Synthesis and structure-antitumor activity relationship of sulfonyl 5-fluorouracil derivatives

Article abstract of DOI:10.1080/10426500902754260

Novel sulfonyl 5-fluorouracil derivatives 2 (5-fluoro-1-(arylsulfonyl) pyrimidine-2,4(1H,3H)-diones) have been synthesized via the reaction of 5-fluorouracil with sulfonyl chloride. Their chemical structures were confirmed by means of ¹H NMR, <

Full text of DOI:10.1080/10426500902754260

Phosphorus, Sulfur, and Silicon, 185:158–164, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500902754260
SYNTHESIS AND STRUCTURE–ANTITUMOR ACTIVITY
RELATIONSHIP OF SULFONYL 5-FLUOROURACIL
DERIVATIVES
Xiaowei Yan,1 Yong Hou,2 Fan Chen,1 Kejian Zhao,1
and Maolin Hu1
1College of Chemistry and Materials Engineering, Wenzhou University,
Wenzhou, PR China
2Institute of Biotechnology and Nucleic Technology, Sichuan Academy
of Agricultural Sciences, Chengdu, PR China
Novel sulfonyl 5-fluorouracil derivatives 2 (5-fluoro-1-(arylsulfonyl)pyrimidine-2,4(1H,3H)-
diones) have been synthesized via the reaction of 5-fluorouracil with sulfonyl chloride. Their
chemical structures were confirmed by means of 1H NMR, 13C NMR, IR, mass spectra, and
elemental analyses, and, in the case of 2a, its structure was established by single crystal X-
ray diffraction. Some of the compounds were assayed for anticancer (HL-60 and BEL-7402
cells) activities. Structure–activity relationship (SAR) analysis discovered that the anticancer
activity was related to the configuration, and that electron-withdrawing groups at 2-position
or 4-position on the aryl group of arylsulfonyl derivatives of 5-fluorouracil could enhance
the anticancer activity against the BEL-7402 cells.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental
file.
Keywords Anticancer activities; crystal structure; sulfonyl 5-fluorouracil derivatives
INTRODUCTION
Compounds that exhibit the functionality of 5-fluorouracil (5-FU) have been ex-
tensively employed in the area of pharmaceuticals,1 which is reflected by their use as
antiviral,2 antitumor,3 and antibacterial4 agents. The high profile of biological applications
of compounds with 5-FU derivative has prompted extensive study for their synthesis and bi-
ological properties.5 The common feature of these prodrugs is that they are all N1-modified
derivatives through different biodegradable linkages.
Received 4 December 2008; accepted 30 December 2008.
We acknowledge financial support from the National Natural Science Foundation of China (No. 20571057),
the Wenzhou Technology Project Foundation of China (No. S20060026), and the National Center for Drug
Screening, Shanghai, China, for evaluation of antitumor activities.
Address correspondence to Maolin Hu, College of Chemistry and Materials Engineering, Wenzhou Univer-
sity, Wenzhou 325027, PR China. E-mail: hu403cn@yahoo.com.cn
158

SULFONYL 5-FLUOROURACIL DERIVATIVES
159
Sulfonamide compounds have been widely used for the treatment of bacterial or viral
infections around the world because of their low cost, low toxicity, and excellent activity
against common bacterial diseases. Moreover, sulfonamides represent an important class
of medicinally important molecules and are known to possess wide varieties of biologi-
cal activities, including antimalarial, saluretics, carbonic anhydrase inhibitors, antithyroid
agents, antitumor drugs, etc.6–8
In accordance with the continuing interest in the synthesis of 5-FU derivatives,9 we
herein have synthesized a variety of sulfonyl 5-FU derivatives by the reaction of 5-FU
with sulfonyl chloride and evaluated their biological activities. In this article we report
the synthesis and biological activities of some new 5-fluoro-1-(arylsulfonyl)pyrimidine-
2,4(1H,3H)-diones.
RESULTS AND DISCUSSION
To synthesize our target compounds 2, we used the modified Schotten–Baumann
conditions. A typical procedure involves adding the sulfonyl chloride slowly into an amine
solution in a biphasic system of organic solvents and a basic (Na2CO3) aqueous solution,10
which is shown in Scheme 1. In this route, acetone and ethyl acetate were used as the
organic co-solvents and tetrabutylammonium bromide (TBAB) was used as the phase
transfer catalyst. The target compound 5 precipitated completely at a pH of 3, while most
of byproducts still remained in the solution.
O
F
F
O
HN
N S R5
TBAB
R5SO2Cl
O
Na2CO3
HN
O
N
O
O
H
2
5-FU
2a: R5 = 2-Cl-3-pyridine
2b: R5 = C6H5
2f: R5 = 2-NO2C6H4
2g: R5 = 3-COOHC6H4
2h: R5 = 4-MeCONHC6H4
2i: R5 = 4-CF3C6H4
2c: R5 = 4-MeC6H4
2d: R5 = 4-BrC6H4
2e: R5 = 3-NO2C6H4
Scheme 1
A single crystal of 2a was grown from acetone, and acetic ether (1:1, v/v) was con-
firmed by X-ray diffraction analysis as shown in Figure 1. Diffraction data were collected
at 25(2)◦C using a graphite monochromated Mo Kα (λ = 0.071073 nm) radiation with
a ω-scan technique. Determination of the crystal class, orientation matrix, and cell di-
mensions was performed according to the established procedures. Lorentz polarization
and absorption corrections were applied. Empirical absorption corrections were performed
with SADABS program.11 Most of the non-hydrogen atoms were located using direct
methods, and those remaining were derived by subsequent Fourier syntheses. All non-
hydrogen atoms were refined anisotropically, and all hydrogen atoms were held stationary
and included in the final stage of full-matrix least-squares refinement based on F2 using

160
X. YAN ET AL.
Figure 1 ORTEP drawing of the compound 2a showing the atom numbering scheme.
SHELXS-97 and SHELXL-97 program packages.12 Crystal data are summarized in Table
I. The crystallographic data was deposited at CCDC.13
A displacement ellipsoid plot with the numbering is shown in Figure 1. The selected
bond distances and bond angles are listed in Table II. In the crystal structure of 2a, the
bond lengths and angles are within normal ranges. The pyridine ring (C5, C6, C7, C8, C9,
N3) is essentially planar with an r.m.s. deviation of 0.0099 Å. The uracil ring (C1, C2, C3,
Table I Crystal data and summary of data collection and structure refinement of 2a
Formal
C9 H5ClFN3O4S
Temperature (K)
298(2)
Wavelength (Å)
0.71073
Crystal system
Orthorhombic
Space group
P b c a
a (Å)
10.1156 (9)
b (Å)
15.0665 (14)
c (Å)
15.2151 (14)
90
90
90
α (◦)
β (◦)
γ (◦)
Volume (Å3)
2318.9 (4)
Z
4
Calculated density (Mg mm−3
)
1.751
0.537
1232
Absorption coefficient (mm−1
F(000)
)
Crystal size (mm)
0.31 × 0.14 × 0.11
θ Range for data collection (◦)
Limiting indices ≤19
2.68–25.02
−11 ≤ h ≤ 12, −14 ≤ k ≤ 17, −14 ≤ l ≤ 18
11370 / 2040 [R(int) = 0.0343]
100.0%
Semi-empirical from equivalents
Full-matrix least-squares on F2
1.062
Reflections collection/unique
Completeness to θ = 25.19◦
Absorption correction
Refinement method
Goodness-of fit on F2
Final R indices [I >2σ (I)]
Largest diffusion peak and hole (e A−3
R1 = 0.0749, wR2 = 0.1615
)
0.386 and −0.514

SULFONYL 5-FLUOROURACIL DERIVATIVES
161
Table II Selected bond lengths (Å) and bond angles (◦)
Cl(1) C(6)
S(1) O(4)
S(1) O(3)
S(1) N(1)
S(1) C(5)
F(1) C(3)
O(1) C(1)
O(2) C(2)
C(4) N(1) C(1)
C(1) N(1) S(1)
O(1) C(1) N(2)
N(2) C(1) N(1)
O(2) C(2) C(3)
N(1) S(1) C(5)
1.728(5)
1.412(4)
1.414(4)
1.707(4)
1.768(4)
1.342(5)
1.201(5)
1.210(5)
122.4(4)
118.6(3)
123.3(4)
113.5(4)
125.7(5)
103.99(19)
N(1) C(4)
N(1) C(1)
N(2) C(1)
N(2) C(2)
N(3) C(6)
N(3) C(7)
C(2) C(3)
C(3) C(4)
O(4) S(1) N(1)
C(1) N(2) C(2)
O(1) C(1) N(1)
O(2) C(2) N(2)
N(2) C(2) C(3)
C(4) C(3) C(2)
1.395(6)
1.402(6)
1.375(6)
1.383(6)
1.314(6)
1.342(6)
1.451(7)
1.318(7)
103.8(2)
128.6(4)
123.2(4)
122.1(5)
112.2(4)
123.1(4)
C4, N1, and N2) comparable to that found in a previous similar study is puckered, with an
r.m.s. deviation of 0.0276 Å,14 and makes a dihedral angle of 82.31(0.12)◦ with the pyridine
ring. The electron-withdrawing effect of the S atom and thiophene groups is observed in
this structure, which reduces the planarity of the uracil ring.15
Sulfonyl 5-FU derivatives 2 have been investigated for their anticancer activities
against human HL-60 and Bel-7402 cell lines. The antitumor activities in vitro for these
compounds were evaluated by SRB method for BEL-7402 cells, and MTT method for HL-
60 cells. The results of these assays are shown in Tables III and IV (see the Supplemental
Materials available online). The results indicated that among the tested compounds, almost
all of the newly prepared compounds showed a moderate to good inhibiting effect on
the growth of the HL-60 and BEL-7402 cells at different concentrations of 10−4 mol/L,
10−5 mol/L, 10−6 mol/L, 10−7 mol/L, and 10−8 mol/L, which might indicated that the
sulfonyl derivatives biodegradable linkage was better than peptide derivatives and which
could be more easily to released 5-FU.9,16 The inhibition effect of all the compounds against
the HL-60 cells was different from that of the BEL-7402 cells, which suggested that these
compounds possibly had different inhibition mechanisms against various tumor cells.17
By inspection of the chemical structure of 2 (Scheme 1 and Table IV), it was observed
that the substitutes of the phenyl affected the anticancer activity against the BEL-7402 cells.
Replacement of electron-withdrawing groups [ Br (2d), CF3 (2j)] at 4-position on phenyl
ring by electron-donating groups [( CH3 (2c), NHCOCH3 (2h)] resulted in the obvious
decrease of anticancer activity under 10−4 mol/L and 10−5 mol/L. Similarly, the nitro group
at 2-position (2f) had more anticancer activity under 10−4 mol/L and 10−5 mol/L than
at 3-position (2e). This might explain why sulfonyl derivatives of 5-FU with electron-
withdrawing groups at 2-position or 4-position on phenyl ring showed better anticancer
activity against the BEL-7402 cells.
EXPERIMENTAL
The melting point was measured with a X-4 melting point apparatus. Mass spectra
were obtained on a DECAX-3000LCQ DecaXPPlus. The elemental analyses were per-
formed on a Carlo-Erba 1112 Elemental Analyzer. Infrared (IR) spectrum was recorded
on a Perkin Elmer 2000 system in the range of 4000−400 cm−1 with KBr disk technique.

162
X. YAN ET AL.
Nuclear magnetic resonance (NMR) spectra were obtained with Bruker Avance-300 spec-
trometer with DMSO-d6 as solvent. The crystallographic data were collected on a Bruker
Smart-Apex CCD diffractometer. All chemicals and solvents were purchased from Aldrich
and Fluka. Antimicrobial activities of the title compound were evaluated at The National
Center for Drug Screening in Shanghai, China.
General Procedure for the Synthesis of Compound 2
A solution of ethyl acetate (10 mL) and acetone (10 mL) with TBAB (0.32 g, 1 mmol)
and sulfonyl chloride (5 mmol) was dropped in a water solution (20 mL) of 5-FU (0.65 g,
5 mmol) and Na2CO3 (1.59 g, 15 mmol) at 0◦C over a period of 30 min. The resulting
reaction mixture was left to stand at room temperature overnight. After filtration and
separation, the separated aqueous layer was acidified with hydrochloric acid with pH = 3.
The white solid was collected by filtration and washed with water and dried.
1-(2-Chloropyridin-3-ylsulfonyl)-5-fluoropyrimidine-2,4(1H,3H)-dione
(2a). Yield: 62%; mp: 183–184◦C; IR νmax (KBr)/cm−1 3445 (N H), 3027 ( C H),
1
1733 (C O), 1676 (C O), 1394 (S O), 1186 (S O); H NMR (300 MHz, DMSO-d6,
ppm): δ = 12.44 (s, 1H), 8.80 (dd, J = 4.8 Hz, J = 1.8 Hz, 1H), 8.67 (dd, J = 6.4 Hz, J =
1.8 Hz, 1H), 8.50 (d, J = 6.3 Hz, 1H), 7.80 (dd, J = 6.4 Hz, J = 4.8 Hz, 1H); 13C NMR
(75 MHz, DMSO-d6, ppm): δ = 157.0 (d, JC-F = 27.5 Hz), 155.3, 146.3 (d, JC-F = 33.4 Hz),
143.5, 140.3(d, JC-F = 237.8 Hz), 131.4, 123.9, 123.3, 122.8; MS (ESI, m/z,%) 304.2
([M-H]+, 100); Anal. Calcd. for C9H5N3SClFO4 (%): C 35.35, H 1.64, N 13.75; Found
(%): C 35.41, H 1.58, N 13.81.
5-Fluoro-1-(phenylsulfonyl)pyrimidine-2,4(1H,3H)-dione (2b). Yield: 70%,
mp: 191–193◦C; IR νmax (KBr)/cm−1 3429 (N H), 3102 ( C H), 1709 (C O), 1394
(S O), 1181 (S O). 1H NMR (300 MHz, DMSO-d6, ppm): δ = 12.24 (s, 1H), 8.42 (d, J
= 6.3 Hz, 1H), 8.06 (d, J = 7.8 Hz, 2H), 7.71 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 7.2 Hz,
1H); 13C NMR (75 MHz, DMSO-d6, ppm): δ = 157.2 (d, JC-F = 27.1 Hz), 146.1, 140.4 (d,
J = 236.7 Hz), 136.0, 135.4, 131.8, 129.4, 129.0 (d, JC-F = 3.8 Hz), 125.6, 122.7 (d, JC-F
= 36.8 Hz); MS (ESI, m/z,%) 269.3 ([M-H]+, 100); Anal. Calcd. for C10H7N2SFO4 (%):
C 44.44, H 2.60, N 10.37; Found (%): C 44.67, H 2.58, N 10.25.
5-Fluoro-1-tosylpyrimidine-2,4(1H,3H)-dione (2c). Yield: 67%, mp: 211–
213◦C; IR νmax (KBr)/cm−1 3425 (N H), 3066 (N H), 1749 (C O), 1695 (C O), 1383
(S O), 1174 (S O); 1H NMR (300 MHz, DMSO-d6, ppm): δ = 12.20 (s, 1H,), 8.40 (d, J
= 6.0 Hz, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.1 Hz, 2H), 2.43(s, 3H); 13C NMR
(75 MHz, DMSO-d6, ppm): δ = 157.1 (d, JC-F = 25.4 Hz), 156.4, 146.2 (d, JC-F = 27.8
Hz), 140.2(d, JC-F = 237.2 Hz), 132.9, 129.8, 129.0, 122.7 (d, JC-F = 36.1 Hz), 21.1; MS
(ESI, m/z,%) 283.2 ([M-H]+, 100); Anal. Calcd. for C11H9N2SFO4 (%): C 46.48, H 3.17,
N 9.86; Found (%): C 46.76, H 3.15, N 9.88.
1-(4-Bromophenylsulfonyl)-5-fluoropyrimidine-2,4(1H,3H)-dione (2d).
Yield: 52%, mp: 201–203◦C; IR νmax (KBr)/cm−1 3275 (N H), 3107 ( C H), 1731
1
(C O), 1664 (C O), 1568 (C N), 1381 (S O), 1185 (S O); H NMR (300 MHz,
DMSO-d6, ppm): δ = 12.26 (s, 1H), 8.40 (d, J = 6.6 Hz, 1H), 7.98 (d, J = 8.7 Hz, 2H), 7.93
(d, J = 8.7 Hz, 2H); 13C NMR (75 MHz, DMSO-d6, ppm): δ = 157.2 (d, JC-F = 26.9 Hz),
146.6 (d, JC-F = 66.3 Hz), 140.4 (d, JC-F = 235.7 Hz), 135.0, 132.5, 131.0, 129.8, 122.6
(d, JC-F = 38.2 Hz); MS (ESI, m/z,%) 349.1 ([M+2-H]+, 98), 347.1 ([M-H]+, 100); Anal.
Calcd. for C10H6N2SBrFO4 (%): C 34.43, H 1.72, N 8.03; Found (%): C 34.60, H 1.68, N
7.95.

SULFONYL 5-FLUOROURACIL DERIVATIVES
163
5-Fluoro-1-(3-nitrophenylsulfonyl)pyrimidine-2,4(1H,3H)-dione
(2e).
Yield: 66%, mp: 194–196◦C; IR νmax (KBr)/cm−1 3437 (N H), 3198 (N O), 3098
( C H), 1736 (C O), 1697 (C O), 1536 (C N), 1391 (S O), 1189 (S O); 1H NMR
(300 MHz, DMSO-d6, ppm): δ = 12.30 (s, 1H,), 8.75 (t, J = 2.0 Hz, 1H), 8.63–8.66 (m,
1H), 8.46–8.50 (m, 2H), 8.00 (t, J = 8.1 Hz, 1H); 13C NMR (75 MHz, DMSO-d6, ppm):
δ = 157.2 (d, JC-F = 26.6 Hz), 147.7, 146.2, 140.5 (d, JC-F = 236.7 Hz), 137.1, 135.3,
131.2, 129.8, 124.3, 122.7 (d, JC-F = 38.9 Hz); MS (ESI, m/z,%) 314.1 ([M-H]+, 100);
Anal. Calcd. for C10H6N3SFO6 (%):C 38.08, H 1.90, N 13.33; Found (%):C 38.00, H 2.01,
N 13.31.
5-Fluoro-1-(2-nitrophenylsulfonyl)pyrimidine-2,4(1H,3H)-dione
(2f).
Yield: 58%, mp: 199–201◦C; IR νmax (KBr)/cm−1 3463 (N H), 3199 (N O), 3095
1
( C H), 1709 (C O), 1539 (C N), 1393 (S O), 1189 (S O); H NMR (300 MHz,
DMSO-d6, ppm): δ = 12.52 (s, 1H,), 8.40 (dd, J = 8.1 Hz, J = 1.5 Hz, 1H), 8.29 (d, J
= 6.3 Hz, 1H), 8.19 (dd, J = 7.5 Hz, J = 1.5 Hz, 1H), 8.00–8.13 (m, 2H); 13C NMR
(75 MHz, DMSO-d6, ppm): δ = 157.0 (d, JC-F = 26.9 Hz), 147.4, 146.1, 140.2 (d, JC-F
=
236.9 Hz), 137.3, 134.5, 133.2, 128.3, 125.7, 122.7 (d, JC-F = 39.4 Hz); MS (ESI, m/z,%)
314.1 ([M-H]+, 100); Anal. Calcd. for C10H6N3SFO6 (%):C 38.08, H 1.90, N 13.33;
Found (%): C 37.99, H 1.97, N 13.52.
3-(5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-ylsulfonyl)benzoic
acid (2g). Yield: 50%, mp: 214–216◦C. IR νmax (KBr)/cm−1 3433 (N H), 3061 ( C H,
O H), 1696 (C O), 1391 (S O), 1184 (S O). 1H NMR (300 MHz, DMSO-d6, ppm):
δ = 13.69 (s, 1H), 12.25, 8.52 (t, J = 1.8 Hz, 1H), 8.46 (d, J = 6.0 Hz, 1H), 8.28–8.35 (m,
2H), 7.84 (t, J = 7.8 Hz, 1H). 13C NMR (75 MHz, DMSO-d6, ppm): δ = 165.5, 157.0,
146.2, 140.5 (d, JC-F = 239.0 Hz), 136.4, 135.7, 133.1, 131.9, 130.1, 129.8, 122.6 (d, JC-F
=
37.4 Hz). MS (ESI, m/z,%) 313.3 ([M-H]+, 100); Anal. Calcd. for C11H7N2SFO6 (%): C
42.34, H 2.23, N 8.92; Found (%): C 42.33, H 2.27, N 8.90.
N-(4-(5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-ylsulfonyl)phenyl)
acetamide (2h). Yield: 73%, mp: 199–200◦C; IR νmax (KBr)/cm−1 3338 (N H), 3049
( C H), 1703 (C O), 1385 (S O), 1179 (S O); 1H NMR (300 MHz, DMSO-d6, ppm):
δ = 10.57 (s, 1H), 8.18 (d, J = 6.3 Hz, 1H), 7.94 (d, J = 9.0 Hz, 2H), 7.82 (d, J = 8.7 Hz,
2H), 2.10 (s, 3H); 13C NMR (75 MHz, DMSO-d6, ppm): δ = 169.4, 159.8, 147.9, 144.9,
141.0 (d, JC-F = 236.9 Hz), 130.4, 129.5, 121.6 (d, JC-F = 38.7 Hz), 118.3, 24.2; MS (ESI,
m/z,%) 326.1 ([M-1]+, 100); Anal. Calcd. for C12H10N3SFO5 (%): C 44.38, H 3.06, N
12.84; Found (%): C 44.35, H 3.14, N 13.00.
5-Fluoro-1-(4-(trifluoromethyl)phenylsulfonyl) pyrimidine-2,4(1H, 3H)-
dione (2i). Yield: 76%, mp: 205–206◦C; IR νmax (KBr)/cm−1 3488 (N H), 1663 (C O),
1388 (S O), 1176 (S O); 1H NMR (300 MHz, DMSO-d6, ppm): δ = 8.15 (d, J = 8.4 Hz,
2H), 7.99 (d, J = 8.4 Hz, 2H), 7.87 (d, J = 6.6 Hz, 1H); 13C NMR (75 MHz, DMSO-d6,
ppm): δ = 165.3 (d, JC-F = 16.8 Hz), 151.0, 142.5 (d, JC-F = 245.0 Hz), 142.4, 133.2
(q, JC-F = 31.7 Hz), 129.3, 126.3 (q, JC-F = 3.7 Hz), 125.2, 121.6, 119.2 (d, JC-F = 40.2
Hz); MS (ESI, m/z,%) 337.1 ([M-H]+, 100); Anal. Calcd. for C11H6N2SF4O4 (%): C
39.05, H 1.78, N 8.28; Found (%): C 39.11, H 1.73, N 8.28.
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