Synthesis and antitumor activity of novel 1-(2′-alkyl(or phenyl)thioethoxy)methyl-5-fluorouracils and their oxidation products

Article abstract of DOI:10.1002/hc.20059

A series of novel 1-(2′-alkyl(or phenyl)-thioethoxy)methyl-5-fluorouracils (6) were synthesized in three steps from 5-fluorouracil. They were oxidized into sulfoxide (7) and sulfone (8) derivatives by NaIO₄ and H₂O₂ 30%/DEAD (diethyl azodicarboxylate), respectively, in high yields. In order to obtain structural information, sulfoxide 7g was characterized by X-ray diffraction analysis. The preliminary bioassay indicated that the compounds 6a and 7g exhibit potential antitumor activity.

Full text of DOI:10.1002/hc.20059

Heteroatom Chemistry
Volume 15, Number 7, 2004
Synthesis and Antitumor Activity of Novel
ꢀ
1-(2 -Alkyl(or phenyl)thioethoxy)methyl-
5-fluorouracils and Their Oxidation Products
Xue-Jun Liu,1 Ru-Yu Chen2 and Dong-Lu Bai1
1Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese
Academy of Science, 555 Zuchongzhi Road, Shanghai 201203, People’s Republic of China
2Institute and National Key Laboratory of Elemento-Organic Chemistry, Nankai University,
Tianjin 300071, People’s Republic of China
Received 20 May 2004; revised 6 September 2004
pyrimidine thionucleoside analogues also exhibit
ABSTRACT: A series of novel 1-(2ꢀ-alkyl(or phenyl)-
antitumor properties [3–5]. The introduction of a
thioethoxy)methyl-5-fluorouracils (6) were synthe-
single sulfur atom into the nucleosides led to the
sized in three steps from 5-fluorouracil. They were ox-
efficient antiviral or antitumor agents. For exam-
idized into sulfoxide (7) and sulfone (8) derivatives
ple, lamivudine ((−)-L-ꢀ-1,3-oxathiolanyl cytosine) is
by NaIO4 and H2O2 30%/DEAD (diethyl azodicarboxy-
used in the treatment of AIDS and chronic hepati-
late), respectively, in high yields. In order to obtain
tis B [6,7]; and 4ꢀ-thioFAC (1-(2-deoxy-2-fluoro-ꢀ-D-
structural information, sulfoxide 7g was characterized
4-thio-arabinopentofuranosyl) cytosine) is shown to
by X-ray diffraction analysis. The preliminary bioas-
be a promising orally active antitumor agent [8].
say indicated that the compounds 6a and 7g exhibit
The novel prodrug derivatives of 5-fluorouracil
ꢁ
C
potential antitumor activity.
2004 Wiley Periodicals,
(5-FU) were developed [9–12]. They possess a
broader spectrum of antitumor activity and lower
toxicity. Some of 5-FU acyclonucleosides exhibited
potential antitumors activity [13,14]. There has been
little research done on the 5-FU acyclic thionu-
cleoside. As part of our research program [15,16],
we synthesized the title compounds, 1-(2ꢀ-alkyl(or
phenyl)thioethoxy)methyl-5-fluorouracils, 6, and
their oxidation products 7, 8. The synthetic route is
shown in Scheme 1.
Inc. Heteroatom Chem 15:543–548, 2004; Published online
in Wiley InterScience (www.interscience.wiley.com). DOI
10.1002/hc.20059
INTRODUCTION
A large number of sulfur nucleosides, nucleotides,
and oligonucleotides were synthesized for the pur-
pose of finding new chemical therapeutic agents and
biological tools. Some of them were developed as
important tools in the study of protein and nucleic
acid structures, functions and interactions, and an-
tisense modulation of gene expression [1,2]. Many
RESULTS AND DISCUSSION
Synthesis of 1-(2ꢀ-Alkyl(or phenyl)thioethoxy)-
methyl-5-fluorouracils (6), 1-(2ꢀ-Alkyl(or
phenyl)sulfinylethoxy)methyl-5-fluorouracils
(7), and 1-(2ꢀ-Alkyl(or phenyl)sulfonylethoxy)-
methyl-5-fluorouracils (8)
Correspondence to: Xue-Jun Liu; e-mail: liuxuejun88@yahoo.
com.cn.
Contract grant sponsor: National Natural Science Foundation
of China.
Contract grant number: 20172027.
5-Fluorouracil (1) reacted with hexamethyldisily-
lazane (HMDS) by means of an improved procedure
c
ꢁ
2004 Wiley Periodicals, Inc.
543

544 Liu, Chen, and Bai
SCHEME 1
1
of the literature [17] to give 2,4-di(trimethylsilyloxy)-
5-fluoropyrimidine 2. According to the standard
chloromethyl ether method [18], the condensation
of 2 with 2-(chloromethoxy)ethyl chloride 4, ob-
tained from 2-chloroethanol (3), gave the key inter-
mediate 5 (79% yield) in the presence of anhydrous
K2CO3. The compounds 6a–g were obtained by the
method for synthesis of unsymmetrical thioethers
(NaH/RSH, THF) in yields of 93–98%; a slight ex-
cess of aqueous NaIO4 [19] was added to a solution of
compounds 6 in ethanol to afford compounds 7. The
resultant 7 were oxidized by 30% H2O2 to produce
the sulfone derivatives 8 at very slow rates. However,
when DEAD (EtO2CN NCO2Et) was added to this
system, the reaction was considerably accelerated to
give 8 in high yields. The investigation of this reac-
tion mechanism is under progress. The compounds
8 have also been obtained directly by oxidation of 6
with H2O2 30%/DEAD (Scheme 2).
In the H NMR spectra of the title compounds
(6–8), the methylene protons of the methoxy appear
as a set of characteristic singlet peak in the range of
δ 5.10–5.19. The protons of the ethylene group ex-
hibit two sets of peaks at δ 2.66–3.09 and 3.69–3.73
(sulfides), 2.86–2.92 and 4.01–4.10 (sulfoxides), and
3.16–3.42 and 3.89–4.05 (sulfones). The hydrogens of
another methylene (or methyl) linking with the sul-
fur atom display in the range of δ 2.09–2.53 (sulfides),
2.64–2.76 (sulfoxides), and 2.95–3.08 (sulfones). The
1H NMR spectrum also reveals two sets of peaks at
δ 7.36–7.42 (doublet), 8.98–9.90 (singlet), support-
ing the 5-fluorouracil structure. The IR spectra of
compounds (6–8) showed normal stretching absorp-
tion bands indicating the existence of the groups NH
(∼3400 cm−1), C O (1694–1741), C C (1654–1685),
S O (1037–1052), O S O (1160–1182, 1320–1349),
C O C (1115–1139).
The Molecular Structure and Crystal Structure
of Compound 7g
The Structure of Products
1
All compounds 6–8 have been characterized by H
In order to obtain information about the molecu-
lar structure of the compound 7g, a single crystal
of this compound was analyzed by X-ray diffrac-
tion. The colorless crystal of 7g, C13H15FN2O5S
(C13H13FN2O4S·H2O), was obtained by evaporating
from its saturated methanol solution. A crystal with
the size of 0.25 × 0.15 × 0.05 mm3 was examined
on a Bruker Smart 1000 four-circle diffractome-
NMR, elemental analysis, and IR. Some of the ex-
perimental results of compounds 6–8 were listed in
Tables 1 and 2.
˚
SCHEME 2
ter with Mo Kꢁ radiation (ꢂ = 0.71073 A). The

Synthesis and Antitumor Activity of Novel 1-(2ꢀ-Alkyl(or phenyl)thioethoxy)methyl-5-fluorouracils 545
TABLE 1 The Physical Constants and Elementary Analyses of Compounds 6a–g, 7a–g, and 8a–g
IR (v, cm−1
NH C O C C S O (or O S O) C O C Yield (%) mp ( ◦C)
)
Elementary Analysis (Calcd.%)
No.
R
C
H
N
6a
6b
6c
6d
6e
6f
6g
7a
7b
7c
7d
7e
7f
Me
Et
Pr
3419 1696 1657
3420 1694 1655
3410 1703 1654
3418 1697 1654
–
–
–
–
–
–
–
1042
1046
1045
1052
1045
1046
1037
1120
1129
1130
1115
1122
1120
1132
1120
1120
1131
1138
1132
1132
1138
1123
1125
1125
1125
1131
1139
1136
96
95
97
93
94
91
94
95
90
94
95
89
88
83
89
90
94
91
85
78
86
74–75 44.08(44.31) 5.46(5.59) 12.74(12.95)
59–60 46.57(46.94) 6.00(6.13) 11.82(12.16)
61–62 49.16(49.16) 6.52(6.60) 11.69(11.47)
54–55 51.12(51.14) 7.15(7.02) 10.95(10.84)
56–57 52.77(52.92) 7.33(7.40) 10.06(10.29)
72–73 61.30(61.59) 9.09(9.25) 8.00(7.56)
92–93 52.42(52.69) 4.32(4.42) 9.51(9.45)
112–113 41.67(41.37) 4.91(5.21) 12.10(12.06)
120–121 43.78(43.89) 5.65(5.73) 11.31(11.37)
108–109 46.26(46.14) 6.18(6.20) 10.44(10.76)
104–105 48.07(48.16) 6.56(6.61) 10.24(10.21)
96–97 50.03(49.98) 6.63(6.99) 9.52(9.71)
91–92 58.88(59.04) 8.67(8.86) 7.14(7.25)
83–84 49.59(49.99) 4.19(4.33) 8.78(8.97)
159–160 38.94(38.70) 4.86(4.88) 11.16(11.29)
101–102 41.10(41.21) 5.25(5.38) 10.36(10.68)
83–84 43.61(43.47) 5.63(5.84) 10.01(10.14)
74–75 45.89(45.54) 6.36(6.25) 9.70(9.66)
130–131 47.02(47.35) 6.50(6.62) 9.16(9.20)
128–129 56.85(56.69) 8.47(8.51) 6.66(6.96)
134–135 50.48(50.56) 4.24(4.50) 9.06(8.99)
Bu
Pent 3432 1740 1684
12H25 3422 1734 1682
C6H5 3398 1741 1668
Me
Et
Pr
Bu
Pent 3440 1712 1682
12H25 3418 1719 1670
C6H5 3428 1719 1669
Me
Et
Pr
Bu
C
3419 1714 1670
3414 1710 1665
3430 1718 1672
3428 1709 1670
C
7g
8a
8b
8c
8d
8e
8f
3430 1705 1655 1165
1321
3409 1732 1654 1178
3450 1724 1667 1160
3438 1711 1685 1169
1325
1325
1320
1334
1325
1349
Pent 3401 1735 1671 1162
12H25 3455 1709 1680 1170
C6H5 3418 1712 1665 1182
C
8g
compound 7g crystallized in the orthorhombic space
Biological Assays
˚
group Pca2 with cell dimensions a = 12.878(3) A,
The preliminary biological activities were deter-
mined for the title compounds 6–8. The anticancer
activities given in Table 5 indicate that compound 6a
has potential inhibitory activities on P-388 (lympho-
cytic leukemia) and A-549 (human lung carcinoma)
cell lines. Compound 7g also has inhibiting activities
on the A-549 cell lines.
◦
◦
3
˚
˚
b = 15.379(3) A, c = 7.6570(15) A, ꢁ = 90 , ꢀ = 90 ,
◦
3
˚
ꢃ = 90 , 1516.5(5) A , Z = 4, and Dc = 1.447 Mg/m .
The structure was solved by the direct method and re-
fined by the full-matrix least squares on F2, and the fi-
nal crystallographic discrepancy (see Tables 3 and 4).
The structure of compound 7g is shown in the Fig. 1.
In the crystal cell (Fig. 2), there are two kinds of
intermolecular hydrogen bonds. One forms between
the O atom of sulfinyl group and the hydrogen atom
of the imino group at the 3-position of 5-fluorouracil,
the other between the O atom of the carbonyl group
at the 4-position of 5-fluorouracil and the hydrogen
atom of H2O molecule.
EXPERIMENTAL
Elemental analyses were performed with a Chn-
corderd MT-3 elementary analyzer. NMR spectra
were recorded with a Bruker AC-P200 spectrome-
ter with TMS as the internal reference and CDCl3 as
the solvent. IR spectra were obtained on Shimadzu-
435. Melting points were determined with a Thomas–
Hoover melting point apparatus and are uncor-
rected. Column chromatography was performed on
silica gel GF254 (Qing dao Hai yang Chemical Group
Co. of China).
2-(Chloromethoxy)ethyl Chloride (4)
A suspension of 0.65 g (10 mmol) 2-chloroethanol
and 0.70 g of paraformaldehyde in 18 mL of dry
methylene chloride was cooled to 0◦C. Dry hydrogen
chloride was bubbled through the stirred suspension
for 3 h until saturated. The mixture was allowed
FIGURE 1 Molecular structure of compound 7g.

546 Liu, Chen, and Bai
TABLE 2 The 1H NMR Data (δ) of Compound 6a–g, 7a–g, and 8a–g
No
1H NMR (ppm)
6a
2.09 (s, 3H, CH3S) 2.66 (t, 2H, 3 J HCCH = 6.2 Hz, SCH2CH2O) 3.73 (t, 2H, 3 J HCCH = 6.2 Hz, SCH2CH2O) 5.16 (s,
2H, OCH2O) 7.42 (d, 1H, 3 J HCCF = 5.2 Hz, CF CHN) 9.90 (s, 1H, CONH)
6b
6c
1.22 (t, 3H, 3 J HCCH = 7.4 Hz, CH3CH2) 2.53 (q, 2H, 3 J HCCH = 7.4 Hz, CH2S) 2.70 (t, 2H, 3 J HCCH = 6.5 Hz,
SCH2CH2O) 3.72 (t, 2H, 3 J HCCH = 6.5 Hz, SCH2CH2O) 5.16 (s, 2H, OCH2O) 7.40 (d, 1H, 3 J HCCF = 5.2 Hz,
CF CHN) 9.45 (s, 1H, CONH)
0.95 (t, 3H, 3 J HCCH = 7.3 Hz, CH3CH2) 1.58 (m, 2H, CH3CH2) 2.47 (t, 2H, 3 J HCCH = 7.5 Hz, CH2S) 2.68 (t, 2H,
3 J HCCH = 6.7 Hz, SCH2CH2O) 3.71 (t, 2H, 3 J HCCH = 6.7 Hz, SCH2CH2O) 5.15 (s, 2H, OCH2O) 7.40 (d, 1H,
3 J HCCF = 5.2 Hz, CF CHN) 9.45 (s, 1H, CONH)
6d
6e
6f
0.89 (t, 3H, 3 J HCCH = 6.9 Hz, CH3CH2) 1.28–1.65 (m, 4H, 2×CH2) 2.52 (t, 2H, 3 J HCCH = 7.3 Hz, CH2S) 2.69 (t, 2H,
3 J HCCH = 6.0 Hz, SCH2CH2O) 3.73 (t, 2H, 3 J HCCH = 6.0 Hz, SCH2CH2O) 5.16(s, 2H, OCH2O) 7.40 (d, 1H,
3 J HCCF = 5.2 Hz, CF CHN) 9.31 (s, 1H, CONH)
0.86 (t, 3H, 3 J HCCH = 6.9 Hz, CH3CH2) 1.23–1.66 (m, 6H, 3×CH2) 2.50 (t, 2H, 3 J HCCH = 7.4 Hz, CH2S) 2.68(t, 2H,
3 J HCCH = 6.7 Hz, SCH2CH2O) 3.71 (t, 2H, 3 J HCCH = 6.7 Hz, SCH2CH2O) 5.17 (s, 2H, OCH2O) 7.39 (d, 1H,
3 J HCCF = 5.2 Hz, CF CHN) 9.28(s, 1H, CONH)
0.85 (t, 3H, 3 J HCCH = 7.1 Hz, CH3CH2) 1.19–1.62 (m, 20H, 10×CH2) 2.50 (t, 2H, 3 J HCCH = 7.4 Hz, CH2S) 2.68 (t,
2H, 3 J HCCH = 6.3 Hz, SCH2CH2O) 3.69 (t, 2H, 3 J HCCH = 6.3 Hz, SCH2CH2O) 5.15 (s, 2H, OCH2O) 7.39 (d, 1H,
3 J HCCF = 5.2 Hz, CF CHN) 9.18 (s, 1H, CONH)
6g
7a
3.09 (t, 2H, 3 J HCCH = 6.2 Hz, SCH2CH2O) 3.73 (t, 2H, 3 J HCCH = 6.2 Hz, SCH2CH2O) 5.10 (s, 2H, OCH2O)
7.05–7.34 (m, 6H, CF CHN + C H5) 9.30 (s, 1H, CONH)
2.64 (s, 3H, CH3SO) 2.92 (m, 2H, 6OSCH2CH2O) 4.03 (m, 2H, OSCH2CH2O) 5.15 (s, 2H, OCH2O) 7.37 (d, 1H,
3 J HCCH = 5.2 Hz, CF CHN) 8.98 (s, 1H, CONH)
7b
7c
7d
7e
7f
1.31 (t, 3H, 3 J HCCH = 7.1 Hz, CH3CH2) 2.76 (m, 2H, CH2SO) 2.88 (m, 2H, OSCH2CH2O) 4.01 (m, 2H,
OSCH2CH2O) 5.19 (s, 2H, OCH2O) 7.38 (d, 1H, 3 J FCCH = 5.2 Hz, CF CHN) 9.18 (s, 1H, CONH)
1.06 (t, 3H, 3 J HCCH = 7.5 Hz, CH3CH2) 1.74 (m, 2H, CH3CH2) 2.75 (m, 2H, CH2SO) 2.89 (m, 2H, OSCH2CH2O)
4.02 (m, 2H, OSCH2CH2O) 5.16 (s, 2H, OCH2O) 7.39(d, 1H, 3 J FCCH = 5.2 Hz CF CHN) 9.50 (s, 1H, CONH)
0.92 (t, 3H, 3 J HCCH = 7.5 Hz, CH3CH2) 1.30–1.81 (m, 4H, 2×CH2) 2.73 (m, 2H, CH2SO) 2.86 (m, 2H, OSCH2CH2O)
4.01 (m, 2H, OSCH2CH2O) 5.19 (s, 2H, OCH2O) 7.38 (d, 1H, 3 J FCCH = 5.1 Hz, CF CHN) 9.36 (s, 1H, CONH)
0.87 (t, 3H, 3 J HCCH = 6.9 Hz, CH3CH2) 1.37–1.74 (m, 6H, 3×CH2) 2.76 (m, 2H, CH2SO) 2.88 (m, 2H, OSCH2CH2O)
4.03 (m, 2H, OSCH2CH2O) 5.19 (s, 2H, OCH2O) 7.38 (d, 1H, 3 J FCCH = 5.1 Hz, CF CHN) 9.53 (s, 1H, CONH)
0.82 (t, 3H, 3 J HCCH = 6.8 Hz, CH3CH2) 1.24–1.78 (m, 20H, 10×CH2) 2.70 (m, 2H, CH2SO) 2.89 (m, 2H,
OSCH2CH2O) 4.02 (m, 2H, OSCH2CH2O) 5.19 (s, 2H, OCH2O) 7.38 (d, 1H, 3 J FCCH = 5.2 Hz, CF CHN) 9.23 (s,
1H, CONH)
7g
8a
8b
3.01 (m, 2H, 3 J HCCH = 6.2 Hz, OSCH2CH2O) 3.89 (m, 1H, OSCH2CHHO) 4.10 (m, 1H, OSCH2CHHO) 5.13 (s, 2H,
OCH2O) 7.39 (d, 1H, 3 J FCCH = 5.2 Hz, CF CHN) 7.48–7.60 (m, 5H, C6H5) 9.80 (s, 1H, CONH)
2.95 (s, 3H, CH3SO2) 3.31 (t, 2H, 3 J HCCH = 5.5 Hz, O2SCH2CH2O) 3.89 (t, 2H, 3 J HCCH = 5.5 Hz, O2SCH2CH2O)
5.15 (s, 2H, OCH2O) 7.39 (d, 1H, 3 J FCCH = 5.1 Hz, CF CHN) 9.32 (s, 1H, CONH)
1.35 (t, 3H, 3 J HCCH = 7.2 Hz, CH3CH2) 3.01 (q, 2H, 3 J HCCH = 7.2 Hz, CH2SO2) 3.16 (t, 2H, 3 J HCCH = 5.9 Hz,
O2SCH2CH2O) 4.01 (t, 2H, 3 J HCCH = 5.9 Hz, O2SCH2CH2O) 5.16 (s, 2H, OCH2O) 7.39 (d, 1H, 3 J FCCH = 5.0 Hz,
CF CHN) 9.34 (s, 1H, CONH)
8c
8d
8e
8f
1.04 (t, 3H, 3 J HCCH = 7.8 Hz, CH3CH2) 1.86 (m, 2H, CH3CH2) 3.05 (t, 2H, 3 J HCCH = 7.9 Hz, CH2SO2) 3.28 (t, 2H,
3 J HCCH = 5.9 Hz, O2SCH2CH2O) 4.03 (t, 2H, 3 J HCCH = 5.9 Hz, O2SCH2CH2O) 5.16 (s, 2H, OCH2O) 7.39 (d, 1H,
3 J FCCH = 5.2 Hz, CF CHN) 9.29 (s, 1H, CONH)
0.98 (t, 3H, 3 J HCCH = 7.6 Hz, CH3CH2) 1.39–1.91 (m, 4H, 2×CH2) 3.08 (t, 2H, 3 J HCCH = 7.2 Hz, CH2SO2) 3.22 (t,
2H, 3 J HCCH = 6.8 Hz, O2SCH2CH2O) 4.05 ((t, 2H, 3 J HCCH = 6.8 Hz, O2SCH2CH2O) 5.17 (s, 2H, OCH2O) 7.37 (d,
1H, 3 J FCCH = 5.2 Hz, CF CHN) 9.18(s, 1H, CONH)
0.85 (t, 3H, 3 J HCCH = 7.6 Hz, CH3CH2) 1.40–1.88 (m, 6H, 3×CH2) 3.02 (t, 2H, 3 J HCCH = 7.4 Hz, CH2SO2) 3.25 (t,
2H, 3 J HCCH = 6.5 Hz, O2SCH2CH2O) 4.02 (t, 2H, 3 J HCCH = 6.5 Hz, O2SCH2CH2O) 5.19 (s, 2H, OCH2O) 7.39 (d,
1H, 3 J FCCH = 5.2 Hz, CF CHN) 9.25 (s, 1H, CONH)
0.80 (t, 3H, 3 J HCCH = 7.2 Hz, CH3CH2) 1.26–1.89 (m, 20H, 10×CH2) 3.05 (t, 2H, 3 J HCCH = 7.4 Hz, CH2SO2) 3.23 (t,
2H, 3 J HCCH = 6.2 Hz, O2SCH2CH2O) 4.02 (t, 2H, 3 J HCCH = 6.2 Hz, O2SCH2CH2O) 5.17 (s, 2H, OCH2O) 7.36 (d,
1H, 3 J FCCH = 5.3 Hz, CF CHN) 9.39 (s, 1H, CONH)
8g
3.42 (m, 2H, O2SCH2CH2O) 4.04 (m, 2H, O2SCHCH2O) 5.19 (s, 2H, OCH2O) 7.36 (d, 1H, 3 J FCCH = 5.3 Hz,
CF CHN) 7.55–7.90 (m, 5H, C6H5) 9.88 (s, 1H, CONH)

Synthesis and Antitumor Activity of Novel 1-(2ꢀ-Alkyl(or phenyl)thioethoxy)methyl-5-fluorouracils 547
FIGURE 2 Molecular packing of compound 7g in unit cell.
78%); mp 103–104◦C; 1H MNR (CDCl3, δ). 3.61 (t, 2H,
J = 5.6 Hz) 3.86 (t, 2H, J = 5.6 Hz) 5.19 (s, 2H) 7.41
(d, 1H, J = 5.2 Hz) 9.76 (s, 1H).
to stand in a refrigerator overnight and then dried
over anhydrous CaCl2. It was filtered and the sol-
vent removed under reduced pressure to give an oily
residue, which was used directly in the next step
to prepare 1-(2ꢀ-chloroethoxy)methyl-5-fluorouracil
(5).
1-(2ꢀ-Alkyl(or phenyl)thioethoxy)methyl-
5-fluorouracils (6)
To a suspension of 0.312 g (6.5 mmol) of 50% NaH
in THF (15 mL) was added dropwise 6 mmol of HSR
(or PhSH) at 0◦C. The reaction mixture was warmed
to room temperature and stirred for 2 h, and then
0.67 g (3 mmol) of 5 was added to the reaction mix-
ture and stirring was continued for 5 h. The resul-
tant mixture was adjusted to pH 6–7 with 1 M HCl
and extracted with CHCl3 (3 × 50 mL). The organic
layers were combined and dried over MgSO4. The
solvent was removed in vacuo, and the residue was
then purified by flash chromatography on silica gel
(CHCl3:CH3OH = 20:1) to give 6. The appropriate
experimental data are listed in Tables 1 and 2.
When R CH3, chloride 5 was added to a solution
of NaSCH3 (5 mL), the mixture was stirred over 8 h,
and then adjusted to pH 7. The reaction mixture was
extracted with chloroform (3 × 50 mL). The organic
phases were combined and dried over MgSO4. The
solvent was removed in vacuo, and the residue was
then purified by flash chromatography on silica gel
(CHCl3:CH3OH = 20:1) to give 6a. The appropriate
experimental data are listed in Tables 1 and 2.
1-(2ꢀ-Chloroethoxy)methyl-5-fluorouracil (5)
To a mixture of 5-fluorouracil (10 mmol, 1.30 g) and
hexamethyldisilazane (4 mL) was added trimethylsi-
lyl chloride (1 mL). The resultant suspension was re-
fluxed for 3 h. The excess hexamethyldisilazane was
removed from the reaction mixture in vacuo to give
the crude silylation product of 5-fluorouracil as a
solid, which was used in the next step without further
purification.
A suspension of 0.2 g of anhydrous K2CO3 and
1.29 g (10 mmol) of ClCH2OCH2CH2Cl in 15 mL
of dry CH2Cl2 was stirred at room temperature for
5 min under N2 atmosphere. The crude silylation
product of 5-fluorouacil was added into this system.
The mixture was stirred overnight at room temper-
ature. The resultant reaction mixture was adjusted
to pH 7 with 0.1 M HCl and extracted with chloro-
form (3 × 60 mL). The organic extracts were com-
bined and dried over MgSO4 and concentrated in
vacuo. The residue was purified by silica gel flash
chromatography to give 5 as a white solid (1.74 g,
˚
TABLE 3 Selected Bond Lengths (A) of Compound 7g
S(1) O(1)
F(1) C(6)
N(1) C(7)
C(6) C(7)
N(2) C(4)
C(12) C(13)
O(2) C(2)
C(15) C(16)
1.507(2)
1.351(4)
1.372(5)
1.325(5)
1.371(4)
1.377(6)
1.430(4)
1.402(7)
O(4) C(5)
S(1) C(1)
C(5) C(6)
N(1) C(3)
C(11) C(16)
O(2) C(3)
C(14) C(15)
1.216(4)
1.809(4)
1.434(5)
1.467(4)
1.383(5)
1.387(4)
1.369(8)
S(1) C(11)
C(1) C(2)
N(1) C(4)
C(11) C(12)
N(2) C(5)
C(13) C(14)
O(3) C(4)
1.788(4)
1.508(5)
1.382(4)
1.376(6)
1.376(4)
1.360(7)
1.223(4)

548 Liu, Chen, and Bai
TABLE 4 Selected Bond Angles (◦) of Compound 7g
O(1) S(1) C(11)
N(2) C(5) C(6)
C(7) N(1) C(4)
F(1) C(6) C(5)
C(4) N(2) C(5)
C(12) C(11) S(1)
O(2) C(2) C(1)
C(14) C(13) C(12)
O(3) C(4) N(1)
C(11) C(16) C(15)
106.75(17)
112.3(3)
121.0(3)
115.2(3)
127.5(3)
121.1(3)
106.9(3)
119.8(5)
122.4(3)
118.2(5)
O(4) C(5) C(6)
C(11) S(1) C(1)
C(7) C(6) C(5)
C(4) N(1) C(3)
C(12) C(11) C(16)
C(2) C(1) S(1)
C(11) C(12) C(13)
O(3) C(4) N(2)
C(14) C(15) C(16)
O(4) C(5) N(2)
126.5(3)
98.51(15)
122.7(3)
120.4(3)
120.9(4)
110.9(2)
119.9(4)
122.1(3)
119.9(5)
121.2(3)
O(1) S(1) C(1)
C(7) C(6) F(1)
C(7) N(1) C(3)
C(6) C(7) N(1)
C(3) O(2) C(2)
C(16) C(11) S(1)
O(2) C(3) N(1)
C(13) C(14) C(15)
N(2) C(4) N(1)
104.70(15)
122.0(3)
118.6(3)
120.9(3)
113.5(2)
117.9(3)
113.5(3)
121.2(5)
115.4(3)
TABLE 5 Inhibitory Effects of Compounds 6–8 (10−5 M) on Cell Lines P-388 and A-549
Compounds 6a 6b 6c 6d 6e 6f 6g 7a 7b 7c 7d 7e 7g 8a 8b 8c 8d 8e 8f 8g
Inhibition rate 86 64 59 71 63 74 60 49 37 31 22 35 69 40 32 25 19 34 21 49
(P-388) (%)
Inhibition rate 89 71 73 58 65 55 51 43 56 62 36 57 87 53 18 36 45 26 29 53
(A-549) (%)
1-(2ꢀ-Alkyl(or phenyl)sulfinylethoxy)methyl-
5-fluorouracils (7)
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0.5 mL of 30% H2O2 and 1.2 mmol of DEAD (di-
ethyl azodicarboxylate) were added to a solution
of 1 mmol of compounds 7 in THF (5 mL). The
mixture was stirred at 50–55◦C for 2 h. Additional
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