J6,5 ˆ 7.5 HZ); 4.25 (m, 4H, CH3CH2O); 1.25 (m, 6H,
CH3CH2O); Anal. Calc. for: C12H15O5N3 ; C, 51.24; H, 5.37; N, 14.93;
Found; C, 51.11; H, 5.47, N, 14.83.
(Z)-Diethyl 2-(Adenin-9-yl)-but-2-enedioate (6d)
mp : 2047206 ꢀC (Ether); Rf : 0.50 (CH2Cl2=MeOH: 90=10); UV
(MeOH) lmax 254 nm (e ˆ 38 400); FAB-MS, 306 (M‡H); 1H NMR
0
(CDCl3): 8.45 (s, 1H, H8); 7.90 (s, 1H, H2); 7.35 (s, 1H, H3 ); 5.65 (s, 2H,
NH2); 4.48 (q, 2H, CH3CH2O, J ˆ 7.1 Hz); 4.28 (q, 2H, CH3CH2O,

a-ETHENYL ACYCLONUCLEOSIDES
1445
J ˆ 7.1 Hz); 1.34 (m, 6H, CH3CH2O); Anal. Calc. for: C13H15O4N5; C, 51.14;
H, 4.95; N, 22.94; Found; C, 51.07; H, 4.93; N, 22.91.
(E)-Diethyl 2-(Adenin-9-yl)-but-2-enedioate (7d)
mp 1407142 ꢀC (Ether); Rf : 0.47 (CH2Cl2=MeOH: 90=10); UV
(MeOH) lmax 255 nm (e ˆ 19 600); FAB-MS, 306 (M‡H); 1H NMR
0
(CDCl3): 8.33 (s, 1H, H8); 7.90 (s, 1H, H2); 7.35 (s, 1H, H3 ); 5.88 (s, 2H,
NH2); 4.36 (q, 2H, CH3CH2O, J ˆ 7.1 Hz); 4.07 (q, 2H, CH3CH2O,
J ˆ 7.1 Hz); 1.32 (t, 3H, CH3CH2O; J ˆ 7.1 Hz); 1.08 (t, 3H, CH3CH2O;
J ˆ 7.1 Hz); Anal. Calc. for: C13H15O4N5;C, 51.14; H, 4.95; N, 22.94; Found;
C, 51.10; H, 4.98; N, 22.92.
(Z)-Diethyl 2-(N-Acetylguanin-9-yl)-but-2-enedioate (6e)
mp : 1987200 ꢀC (MeOH); Rf : 0.43 (CH2Cl2=MeOH : 90=10); UV
(MeOH) lmax 280 nm (e ˆ 13 700); lmax 251 nm (e ˆ 23 144); FAB-MS, 364
(M‡H); 1H NMR (CDCl3): 12.30 (s, 1H, NH-Ac); 11.15 (s, 1H, NH-1); 8.20
0
(s, 1H, H8); 7.80 (s, 1H, H3 ); 4.20 (m, 4H, CH3CH2O); 2.20 (s, 3H, CH3CO);
1.40 (m, 6H, CH3CH2O); Anal. Calc. for: C15H17O6N5; C, 49.59; H, 4.72; N,
19.28; Found; C, 49.38, H, 4.73; N, 19.11.
(E)-Diethyl 2-(N-Acetylguanin-9-yl)-but-2-enedioate (7e)
Rf : 0.41 (CH2Cl2=MeOH: 90=10); UV (MeOH) lmax 282 nm (shoulder)
l
max 248 (e ˆ 9200); FAB-MS, 364 (M‡H); 1H NMR (CDCl3): 12.30 (s, 1H,
0
NH-Ac); 11.15 (s, 1H, NH-1); 8.00 (s, 1H, H8); 7.10 (s, 1H, H3 ); 4.20 (m, 4H,
CH3CH2O); 2.75 (s, 3H, CH3CO); 1.25 (m, 6H, CH3CH2O); Anal. Calc. for:
C15H17O6N5; C, 49.58; H, 4.71; N, 19.27; Found; C, 49.18, H, 4.70; N, 19.20.
1, 3-Bis(diethylbut-2-enedioate-2-yl)uracil (8a)
Rf : 0.71 (CH2Cl2=MeOH: 95=5); UV (MEOH) lmax 262 nm (e ˆ 9 200);
FAB-MS, 453 (M‡H); 1H NMR (DMSO-d6): 7,878 (m, 1H, H6); 777.15 (m,
0
2H, H3 ); 5.9576.05 (m, 1H, H5); 4,15 (m, 8H, CH3CH2O); 1,3 (m, 12H,
CH3CH2O); Anal. Calc. for: C20H24O10N2; C, 53.10; H, 5.35; N, 6.19; Found;
C, 53.17; H, 5.34; N, 5.97.
1, 3-Bis(diethylbut-2-enedioate-2-yI)thymine (8b)
Rf : 0.77 (CH2Cl2=MeOH: 95=5) UV (MeOH) lmax 264 nm (e ˆ 13 500);
FAB-MS, 467 (M‡H); H NMR (CDCl3) : 7.16 and 6.95 (2s, 2H, H6); 7.02
1

1446
REDWANE ET AL.
0
and 6.30 (2s, 2H, H3 ); 4.30 (m, 8H, CH3CH2O); 2.00 (s, 3H, CH3); 1.30 (m,
12H, CH3CH2O); Anal. Calc. for: C21H26O10N2;C, 54.05; H, 5.62; N, 6.01;
Found; C, 54.14; H, 5.60; N, 5.97.
ANTIVIRAL ASSAY PROCEDURES
Cytotoxicity measurements were based on either microscopic exam-
ination of alteration of normal cell morphology, or inhibition of cell growth.
The cell lines used for both the antiviral activity and cytotoxicity assays were
CEM cells and human embryonic skin-muscle (E6SM) ®broblasts. The dif-
ferent compounds were evaluated for their antiviral activity according to
well-established procedures.22,23 The origin of the viruses [human immuno-
de®ciency virus type 1 (HIV-1) (strain HTLV-IIIB=LAI), HIV-2 (LAV-
2ROD), herpes simplex virus type 1 (HSV-1) (strain KOS), thymidine
kinase-de®cient (TKÀ ) HSV-1 (strain B2006), herpes simplex virus type 2
(HSV-2) (strain G), vaccinia virus and vesicular stomatitis virus] has been
described previously.22,23
ANTITUMOR SCREENING
Compounds 6a-e, 7a-e and 8a-e were subjected to the NCI in vitro
screening panel assay as described elswhere.20,21
ACKNOWLEDGMENTS
This work was supported in part by the Biomedical Research Pro-
gramme of the European Commission and by the ``Cooperation Inter-
universitaire France=Maroc (AI 96=1141)''. We thank the CNR (Maroc) and
the DFG (Germany) for supporting this work. The authors would like to
express their gratitude and thanks to V. L. Narayanan, Chief, Drug Synthesis
and Chemistry Branch and the sta€ of the antitumor screening division,
National Cancer Institute, Bethesda, MD, for carrying out the in vitro anti-
tumor testing. We thank Mrs. A. Absillis, Mrs. F. De Meyer and Mrs. A.
Van Lierde for excellent technical assistance.
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Received June 20, 2000
Accepted December 30, 2000