Synthesis of C4-fluorinated solamins and their growth inhibitory activity against human cancer cell lines

Article abstract of DOI:10.1016/j.bmcl.2008.10.069

C4-Fluorinated analogues of solamin, an antitumor acetogenin, were synthesized and investigated for their antitumor activities against 39 tumor cell lines. C4-Fluorinated solamins showed more potent growth inhibitory activity against cancer cell lines tha

Full text of DOI:10.1016/j.bmcl.2008.10.069

Bioorganic & Medicinal Chemistry Letters 18 (2008) 6451–6453
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of C4-fluorinated solamins and their growth inhibitory activity
against human cancer cell lines
Naoto Kojima a, Hiromi Hayashi a, Satoshi Suzuki a, Hiroaki Tominaga a, Naoyoshi Maezaki b,
c
Tetsuaki Tanaka a, , Takao Yamori
*
a Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
b Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-Kita, Tondabayashi, Osaka 584-8540, Japan
c Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koutou-ku, Tokyo 135-8550, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
C4-Fluorinated analogues of solamin, an antitumor acetogenin, were synthesized and investigated for
their antitumor activities against 39 tumor cell lines. C4-Fluorinated solamins showed more potent
growth inhibitory activity against cancer cell lines than solamin.
Received 11 August 2008
Revised 8 October 2008
Accepted 16 October 2008
Available online 19 October 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Annonaceous acetogenins
Fluorinated analogues
Antitumor agents
Structure–activity relationships
Annonaceous acetogenins are polyketides isolated from Annona-
ceae species growing in the tropics. Most acetogenins are charac-
terized by one to three tetrahydrofuran (THF) ring(s) with
various stereochemistries at the center of a long hydrocarbon chain
against human cancer cell lines greatly differs in spite of their
structural similarity. We have also examined in detail the growth
inhibitory activity of our synthetic samples against 39 human can-
cer cell lines. Murisolin showed 400 times stronger growth inhib-
itory activity against the human lung cancer cell line, DMS114,
than solamin. It is well known that fluorine atom mimics hydrogen
atom. Substitution of the hydroxyl group of biologically active
compounds with an isoelectronic function, fluorine, produced
more potent analogues.7 Therefore, we were interested in whether
C4-fluorinated solamin (1) showed similar activity to solamin or
murisolin. Herein we describe the synthesis of C4-fluorinated
having an a,b-unsaturated c-lactone moiety at the end. More than
400 acetogenins have been isolated and they exhibit a broad range
of biological activities, including immunosuppressive, pesticidal,
and antitumor activities.1 Regarding their antitumor activity, they
have been shown to function by blocking NADH-ubiquinone oxido-
reductase (complex I) in mitochondria. This leads to depletion of
ATP and subsequent apoptosis.2 Many researchers are engaged in
the synthesis of natural acetogenins due to their attractive biolog-
ical activities and unique structural features.3 The synthesis and
evaluation of acetogenin analogues have also been reported.4 Fluo-
rination of biologically active natural products is known to some-
times enhance the activity. Because of this, in medicinal
chemistry, the fluorination of such compounds is often designed.5
However, to our knowledge, the synthesis of fluorinated acetoge-
nins has not been reported so far. Because we are very interested
in the bioactivity of fluorinated acetogenins, we planned the syn-
thesis of C4-fluorinated solamin (1). Solamin, a threo/trans/threo-
type mono-THF ring acetogenin, was isolated from Annona muri-
cata (Fig. 1).6 Murisolin, a C4-hydroxyl solamin, was also isolated
from the same plant. Interestingly, their growth inhibitory activity
Me
R
O
n-C12H25
HO
O
OH
R = H; solamin
R = OH; murisolin
O
O
Me
F
n-C12H25
HO
O
O
OH
C4-fluorinated solamin (1)
* Corresponding author.
E-mail address: t-tanaka@phs.osaka-u.ac.jp (T. Tanaka).
Figure 1. Design of C4-fluorinated solamin.
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.10.069

6452
N. Kojima et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6451–6453
solamins and the evaluation of their growth inhibitory activity
against 39 tumor cell lines.
known
tioselective
The preparation of fluorinated
rized in Scheme 2. Enantioselective a
a
-sulfenyl-
-fluorination of known aldehyde (6) (Scheme 1).10
-lactone segment (3) is summa-
-fluorination of known
c
-lactone (5)9 with iodide (4) prepared by enan-
a
C4-Fluorinated solamin (1) was prepared by Sonogashira cou-
c
pling of THF-ring segment (2)8 with fluorinated
c
-lactone segment
(3). Fluorinated segment (3) was synthesized by
a
-alkylation of
aldehyde (6) was accomplished with MacMillan’s conditions
(N-fluorobenzenesulfonimide (NFSI), (R)-5-benzyl-2,2,3-trimethyl-
imidazolidin-4-one dichloroacetic acid salt),11 and the resulting
Me
a-fluoroaldehyde was immediately reduced to give b-fluoroalcohol
F
n-C12H25
TBSO
1
+
I
O
O
OH
O
2
3
Table 1
GI50 values of C4-fluorinated solamins (1 and 12), solamin, and murisolin against 39
human tumor cell lines.
Me
a
F
Human tumor cell line
Compound/Growth inhibitory activity (GI50 in
l
M)
I
+
O
CHO
I
I
1
12
Solamin
Murisolin
PhS
6
O
Breast
HBC-4
BSY-1
HBC-5
4
5
>100
>100
>100
56
>100
69
>100
37
>100
>100
>100
71
>100
8.3
9.7
Scheme 1. Retrosynthesis of C4-fluorinated solamin (1).
MCF-7
3.9
MDA-MB-231
>100
>100
>100
>100
CNS
U251
>100
>100
37
>100
84
>100
>100
31
>100
58
>100
>100
40
>100
>100
>100
>100
>100
7.3
88
39
SF-268
SF-295
SF-539
SNB-75
SNB-78
F
F
i, ii
iii
I
CHO
I
OH
I
I
6
7
4
Me
Me
>100
>100
78
F
F
iv
v, vi
Colon
I
O
I
O
HCC2998
KM-12
HT-29
>100
>100
>100
>100
2.0
>100
>100
92
>100
27
>100
>100
>100
>100
>100
>100
>100
>100
51
PhS
8
O
O
3
HCT-15
HCT-116
Scheme 2. Reagents and conditions: (i) NFSI, (R)-5-benzyl-2,2,3-trimethylimidaz-
olidin-4-one dichloroacetic acid salt, THF–i-PrOH, À10 °C; (ii) NaBH4, CH2Cl2–EtOH,
rt, 53% (>98% ee) in two steps; (iii) I2, PPh3, DMF, 60 to 100 °C, 90%; (iv) 5, t-BuOK,
DMSO, rt, 74%; (v) m-CPBA, CH2Cl2, 0 °C; (vi) toluene, reflux, 70% in two steps.
3.7
Lung
NCI-H23
NCI-H226
NCI-H522
NCI-H460
A549
23
58
25
>100
>100
>100
0.26
5.1
40
16
>100
>100
>100
0.46
73
>100
58
>100
>100
>100
4.3
0.22
29
3.6
>100
96
72
i
DMS273
DMS114
n-C12H25
O
<0.01
TBSO
OH
Melanoma
LOX-IMVI
2
Me
6.5
97
29
1.9
F
F
ii
Ovarian
n-C12H25
TBSO
O
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
SK-OV-3
>100
>100
>100
62
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
15
6.9
>100
38
>100
O
OH
O
O
9
Me
iii
>100
1
n-C12H25
TBSO
O
O
Renal
RXF-631L
ACHN
OH
>100
>100
>100
>100
>100
>100
40
>100
10
Stomach
St-4
Scheme 3. Reagents and conditions: (i) 3, Pd(PPh3)2Cl2, CuI, Et3N, rt, 84%; (ii)
TsNHNH2, NaOAc, 1,2-dimethoxyethane–H2O, reflux, 56%; (iii) 48% HF aq., CH3CN–
THF, rt, 88%.
74
>100
>100
19
>100
43
>100
>100
13
14
>100
>100
41
20
0.70
2.8
>100
4.6
MKN1
MKN7
MKN28
MKN45
MKN74
>100
0.96
41
>100
>100
>100
Me
F
Prostate
DU-145
PC-3
F
6
>100
>100
54
2.33
2.59
>100
84
63
2.14
2.34
>100
>100
76
1.24
1.36
>100
17
20
3.3
4.00
I
O
I
OH
MG-MIDb
Deltac
O
ent-7
11
Ranged
Me
F
a
Concentration for 50% inhibition of cell growth relative to control. Cell growth
was determined according to the sulforhodamine B assay.
O
n-C12H25
HO
O
b
Mean GI50 value in all cell lines tested.
Difference between log GI50 value of the most sensitive cell line and the MG-
OH
O
c
12
MID value.
d
Difference in log GI50 value between the most and least sensitive cell lines.
Scheme 4. Synthesis of C4-epi-fluorinated solamin 12.

N. Kojima et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6451–6453
6453
(7, >98% ee12) due to instability of the
of 7 with iodine and PPh3 gave iodide (4) in 90% yield. Alkylation of
known
-lactone (5) with 4 in the presence of t-BuOK13 gave sul-
fide (8) in 74% yield. Oxidation of sulfide (8) into the sulfoxide, fol-
a
-fluoroaldehyde. Iodination
on Priority Area ‘Creation of Biologically Functional Molecules’
from The Ministry of Education, Culture, Sports, Science, and Tech-
nology, Japan.
c
lowed by thermal elimination, afforded fluorinated
segment (3).
c-lactone
References and notes
THF-ring segment (2) was prepared with our developed syn-
thetic method14 with high stereoselectivity. Assembly of fragments
2 and 3 was performed with the Sonogashira reaction.15 Selective
reduction of resulting enediyne 9 with diimide, followed by depro-
tection of TBS ether, gave C4-fluorinated solamin (1) (Scheme 3).
Epimer (12) at C4 position was synthesized from ent-7 prepared
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by
a
-fluoriation of 6 with (S)-MacMillan’s catalyst (Scheme 4).
Synthesized C4-fluorinated solamin (1) and C4-epi-fluorinated
solamin (12) were tested for in vitro antiproliferative activity
against a panel of 39 human cancer cell lines.16 Table 1 shows
the 50% growth inhibitory concentration relative to control
(GI50). The GI50 values of analogues 1 and 12 were lower than those
of solamin for a large number of cell lines, which means that the
two analogues have stronger growth inhibitory activity against
cancer cell lines than solamin. The human lung carcinoma cell line,
DMS114, was most sensitive to synthesized 1 and 12 (GI50: 0.26
and 0.46
lM, respectively), and to natural solamin (4.3
lM) and
murisolin (0.01
lM). We also noted some features in the finger-
prints of the two fluorinated analogues. For example, C4-fluori-
nated solamin (1) exhibited approximately 20 times higher
cytotoxicity to MKN7 than C4-epi-fluorinated solamin (12). Com-
pound (1) showed at least 50 times higher cytotoxicity to HCT-
116 than solamin. Together, the results suggest that the existence
and stereochemistry of fluorine atom at C4-position are recognized
by the cancer cell lines.
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Further synthesis of other fluorinated analogues of acetogenins
and investigation of their growth inhibitory activity are under way.
Acknowledgments
Biological activity was examined by the Screening Committee of
New Anticancer Agents supported by a Grant-in-Aid for Scientific
Research on Priority Area ‘Cancer’ from The Ministry of Education,
Culture, Sports, Science, and Technology, Japan. We acknowledge
financial support through a Grant-in-Aid for Scientific Research