Synthesis and anticancer evaluation of vitamin K3 analogues

Article abstract of DOI:10.1016/S0960-894X(02)00532-2

Novel vitamin K₃ analogues were synthesized and evaluated for their anticancer activity. Compound 6, 9, 10, 11, 14, and (±)15 demonstrated a strong inhibitory activity against the tumor cells of A-549, Hep G2, MCF7, MES-SA, MES-SA/Dx5, MKN45, S

Full text of DOI:10.1016/S0960-894X(02)00532-2

Bioorganic & Medicinal Chemistry Letters 12 (2002) 2729–2732
Synthesis and Anticancer Evaluation of Vitamin K3 Analogues
Chinpiao Chen,a,* Yi-Zhong Liu,a Kak-Shan Shiab and Huan-Yi Tsengb
aDepartment of Chemistry, National Dong Hwa University, Shoufeng, Hualien 974, Taiwan, ROC
bDivision of Biotechnology and Pharmaceutical Research, National Health Research Insitutes,
1-F, 103, Lane 169, Kang Ning St., His Chih Cheng, Taipei Hsien 221, Taiwan, ROC
Received 8 May 2002; accepted 25 June 2002
Abstract—Novel vitamin K3 analogues were synthesized and evaluated for their anticancer activity. Compound 6, 9, 10, 11, 14, and
(Æ)15 demonstrated a strong inhibitory activity against the tumor cells of A-549, Hep G2, MCF7, MES-SA, MES-SA/Dx5,
MKN45, SW-480, and TW-039. Compound (Æ)15 displayed potent tumor cell cytotoxicity, and compound 14 selectively affected
MCF7, even though it did not influence normal cells Detroit551 and WI-38. Compound (Æ)15 inhibited MES-SA and MES-SA/
Dx5, and this specific result shows that compound (Æ)15 may become a good anticancer drug candidate.
# 2002 Elsevier Science Ltd. All rights reserved.
Many clinically successful anticancer drugs are either
natural products or have been developed from naturally
occurring lead compounds.1 Vitamin K3 1 (menadione,
2-methyl[1,4]naphthoquinoline) is currently attracting
much attention because of its interesting pharmaco-
logical activities.2À14 Vitamin K3 has been demonstrated
to exhibit inhibit growth and induce cell death in many
types of cells both in vitro15À19 and in vivo.20,21 Many
researchers have demonstrated that vitamin K3 induced
cell death is associated with apoptosis22À24 and over
expression of the c-myc gene,24 which is considered to
be closely related to apoptosis.25À27
Hep3B cells (Table 1), with compounds as shown in
Figure 1. Growth inhibitory activity declined as the
length of the side-chain increases. The presence of a
sulfur or an oxygen atom at the beginning of the ali-
phatic side-chain facilitated the growth inhibiting effect
of the compounds, as evident when comparing 2 (all-
carbon) with 3, 4, 5 (thioether) or with 6 (thioethanol)
or with 7, 8 (O-ether). The thioethanol derivative 6 was
the strongest analogue of all the compounds considered
in these studies. According to these studies and the
structure–activity relationships, thioether with
a
hydroxyl group must be involved in this series of ana-
logues. This study describes the synthesis and biological
evaluation of new vitamin K3 analogues.
The mechanism by which vitamin K3 inhibits growth
and kills cells is not well understood. Oxidative stress is
considered to be a mechanism of action of quinoid
compounds such as vitamin K3, since toxic oxygen spe-
cies can be generated during redox cycling which
involves the quinoid structures.28À31 Another possible
mechanism that determines the toxicity of vitamin K3
and related quinines is the direct arylation of cellar
thiols, leading to the depletion of glutathione and the
inhibition of sulfhydryl-dependent proteins.32À35
The compounds were prepared following the method of
Borovkov,36 that employed vitamin K3 as starting
material (Scheme 1).41 The National Health Research
Institute, Division of Biotechnology and Pharmaceu-
tical Research in Taiwan tested in vitro cytotoxicitiy
against eight human tumor cell lines and two normal
human cell lines (Table 2).19,37
The 2-hydroxyethylthio group on 2-(2-hydroxyethyl-
thio)-3-methyl[1,4]naphthoquinone 6 was investigated
with respect to the structure–activity relationships. The
carbon chain was extended from a two-methylene chain
to three-, four-, six- and 11-methylene chains, but the
cytotoxic assays revealed that two-, three-, and four-
methylene chains exhibit similar cytotoxic potency.
Carbon chains longer than a six-methylene chain (11
Nishikawa et al. studies of growth inhibition of hepa-
toma cells induced by vitamin K and its analogues9 have
demonstrated that a 50% growth inhibitory dose of
*Corresponding author. Tel.: +886-3-8663875; fax: +886-3-866-3875;
e-mail: chinpiao@mail.ndhu.edu.tw
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00532-2

2730
C. Chen et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2729–2732
Table 1. The growth inhibitory activity is shown as 50% growth
inhibitory dose (mM) for Hep3B cells
and 12) do not exhibit cytotoxic activity. Compound 17,
but with a phenyl group, also do not exhibit cytotoxic
activity. Consequently the binding affinity may be
influenced by the steric hindrance in that region. Two
hydroxyl groups and a carboxylic group were put on
compounds (Æ)16 and 13 to enhance the hydrophilic
effect but they do not exhibit cytotoxic activity. Sur-
prisingly, compound (Æ)15 exhibits strong cytotoxic
activity in relation to most tumor cell lines, except that
of nasopharyngeal carcinoma (IC50 12.52 mM) toward
which it is a little less potent. Comparing compound 6
with compound (Æ)15 reveals a methyl group that was
extended next to the hydroxyl group on compound
(Æ)15. This fine-tuning of the structure may reveal the
highly specific selectivity of the receptor. Compound 11
selectively and effectively inhibited MCF7 (breast ade-
nocarcinoma cell line), and did not influence Detroit551
(embryonic skin normal fibroblast) and WI-38 (normal
lung fibroblast). Drug resistance to a broad spectrum of
chemotherpeutic agents is a major obstacle in the clinical
treatment of human cancer.38À40 Compound (Æ)15 inhib-
ited MES-SA (a human uterine sarcoma cell line) and
MES-SA/Dx5 [a human MDR (multi-drug resistance)
uterine sarcoma cell line]. This specific result shows that
compound (Æ)15 may become a good anticancer drug.
Compd
1
2
3
4
5
6
7
8
ID50 (mM)
1078
14
15 05.160
55
140
Figure 1.
In summary, we have synthesized 2-(n-hydroxyalkyl-
thio)-3-methyl[1,4]naphthoquinones (6, 9, 10, 11, 14,
(Æ)15). These compounds demonstrated a strong
growth inhibitory activity against tumor cell lines.
Among them, (Æ)15 is the most potent with a mean
IC50 5.10 mM. Synthesis and evaluation other types of
heterocyclic analogues of (Æ)15 are currently under
investigation.
Acknowledgements
Scheme 1. Reagents and conditions: RSH, CuSO.45H2O, ethanol, rt,
30–50%.
The authors would like to thank the National Science
Council of the Republic of China for financially
Table 2. IC50(mM)a values of tumor cell lines after 72 h continuous exposure to test compounds 6, 9–17
Tumor type/cell line
6
9
10
11
14
(Æ)15
A-549b
>10
>10
9.53Æ0.15
5.16Æ0.28
>10
>10
>10
>10
>10
>104.74
>105.59
>104.61
>107.11
>105.10
Æ0.09
Æ0.12
Hep G2c
MCF7d
8.40Æ2.72
5.19Æ0.26
>10
Æ0.53
Æ0.22
5.78Æ0.15
9.28Æ3.32
MES-SAe
MES-SA/Dx5f
MKN45g
SW-480h
TW-039i
Detroit551j
WI-38k
>10
>10
>10
>10
Æ0.67
>10
>10
Æ0.31
5.16Æ0.27
5.14Æ0.09
>10
6.40Æ0.47
4.85Æ0.08
>10
6.78Æ0.55
4.51Æ0.10
>10
>105.64
>105.53
>10
>10
>10
3.92Æ0.30
5.19Æ0.27
>10
Æ0.02
>10
>104.61
>105.0
8.17Æ1.31
5.26Æ0.57
7.57Æ0.57
Æ0.24
7.37Æ0.09
>10
>10
6
Æ0.24
aIC50 is the concentration that induces 50% growth inhibition compared with untreated control cells.
bHuman lung carcinoma cell line.
cHuman liver hepatoblastoma cell line.
dMammary gland breast adenocarcinoma cell line.
eHuman uterine sarcoma cell line.
fHuman multidrug resistance uterine sarcoma cell line.
gHuman stomach adenocarcinoma cell line.
hHuman colon adenocarcinoma cell line.
iHuman nasopharyngeal carcinoma cell line.
jNormal human embryonic skin fibroblast cell line.
kNormal human lung fibroblast cell line.

C. Chen et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2729–2732
2731
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41. A typical synthesis of 6 is as follows: 2-Mercapto-ethanol
(1.5 mL, 21.4 mmol) was added to a solution of 2-methyl[1,4]-
naphthoquinone 1 (1 g, 5.8 mmol) in a mixture of methanol
(100 mL) and 2-propanol (80 mL). The reaction mixture was
stirred for 24 h at room temperature, poured into 300 mL of
water, and extracted using ether (3 Â 300 mL). The extract was
washed with a 10% CuSO4 solution, then water (3 Â 300 mL),
and dried over MgSO4. The solvent was removed by evapora-
tion to leave a brown residue. Purification by flash chromato-
graphy, using 30% ethyl acetate/hexanes to elute, yielded 0.7 g
of pure product of 2-(2-hydroxy-ethylthio)-3-methyl[1,4]-
naphthaquinone 6. Yield 47%; mp 79–80 ꢀC. 1H NMR
(300.1 MHz, CDCl3) d2.42 (s, 3H, CH3), 3.36 (t, 2H,
J=5.7 Hz, CH2), 3.81 (t, 2H, J=5.5 Hz, CH2), 7.71–7.75 (d,
2H, J=2.5 Hz, ArH), 8.07–8.11 (d, 2H, J=2.6 Hz, ArH). 13C
NMR (75.5 MHz, CDCl3) d15.6, 37.4, 62.0, 126.7, 126.9,
132.0, 132.6, 133.5, 133.9, 145.7, 148.3, 181.6, 182.3. IR (KBr)
3550, 3066, 2941, 2883, 1871, 1768, 1657, 791 cmÀ1. FABMS
m/z 249 (M++H). FABHRMS calcd for C13H13O3S
(M++H) 249.0586, found 249.0590. The same synthetic pro-
cedures were adopted for the preparation of 9–17. 9: Yield
38%; mp 49–50 ꢀC. 1H NMR (300.1 MHz, CDCl3) d1.90(t,
2H, J=6.4 Hz, CH2), 2.36 (s, 3H, CH3), 3.31 (t, 2H,
J=7.1 Hz, CH2), 3.81 (t, 2H, J=8.5 Hz, CH2), 7.80–7.83 (d,
2H, J=3.6 Hz, ArH), 8.05–8.12 (d, 2H, J=2.7 Hz, ArH). 13C
NMR (75.5 MHz, CDCl3) d15.4, 30.8, 33.0, 61.0, 126.6, 126.8,
132.1, 132.9, 133.4, 133.8, 146.6, 147.2, 181.4, 182.2. IR (KBr)
3298, 3184, 2947, 1984, 1957, 1716, 1652, 754 cmÀ1. FABMS
m/z 263 (M++H). FABHRMS calcd for C14H15O3S
(M++H) 263.0743, found 263.0750. 10: Yield 45%. Mp 75–
76 ꢀC. 1H NMR (300.1 MHz, CDCl3) d1.64–1.72 (m, 4H,
J=3.5 Hz, CH2), 2.36 (s, 3H, CH3), 3.25 (t, 2H, J=6.0Hz,
CH2), 3.67 (t, 2H, J=6.0Hz, CH 2), 7.61–7.73 (d, 2H,
J=6.0Hz, ArH), 8.04–8.10 (d, 2H, J=3.0Hz, ArH). 13C
NMR (75.5 MHz, CDCl3) d15.3, 27.1, 31.6, 34.1, 62.2, 126.6,
126.8, 132.2, 132.9, 133.4, 133.7, 146.8, 146.8, 181.5, 182.2. IR
(KBr) 3348, 3265, 3037, 3010, 2933, 2881, 2850, 1992, 1969,
23. McConkey, D. J.; Hartzell, P.; Nicotera, P.; Wyllie, A. H.;
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1716, 1662, 762 cmÀ1
.
FABMS m/z 277 (M++H).
FABHRMS calcd for C15H17O3S (M++H) 277.0899, found
277.0903. 11: Yield 48%; mp 69–70 ꢀC; 1H NMR (300.1 MHz,
CDCl3) d1.29–1.69 (m, 8H, J=6.0Hz, CH 2), 2.35 (s, 3H,
CH3), 3.21 (t, 2H, J=7.4 Hz, CH2), 3.63 (t, 2H, J=6.5 Hz,
CH2), 7.68–7.71 (d, 2H, J=4.5 Hz, ArH), 8.03–8.11 (d, 2H,
J=5.1 Hz, ArH); 13C NMR (75.5 MHz, CDCl3) d15.3, 25.3,
28.4, 30.6, 32.6, 34.3, 62.9, 126.6, 126.8, 132.1, 133.4, 133.7,
146.7, 147.1, 181.4, 182.3. IR (KBr) 3388, 3326, 3091, 2997,
2931, 2864, 1994, 1965, 1716, 1664, 789 cmÀ1. FABMS m/z
305 (M++H). FABHRMS calcd for C17H21O3S (M++H)

2732
C. Chen et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2729–2732
305.1212, found 305.1214. 12: Yield 8%; mp 71–72 ꢀC. 1H
NMR (300.1 MHz, CDCl3) d1.48–1.70(m, 18H, CH 2), 2.36 (s,
3H, CH3), 3.21 (t, 2H, J=7.2 Hz, CH2), 3.64 (t, 2H,
J=6.6 Hz, CH2), 7.69–7.72 (d, 2H, J=2.1 Hz, ArH), 8.06–8.11
(d, 2H, J=2.4 Hz, ArH). 13C NMR (75.5 MHz, CDCl3) d15.3,
15.3, 25.7, 28.8, 29.2, 29.4, 29.5, 29.6, 30.2, 32.8, 33.3, 63.1,
126.6, 126.8, 132.1, 132.8, 133.3, 133.6, 146.6, 147.3, 181.4,
182.3. IR (KBr) 3552, 3072, 2918, 2848, 1867, 1734, 1662,
795 cmÀ1. FABMS m/z 375 (M++H). FABHRMS calcd for
C22H31O3S 375.1995 (M++H), found 374.1995. 13: Yield
59%; mp 161–162 ꢀC. 1H NMR (300.1 MHz, CDCl3) d2.34 (s,
3H, CH3), 2.78 (t, 2H, J=7.5 Hz, CH2), 3.43 (t, 1H,
J=6.8 Hz, CH2), 7.71–7.82 (d, 2H, J=3.0Hz, ArH), 8.08–8.13
(d, 2H, J=2.1 Hz, ArH). 13C NMR (75.5 MHz, CDCl3) d15.4,
29.4, 35.2, 126.7, 126.9, 132.1, 132.9, 133.4, 133.8, 146.7, 147.2,
181.4, 182.2, 218.1. IR (KBr) 3028, 2914, 1967, 1869, 1826,
1714, 1662, 1589, 1562, 775 cmÀ1. FABMS m/z 277 (M++H).
FABHRMS calcd for C15H17O3S (M++H) 277.0899, found
277.0898. 14 (a mixture of isomers): Yield 11%; 1H NMR
(300.1 MHz, CDCl3) d1.21–1.27 (m, 6H, J=6.3 Hz, CH3), 2.44
(s, 3H, CH3), 3.84–3.90(m, 2H, J=3.0Hz, CH), 7.70–7.75 (d,
2H, J=1.7 Hz, ArH), 7.08–7.10 (d, 2H, J=2.8 Hz, ArH). 13C
NMR (75.5 MHz, CDCl3) d14.2, 15.6, 15.8, 50.7, 69.9, 126.7,
127.0, 132.1, 132.7, 133.6, 133.9, 145.7, 148.4, 181.6, 182.3. IR
(KBr) 2993, 2360, 2341, 1770, 1758, 1660, 844 cmÀ1. FABMS
m/z 277 (M++H). FABHRMS calcd for C15H17O3S
(M++H) 277.0899, found 277.0897. (Æ)15: Yield 43%; mp
39–40 ꢀC. 1H NHR (300.1 MHz, CDCl3) d1.27 (d, 3H,
J=6.2 Hz, CH3), 2.41 (s, 3H, CH3), 3.03–3.10 (q, 1H,
J=8.2 Hz, CH2), 3.34–3.40(dd, 1H, J1=12.0, 3.0 Hz CH2),
3.89 (m, 1H, J=3.6 Hz, CH), 7.69–7.72 (d, 2H, J=1.9 Hz,
ArH), 8.06–8.10 (d, 2H, J=2.7 Hz, ArH). 13C NMR
(75.5 MHz, CDCl3) d15.6, 22.2, 29.7, 67.3, 126.7, 127.0, 132.0,
132.6, 133.5, 133.8, 146.0, 148.2, 181.6, 182.3. IR (KBr) 3489,
3410, 3074, 2962, 2925, 2359, 1662, 1589, 746 cmÀ1. FABMS
m/z 263 (M++H). FABHRMS calcd for C15H17O3S
(M++H) 263.0743, found 263.0739. (Æ)16: Yield 73%; mp
117–118 ꢀC. 1H NMR (300.1 MHz, CDCl3) d2.03 (s, 3H,
CH3), 2.73 (dd, 1H, J=12.0, 1.8 Hz, CH2), 3.65 (dd, 1H,
J=12.0, 1.8 Hz, CH2), 4.40(dd, 1H, J=5.7, 1.5 Hz, CH2), 4.57
(dd, 1H, J=7.2, 1.2 Hz, CH2), 5.19 (q, 1H, J=1.6 Hz, CH),
7.50–7.67 (m, 3H, J=6.0Hz, ArH), 8.08 (dd, 1H, J=10.5,
0.9 Hz, ArH). 13C NMR (75.5 MHz, CDCl3) d12.1, 32.3, 69.1,
74.6, 126.4, 126.5, 129.5, 129.9, 131.2, 132.5, 138.6, 147.4,
180.2. IR (KBr) 3280, 3074, 2956, 2893, 1979, 1954, 1716,
1649, 762 cmÀ1. FABMS m/z 261 (M++H- 18). FABHRMS
calcd for C14H13O3S (M++H- 18) 261.0586, found 261.0578.
17: Yield 65%; mp 180–181 ꢀC; 1H NMR (300.1 MHz, CDCl3)
d2.35 (s, 3H, CH3), 6.78–6.81 (d, 2H, J=3.0Hz, ArH), 7.35–
7.38 (d, 2H, J=6.0Hz, ArH), 7.69–7.71 (d, 2H, J=3.0Hz,
ArH), 8.00–8.01 (d, 2H, J=0.3 Hz, ArH), 8.10–8.12 (d, 2H,
J=6.0Hz, ArH). 13C NMR (75.5 MHz, CDCl3) d15.7, 116.1,
116.4, 124.2, 126.7, 127.0, 128.0, 132.0, 132.3, 132.9, 133.8,
155.6, 156.0, 181.0, 183.2. IR (KBr) 3319, 3062, 3041, 3012,
2921, 2854, 1990, 1961, 1716, 1662, 786 cmÀ1. FABMS m/z
296 (M++1). FABHRMS calcd for C17H12O3S (M++H)
296.0508, found 296.0498.