Design and synthesis of C35-fluorinated solamins and their growth inhibitory activities against human cancer cell lines

Article abstract of DOI:10.1016/j.bmcl.2011.08.011

The convergent synthesis of C35-fluorinated analogues of solamin, a mono-THF Annonaceous acetogenin, has been achieved by the Sonogashira coupling of the THF ring fragment and the fluorinated γ-lactone fragment. It was revealed that the number of fluorine atoms on the γ-lactone moiety affects the growth inhibitory activities against human cancer cell lines.

Full text of DOI:10.1016/j.bmcl.2011.08.011

Bioorganic & Medicinal Chemistry Letters 21 (2011) 5745–5749
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design and synthesis of C35-fluorinated solamins and their growth
inhibitory activities against human cancer cell lines
Naoto Kojima a, , Yuki Suga a, Hiromi Hayashi a, Takao Yamori b, Takehiko Yoshimitsu a,
⇑
Tetsuaki Tanaka a,
⇑
a Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
b Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-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:
The convergent synthesis of C35-fluorinated analogues of solamin, a mono-THF Annonaceous acetogenin,
Received 13 July 2011
Revised 29 July 2011
Accepted 2 August 2011
Available online 10 August 2011
has been achieved by the Sonogashira coupling of the THF ring fragment and the fluorinated
c
-lactone
fragment. It was revealed that the number of fluorine atoms on the
inhibitory activities against human cancer cell lines.
c-lactone moiety affects the growth
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Annonaceous acetogenin
Structure–activity relationship
Antitumor agent
Fluorinated analogue
Chemical synthesis
In 1982, uvaricin, the first Annonaceous acetogenin, was iso-
lated from the roots of Uvaria acuminata (Annonaceae) by Cole
and co-workers.1 Following the isolation of uvaricin, more than
400 related compounds have been isolated from Annona plants
growing in tropical and subtropical regions (Fig. 1).2 Annonaceous
acetogenins are long-chain fatty acids (C32 or C34) whose terminal
carboxylic acid is combined with a 2-propanol unit at the C-2 posi-
for cancer cells that have high metabolic activity, and finally lead-
ing to apoptosis.6 Miyoshi and co-workers proposed a hypothesis
that the polar hydroxylated THF moiety resides at the polar mem-
brane surface in the mitochondrial ND1 subunit with support of
the hydrophobic alkyl tail and spacer, and the
c-lactone moiety
maintained by the flexible alkyl spacer interacts with another
binding site located in the hydrophobic environment of the en-
zyme.7 To our knowledge, there is no information about the mode
tion to form a methyl-substituted a,b-unsaturated c-lactone. Most
of them have one to three 2,5-disubstituted tetrahydrofuran (THF)
systems with one or two flanking hydroxyl groups at the center of
a long hydrocarbon chain. Many total syntheses of natural acetog-
enin3 and their analogues4 have been reported, motivated by their
unique chemical structures and attractive biological activities,
including immunosuppressive, antimalarial, insecticidal, and the
most impressive, antitumor activity. We previously reported the
synthesis of C4-fluorinated solamins, which are first fluorinated
analogues of acetogenins, and revealed their interesting inhibitory
activities against human cancer cell lines.5 In this communication,
we describe the design and synthesis of C35-fluorinated solamins
and their growth inhibitory activities against human cancer cell
lines.
of interaction between the
the target protein. We assumed that the
togenins acts as a Michael acceptor because it is generally accepted
that ,b-unsaturated lactone acts as a Michael acceptor to form a
c
-lactone moiety and the binding site in
c
-lactone moiety in ace-
a
covalent bond with electrophilic residues in specific protein targets
(Fig. 2).8,9
Based on our assumption, we designed C35-fluorinated acetog-
enins because if the
c-lactone in acetogenins acts as a Michael
acceptor, the introduction of fluorine atoms to the
c
-lactone
tail THF core
R
spacer
R'
γ-lactone
CH3
It is well accepted that the mode of action of acetogenins is the
inhibition of NADH-ubiquinone oxidoreductase (complex I) in the
mitochondria, thereby suppressing ATP production particularly
n=1-3
R, R'=hydrocarbon chain having
oxygenated moieties and/or
double bonds
O
O
*
*
*
*
O
n
HO
OH
Annonaceous acetogenins
⇑
Corresponding authors.
E-mail address: kojima@phs.osaka-u.ac.jp (N. Kojima).
Figure 1. Representative structure of Annonaceous acetogenins.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.08.011

5746
N. Kojima et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5745–5749
c
b
TfO
F
RO
F
HO
F
Target protein
Nu
OTBS
OR
11: R = H
12: R = TBS
OTBS
35CH3
O
a
13
Rf
14
CH2F
O
CH2F
OTBS
PhS
CO2Me
e
O
O
O
d
PhS
I
PhS
Rf = CH2F, CHF2, CF3
CO2Me
15
O
8
Figure 2. Design of C35-fluorinated acetogenins based on the plausible mode of
action of Annonaceous acetogenins.
CH2F
I
I
7
O
f
PhS
R
O
33
34
16
Sonogashira coupling
n
-C12H25
O
15
O
1
Scheme 2. Reagents and conditions: (a) TBSCl, imidazole, DMF, 0 °C, 87%; (b) p-
TsOH, MeOH–CH2Cl2 (2:1), 0 °C, 59%; (c) Tf2O, 2,6-lutidine, CH2Cl2, 0 °C, 92%; (d)
LiHMDS, HMPA, THF, ꢀ78 °C, 84%; (e) p-TsOH, toluene, reflux, 81%; (f) LiHMDS,
HMPA, THF, ꢀ78 °C to rt, 75%.
HO
OH
O
solamin (1): R = CH3
3: R = CHF2
2: R = CH2F 4: R = CF3
R
alkylation
n
-C12H25
TBSO
CF3
+
I
O
O
CF3
OH
PhS
CO2H
b
CF3
OH
PhS
O
O
6
5
a
O
PhS
PhS
CO2H
R
O
21
22
10
R = CH2F (8)
CHF2 (9)
I
I
+
O
CF3
I
I
PhS
CF3 (10)
7
O
7
I
O
c
Scheme 1. Retrosynthesis of C35-fluorinated solamins.
PhS
O
23
may affect the LUMO levels of the c-lactone moiety, and we could
Scheme 4. Reagents and conditions: (a) i-Pr2NH, n-BuLi, THF, ꢀ78 °C to rt; (b) p-
TsOH, benzene, rt, 55% in two steps; (c) LiHMDS, HMPA, THF, ꢀ78 °C to rt, 70%.
thus change the biological activities. In hopes of acquiring infor-
mation on the mode of action of acetogenins, we planed the syn-
thesis of C35–CH2F-, C35–CHF2-, and C35–CF3-solamins. Solamin
110,11 has a simple structure, yet it has all the functionalities that
characterize acetogenins. Our approach to C35-fluorinated
solamins is retrosynthetically outlined in Scheme 1. Fluorinated
analogues 2–4 were prepared by the Sonogashira coupling of
vinyl iodide 6 and diyne 5, the latter of which was synthesized
by our method.11a,12,13 Vinyl iodide 6 was synthesized by the
ciently took place, giving
c-lactone 8 in 84% yield. Finally, synthesis
of -lactone fragment 16 was completed by alkylation of 8 with io-
c
dide 7 under basic conditions.
The synthesis of difluoromethyl-c-lactone fragment 20 started
from the triflation of known difluoromethyl alcohol 1716
(Scheme 3). The procedure was the same as that used for the prep-
aration of monofluoromethyl-
romethyl- -lactone fragment 20 in good yield.
Scheme 4 shows the preparation of trifluoromethyl-
fragment 23. The ring-opening reaction of commercially available
1,1,1-trifluoro-2,3-epoxypropane 21 with the dianion prepared
from phenylthioacetic acid, followed by lactonization under acidic
c-lactone fragment 16, giving difluo-
a
-alkylation of
and known iodide 7.14
-lactone fragment with a monofluoromethyl moiety at the C-
34 position was synthesized, as shown in Scheme 2. Known diol
1115 prepared from
-mannitol was converted into bis-TBS ether
c-fluorinated-methyl a-sulfenyl-c-lactones 8–10
c
c-lactone
A
c
D
12. Selective deprotection of 12 followed by triflation gave triflate
14. The coupling reaction of triflate 14 and methyl phenylthioace-
tate under basic conditions gave ester 15 in 81% yield as a 3:2 dia-
stereomeric mixture. Upon treatment of 15 with p-TsOH in
refluxing toluene, removal of the TBS group and lactonization effi-
condition gave
ded trifluoromethyl-
With the fluorinated
c
-lactone 10. Alkylation of 10 with iodide 7 affor-
-lactone 23 in 70% yield.
-lactone fragments in hand, we examined
c
c
the assembly of THF fragment
5 and fluorinated c-lactone
CHF2
F
F
a
PhS
CO2Me
HO
F
TfO
F
OTBS
CO2Me
19
b
PhS
OTBS
17
OTBS
18
CHF2
CHF2
I
I
c
7
O
I
O
d
PhS
PhS
O
O
9
20
Scheme 3. Reagents and conditions: (a) Tf2O, 2,6-lutidine, CH2Cl2, 0 °C, 89%; (b) LiHMDS, HMPA, THF, ꢀ78 °C, 84%; (c) p-TsOH, toluene, reflux, 98%; (d) LiHMDS, HMPA, THF,
ꢀ78 to 0 °C, 97%.

N. Kojima et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5745–5749
5747
R
a
R
b
+
I
O
n
-C12H25
O
n
-C12H25
O
O
PhS
PhS
TBSO
OH
f
TBSO
OH
OH
O
O
16: R = CH2F
20: R = CHF2
23: R = CF3
24: R = CH2F
25: R = CHF2
26: R = CF3
5
R
R
R
c, d
or
c, e
n
-C12H25
O
n
-C12H25
O
n-C12H25
O
( )9
( )9
( )9
O
O
O
PhS
TBSO
TBSO
OH
HO
OH
O
O
O
27: R = CH2F
28: R = CHF2
29: R = CF3
30: R = CH2F
31: R = CHF2
32: R = CF3
2: R = CH2F
3: R = CHF2
4: R = CF3
Scheme 5. Reagents and conditions: (a) Pd(PPh3)2Cl2, CuI, Et3N, rt, 82% from 16, 95% from 20, 83% from 23; (b) Rh(PPh3)3Cl, H2 (1 atm), benzene–MeOH (1:1), rt, 63% from 24,
70% from 25, 60% from 26; (c) mCPBA, CH2Cl2, 0 °C; (d) toluene, 60–65 °C, 90% from 27, 81% from 29; (e) toluene, reflux, 85% from 28; (f) 48% HF aq., MeCN–THF (1:2), rt, 84%
from 30, 83% from 31, 78% from 32.
fragments (Scheme 5). The Sonogashira coupling of 5 and monoflu-
oromethyl- -lactone fragment 16 smoothly proceeded to give
lowed by thermal elimination of the resulting sulfoxide afforded
,b-unsaturated -lactone 30 in high yield. Synthesis of C35–
c
a
c
enediyne 24 in good yield. Hydrogenation of 24 with Wilkinson’s
CH2F-solamin 2 was completed via deprotection of TBS ether under
catalyst gave sulfide 27 in 63% yield. Oxidation of sulfide 27 fol-
acidic condition. C35–CHF2- and C35–CF3-solamins (3 and 4) were
Figure 3. Growth inhibitory profiles of C35-fluorinated solamins 2–4 and solamin 1 across JFCR39. Cell growth inhibition was assessed by the change in total cellular protein
level following treatment for 48 h with a given test compound, and was measured using the sulforhodamine B colorimetric assay. Fingerprints were produced by computer
processing of the 50% growth inhibition (GI50) values. The x-axis represents the logarithm of GI50 values for the 39 cell lines. No bars mean that the GI50 value of the
corresponding cell line is higher than 10ꢀ4 M. CNS = central nervous system.

5748
N. Kojima et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5745–5749
R1
Committee of New Anticancer Agents supported by a Grant-in-
R1
O
F
R2
Aid for Scientific Research on Priority Area ‘Cancer’ from The Min-
istry of Education, Culture, Sports, Science and Technology, Japan
(MEXT). This work was supported by a Grant-in-Aid for Young Sci-
entists (B) [No. 21790113, 23790130], a Grant-in-Aid for Scientific
Research (B) [No. 22390021], and a Grant-in-Aid for Scientific Re-
search on Innovative Areas [No. 22136006] from The Ministry of
Education, Culture, Sports, Science and Technology, Japan.
R2
H
O
O
O
R1 = H or F
R2 = H or F
Scheme 6. E2 elimination of HF moiety in c-fluorinated-methyl a,b-unsaturated c-
lactone.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.08.011.
also synthesized from 20 or 23 using the same procedure as that
for 2, respectively.17
Synthesized C35-fluorinated solamins (2–4) were tested for
in vitro antiproliferative activity against a panel of 39 human can-
cer cell lines (JFCR39).18 Figure 3 shows the 50% growth inhibitory
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concentration relative to control (GI50). C35–CH2F-solamin
2
showed stronger growth inhibitory activity against a larger num-
ber of cancer cell lines than solamin 1. C35–CHF2-solamin 3 also
showed a similar tendency although the number of cell lines inhib-
ited by 3 is less than that inhibited by C35–CH2F-solamin 2.
In contrast, C35–CF3-solamin 4 displayed weaker cytotoxicity
than not only analogues 2 and 3 but also solamin 1. We also noted
interesting features in the fingerprints of fluorinated analogues 2–
4. For example, the inhibitory activity against human lung carci-
noma cells, NCI-H23 (GI50
>100 M for 4) and DMS114 (GI50: 6.9
M for 4), or human prostate carcinoma cells, PC-3 (GI50
M for 2; 60.0 M for 3; >100 M for 4), decreased as the
:
12.3
lM
for 2; 75.0
lM
for 3;
l
l
M for 2; 24.0
lM for 3;
75.0
24.0
l
l
:
l
l
number of fluorine atoms increased. These results did not support
our hypothesis for the mode of action described above because the
increase in the number of fluorine atoms on the
c-lactone ring
should decrease the LUMO levels of electrophiles, and chemical
reactivity and bioactivity should increase if our hypothesis is rea-
sonable. One of the possible reasons for this contradiction is that
the actual structures of the fluorinated analogues when they inter-
act with the target molecules differ among three fluorinated ana-
logues because
may be transformed into
by the E2 elimination of the HF moiety (Scheme 6).19
c
-fluorinated-methyl
a
,b-unsaturated
c
c
-lactone
-lactone
c-methylidene
a,b-unsaturated
Another possibility is that the nucleophile of the target protein
must approach the -lactone moiety of the analogues from the same
c
side as the fluorinated methyl group when the fluorinated analogues
interact with the target protein, perhaps, because of three-dimen-
sional restriction. A sterically demanding and/or electron-rich20 tri-
fluoromethyl group may inhibit the interaction between the target
protein and the c-lactone moiety of the analogues. To verify this
hypothesis, the synthesis of C35-epi-CF3-solamin is under way.
The differences of the detoxification and the effect to the distribu-
tion inside the cells are also thought as other factors.
In conclusion, the convergent synthesis of three C35-fluorinated
analogues of solamin, a mono-THF acetogenin, has been achieved
by the Sonogashira coupling of the THF fragment and the fluori-
nated
atoms on the
ity against human cancer cell lines, indicating that the
moiety in acetogenins may play an important role in the interac-
tion between acetogenins and the target molecules. Further work
aimed at the synthesis of fluorinated analogues and their detailed
biological studies is under way.
c
-lactone fragment. We revealed that the number of fluorine
-lactone moiety affects the growth inhibitory activ-
-lactone
14. Dudley, G. B.; Danishefsky, S. Org. Lett. 2001, 3, 2399.
15. Kawakami, Y.; Asai, T.; Umeyama, K.; Yamashita, Y. J. Org. Chem. 1982, 47, 3581.
16. Xu, Y.; Prestwich, G. D. J. Org. Chem. 2002, 67, 7158.
c
c
17. Characterization data of C35–CH2F-solamin 2: pale yellow powder; mp
78.5ꢀ80.5 °C; ½a D21
ꢁ
+24.5 (c 1.08, CHCl3); 1H NMR (500 MHz, CDCl3) d: 0.88
(t, 3H, J = 7.3 Hz), 1.26ꢀ1.43 (m, 40H), 1.47ꢀ1.55 (m, 2H), 1.56 (qn, 2H,
J = 7.3 Hz), 1.64ꢀ1.72 (m, 2H), 1.95ꢀ2.02 (m, 2H), 2.31 (t, 2H, J = 7.3 Hz), 2.47
(br, 2H), 3.41 (td, 2H, J = 6.1, 4.9 Hz), 3.80 (td, 2H, J = 7.3, 6.1 Hz), 4.51 (ddd, 1H,
J = 46.4, 9.8, 4.9 Hz), 4.62 (ddd, 1H, J = 47.6, 9.8, 3.7 Hz), 5.10 (br d, 1H,
J = 19.5 Hz), 6.99 (s, 1H); 13C NMR (125 MHz, CDCl3) : 14.0, 22.6, 25.3, 25.5 (2C),
27.2, 28.7 (2C), 29.0, 29.2, 29.3, 29.40, 29.49, 29.51 (4C), 29.55, 29.56, 29.58,
29.60, 29.65 (2C), 31.8, 33.3 (2C), 74.0 (2C), 79.0 (d, J = 21.6 Hz), 81.4 (d,
J = 176 Hz), 82.7 (2C), 137.1, 142.3 (d, J = 6.1 Hz), 172.9; IR (neat) cmꢀ1: 3453,
2916, 2849, 1757; MS (FAB) m/z: 583 [M+H]+; HRMS (FAB) m/z: calcd for
Acknowledgments
In vitro antiproliferative activities of C35-fluorinated solamins
against human cancer cell lines were examined by the Screening
C
35H64FO5: 583.4738; found: 583.4740 [M+H]+.

N. Kojima et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5745–5749
5749
Characterization data of C35–CHF2-solamin 3: white powder; mp
29.32, 29.4, 29.51, 29.55 (4C), 29.60, 29.61, 29.63, 29.65, 29.69, 29.70, 31.9,
33.4 (2C), 74.0 (2C), 76.6 (q, J = 35.0 Hz), 82.7 (2C), 121.8 (q, J = 281 Hz), 137.9,
139.3, 171.3; IR (neat) cmꢀ1: 3445, 2918, 2851, 1790; MS (FAB) m/z: 619
[M+H]+; HRMS (FAB) m/z: calcd for C35H62F3O5: 619.4549; found 619.4560
[M+H]+.
72.0ꢀ73.0 °C; ½a D24
ꢁ
+34.5 (c 0.35, CHCl3); 1H NMR (500 MHz, CDCl3) d: 0.88
(t, 3H, J = 6.7 Hz), 1.26ꢀ1.43 (m, 40H), 1.46ꢀ1.55 (m, 2H), 1.58 (qn, 2H,
J = 7.3 Hz), 1.64ꢀ1.72 (m, 2H), 1.96ꢀ2.02 (m, 4H), 2.32ꢀ2.35 (m, 2H), 3.41 (td,
2H, J = 6.7, 4.6 Hz), 3.80 (dt, 2H, J = 7.9, 6.7 Hz), 5.03 (dddd, 1H, J = 12.2, 6.7, 3.7,
1.8 Hz), 5.79 (td, 1H, J = 54.9, 3.7 Hz), 7.03 (d, 1H, J = 1.2 Hz); 13C NMR
(125 MHz, CDCl3) d: 14.1, 22.7, 25.5, 25.6 (2C), 27.1, 28.7 (2C), 29.0, 29.2, 29.3,
29.4, 29.56 (5C), 29.62 (4C), 29.68 (2C), 31.9, 33.4 (2C), 74.0 (2C), 78.3 (dd,
J = 29.2, 28.6 Hz), 82.6 (2C), 112.6 (t, J = 246 Hz), 138.5, 139.7 (dd, J = 3.7,
2.5 Hz), 172.1; IR (KBr) cmꢀ1: 3448, 2918, 2850, 1776; MS (FAB) m/z: 601
[M+H]+; HRMS (FAB) m/z: calcd for C35H63F2O5: 601.4644; found 601.4642
[M+H]+.
18. (a) Dan, S.; Okamura, M.; Seki, M.; Yamazaki, K.; Sugita, H.; Okui, M.; Mukai, Y.;
Nishimura, H.; Asaka, R.; Nomura, K.; Ishikawa, Y.; Yamori, T. Cancer Res. 2010,
70, 4982; (b) Yaguchi, S.; Fukui, Y.; Koshimizu, I.; Yoshimi, H.; Matsuno, T.;
Gouda, H.; Hirono, S.; Yamazaki, K.; Yamori, T. J. Natl. Cancer Inst. 2006, 98, 545;
(c) Yamori, T.; Matsunaga, A.; Saito, S.; Yamazaki, K.; Komi, A.; Ishizu, K.; Mita,
I.; Edatsugi, H.; Matsuba, Y.; Takezawa, K.; Nakanishi, O.; Kohno, H.; Nakajima,
Y.; Komatsu, H.; Andoh, T.; Tsuruo, T. Cancer Res. 1999, 59, 4042.
Characterization data of C35–CF3-solamin 4: white powder; mp 68.0ꢀ70.5 °C;
19. E2 elimination of HF moiety in the
lactone under the weakly basic condition was observed in our synthesis.
20. Matsushima, A.; Kakuta, Y.; Teramoto, T.; Koshiba, T.; Liu, X.; Okada, H.;
c-fluorinated-methyl a,b-unsaturated c-
½ ꢁ
a 2D5 +13.7 (c 0.58, CHCl3); 1H NMR (500 MHz, CDCl3) d: 0.88 (t, 3H, J = 7.3 Hz),
1.22ꢀ1.42 (m, 41H), 1.47ꢀ1.54 (m, 2H), 1.60 (qn, 2H, J = 7.3 Hz), 1.63ꢀ1.71 (m,
2H), 1.95ꢀ2.02 (m, 2H), 2.36 (t, 2H, J = 7.3 Hz), 2.60 (br, 1H), 3.41 (td, 2H,
Tokunaga, T.; Kawabata, S.; Kimura, M.; Shimohigashi, Y. J. Biochem. 2007, 142,
517.
J = 6.1, 4.9 Hz), 3.80 (td, 2H, J = 7.3, 6.1 Hz), 5.17ꢀ5.21 (m, 1H), 6.99 (s, 1H); 13
C
NMR (125 MHz, CDCl3) d: 14.1, 22.7, 25.45, 25.6 (2C), 27.0, 28.7 (2C), 29.0, 29.2,