Preparation and cancer cell invasion inhibitory effects of C16-alkynic fatty acids.

Article abstract of DOI:10.1248/cpb.51.463

Five C(16)-alkynic fatty acids (2-6) were prepared and examined their inhibitory effects on cancer cell invasion. It has been found that hexadeca-6,8,10-triynoic acid (5) and hexadeca-8,10,12-triynoic acid (6) exhibit similar potent inhibitory activities with that of octadeca-8,10,12-triynoic acid (1) which was isolated from Scurrula atropurpurea (Loranthaceae).

Full text of DOI:10.1248/cpb.51.463

April 2003
Notes
Chem. Pharm. Bull. 51(4) 463—466 (2003)
463
Preparation and Cancer Cell Invasion Inhibitory Effects of C -Alkynic
16
Fatty Acids
a
a
b
,a
Kazuyoshi OHASHI, Hendig WINARNO, Mutsuko MUKAI, and Hirotaka SHIBUYA*
a
Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University; Sanzo, 1 Gakuen-cho, Fukuyama, Hiroshima
29–0292, Japan: and Department of Tumor Biochemistry, Osaka Medical Center for Cancer and Cardiovascular
b
7
Diseases; 1–3–3 Nakamichi, Higashinari-ku, Osaka 537–8511, Japan.
Received December 19, 2002; accepted January 22, 2003
Five C -alkynic fatty acids (2—6) were prepared and examined their inhibitory effects on cancer cell inva-
1
6
sion. It has been found that hexadeca-6,8,10-triynoic acid (5) and hexadeca-8,10,12-triynoic acid (6) exhibit simi-
lar potent inhibitory activities with that of octadeca-8,10,12-triynoic acid (1) which was isolated from Scurrula
atropurpurea (Loranthaceae).
Key words C -alkynic fatty acid; cancer cell invasion inhibitory effect; anticancer; hexadeca-6,8,10-triynoic acid; hexadeca-
1
6
8,10,12-triynoic acid
The whole plant of Scurrula atropurpurea (BL.) DANS. C -alkynic fatty acids (2—6) by combination of known sim-
1
6
(
Loranthaceae), a parasitic plant on the tea plant Thea sinen- ple reactions as shown in Fig. 1.
sis L., has been traditionally used for the treatment of cancer A condensation of propargyl alcohol (7) and appropriate
in Java Island, Indonesia. In our previous paper, we reported 1-bromoalkanes (8 or 11) by treatment with n-BuLi and
1)
6)
isolation of six C -fatty acids [(Z)-9-octadecenoic acid, (Z,Z)- potassium 3-aminopropylamide (KAPA) afforded non-8-
1
8
7)
7)
octadeca-9,12-dienoic acid, (Z,Z,Z)-octadeca-9,12,15-trienoic ynol (9) and undec-10-ynol (12) in 80% and 78% yield,
acid, octadeca-8,10-diynoic acid, (Z)-octadec-12-ene-8,10- respectively. Then a coupling reaction of 9 and 12 with
diynoic acid and octadeca-8,10,12-triynoic acid], besides two proper 1-bromoalkanes (10 or 13) by n-BuLi treatment and
8)
xanthines, two flavonol glycosides, a monoterpene glucoside, subsequent CrO oxidation furnished hexadec-8-ynoic acid
3
a lignan glycoside, and four flavanes. Among those C -fatty (2) and hexadec-10-ynoic acid (3) in moderate yields.
1
8
acids, octadeca-8,10,12-triynoic acid (1) showed the most
Hexadeca-8,10-diynoic acid (4) was prepared by use of the
potent inhibitory effect (99.4% inhibition at 10 mg/ml) on above-mentioned non-8-ynol (9). A coupling reaction of 1-
cancer cell invasion through a rat mesothelium monolayer by iodo-1-heptyne (15), which was prepared from 1-heptyne
9)
using MM1 cell line isolated from rat ascites hepatoma (14), with 9 by treatment with CuI and pyrrolidine and sub-
2)
AH130 cells. Furthermore, it was found that the rise of sequent CrO3 oxidation furnished hexadeca-8,10-diynoic
number of unsaturation function in the fatty acids seems to acid (4) in 57% yield from 14.
strengthen the inhibitory activity.
A coupling of propargyl alcohol (7) and 1-bromobutane
On the other hand, we examined cancer cell invasion in- (16) by treatment with n-BuLi and KAPA afforded hept-6-
7
,10)
hibitory effects of four saturated fatty acids, namely myristic ynol (17)
in 78% yield. Then, 17 was converted into
10)
acid (C ), palmitic acid (C ), stearic acid (C ), and nona-6,8-diynol (20) via 10-hydroxy-10-methylundeca-
eicosanoic acid (C ). Among them, palmitic acid (C ) 6,8-diynol (19) by the similar procedure reported by Naka-
1
4
16
18
2
0
16
10)
showed much stronger activity (46.8% inhibition at 10 nishi et al. Finally, 20 was coupled with 1-iodo-1-heptyne
mg/ml) than myristic acid (31.5%), stearic acid (29.5%) and (15) and oxidized by chromic acid to provide hexadeca-
eicosanoic acid (20.5%) at the same concentration.
6,8,10-triynoic acid (5) in a moderate yield.
Therefore, we here describe a simple preparation route for
Undeca-8,10-diynol (21) was prepared from 9 and 3-
five C -alkynic fatty acids [hexadec-8-ynoic acid (2), hexa- methyl-1-pentyn-3-ol (18) through the procedures reported
1
6
11)
dec-10-ynoic acid (3), hexadeca-8,10-diynoic acid (4), hexa- by Zeni et al. 21 was coupled with 1-iodo-1-pentyne (22)
deca-6,8,10-triynoic acid (5) and hexadeca-8,10,12-triynoic in the presence of CuI and pyrrolidine followed by CrO oxi-
3
acid (6)], in order to compare their inhibitory effects with dation to afford hexadeca-8,10,12-triynoic acid (6) in a mod-
that of octadeca-8,10,12-triynoic acid (1) isolated from Scur- erate yield.
rula atropurpurea.
Cancer Cell Invasion Inhibitory Effects of C -Alkynic
16
Preparation of C -Alkynic Fatty Acids (2—6) Among Fatty Acids (2—6) As a result of the assay as shown in
1
6
the C -alkynic fatty acids (2—6), hexadec-8-ynoic acid (2) Table 1, five synthetic C -alkynic fatty acids (2—6) exhib-
1
6
16
3)
was synthesized by Levine et al. using alkylation of 7-bro- ited stronger inhibitory effects on cancer cell invasion than
moheptanoic acid with 1-nonyne, and hexadec-10-ynoic acid palmitic acid and palmitoleic acid. Especially, two triyne de-
4
)
(
3) was reported by Arsequell et al. as a intermediate for rivatives (5, 6) showed potent inhibitory activities over 95%
the synthesis of cyclopropane fatty acids. Also hexadeca- at a concentration of 10 mg/ml. Those activity were similar
,10-diynoic acid (4) was synthesized by Gunstone and with that of the C -trialkynic fatty acid, octadeca-8,10,12-
8
1
8
5)
1)
Sykes using a coupling reaction of 1-bromohept-1-yne with triynoic acid (1) which had been isolated from Scurrula at-
-nonynoic acid. However, so far, the preparation of hexa- ropurpurea (Loranthaceae). Furthermore, the concentration-
8
deca-6,8,10-triynoic acid (5) and hexadeca-8,10,12-triynoic dependent behavior of the triyne derivatives (5, 6) were ex-
acid (6) have not yet been reported. We tried to prepare the amined at 5 mg/ml and 2.5 mg/ml, which indicating those C -
1
6
*
To whom correspondence should be addressed. e-mail: shibuya@fupharm.fukuyama-u.ac.jp
© 2003 Pharmaceutical Society of Japan

464
Vol. 51, No. 4
Fig. 1. Preparation of C -Alkynic Fatty Acids (2—6)
16
Table 1. Cancer Cell Invasion Inhibitory Effects of C -Fatty Acid Derivatives
1
6
Compounds
Concentration (mg/ml)
Inhibitory activity (%)
46.8
1
0
0
Palmitic acid
1
49.7
82.4
Palmitoleic acid
1
0
0
Hexadec-8-ynoic acid (2)
Hexadec-10-ynoic acid (3)
1
77.2
85.6
10
Hexadeca-8,10-diynoic acid (4)
Hexadeca-6,8,10-triynoic acid (5)
1
0
5
2
95.7
85.4
50.3
.5
1
0
5
2
98.7
90.7
60.5
.5
Hexadeca-8,10,12-triynoic acid (6)
Octadeca-8,10,12-triynoic acid (1)
1
0
5
2
99.4
94.9
45.6
.5
.5
1
0
5
2
82.8
59.7
40.1
(ꢀ)-Epigallocatechin-3-O-gallate (EGCG)

April 2003
465
alkynic fatty acids showed over 50% inhibitory effects even mooctane (11, 3.18 g, 16.5 mmol) was added to the mixture and stirred at
room temperature for 12 h. The reaction mixture was poured into aqueous
at 2.5 mg/ml.
saturated NH Cl and the whole was extracted with Et O. The Et O extract
4
2
2
Although no drug possessing cancer cell invasion in-
was worked up in the usual manner to give a product (3.0 g). Purification of
the product by silica gel column chromatography (SiO2 150 g, hexane :
hibitory activity has been produced, (ꢀ)-epigallocatechin-3-
O-gallate (EGCG, 82.8% at 10 mg/ml inhibition, 59.7% inhi- EtOAcꢁ5 : 1) afforded undec-2-ynol (2.12 g, 12.6 mmol), which was treated
1
)
6)
with the KAPA reagent [prepared from 1,3-diaminopropane (40 ml), Li
560 mg, 80 mmol) and potassium t-butoxide (5.4 g, 50 mmol)]. After stir-
bition at 5 mg/ml, 40.1% inhibition at 2.5 mg/ml), genistein
10 mg/ml; 80.5% inhibition, 5 mg/ml; 64.0% inhibition, 2.5
(
(
ring at room temperature for 30 min, the reaction mixture was poured into
ice-water and extracted with CHCl . The CHCl extract was worked up in
the usual manner to give a product (2.5 g). Purification of the product by sil-
12)
mg/ml; 55.7% inhibition) and ginsenoside Rg (25 mg/ml;
8.8% inhibition) have so far been reported as natural oc-
3
3
3
13)
9
curring materials showing the inhibitory activity.
ica gel column chromatography (SiO 100 g, hexane : EtOAcꢁ7 : 2) afforded
2
undec-10-ynol (12, 1.97 g, 11.7 mmol, 78% yield from 7), which physico-
The present work has indicated that the C -triyne fatty
1
8
7)
chemical properties were identical with those in the literature.
acid (1) and the C -triyne fatty acids (5, 6) are potent cancer
1
6
Hexadec-10-ynoic Acid (3) n-BuLi (1.6 M in hexane, 2.5 ml, 4.0 mmol)
was added to a solution of 12 (336 mg, 2.0 mmol) in THF (2.0 ml) and
HMPA (1.0 ml) at ꢀ78 °C and the reaction temperature allowed to ꢀ30 °C.
cell invasion inhibitory materials in spite of the simple chem-
ical structures.
It should be noted that the C - and C -alkynic fatty acids 1-Bromopentane (13, 332 mg, 2.2 mmol) was added to the mixture and
1
8
16
stirred at room temperature for 12 h. The reaction mixture was poured into
aqueous saturated NH Cl and extracted with EtOAc. The EtOAc extract was
(
1—6) show no cytotoxity to the cancer cells used in the pre-
1,2)
4
sent assay.
worked up in the usual manner to give a product (740 mg). Purification of
the product by silica gel column chromatography (SiO2 40 g, hexane :
EtOAcꢁ5 : 1) gave hexadec-10-ynol (390 mg, 1.64 mmol). The chromic acid
Experimental
8)
The instruments used to obtain physical data and experimental conditions reagent (1.7 ml, 3.4 mmol) was added to the solution of hexadec-10-ynol
for chromatography were the same as in our previous paper.
Myristic acid, palmitic acid, stearic acid, eicosanoic acid and palmitoleic The reaction mixture was treated with 2-propanol and extracted with EtOAc.
1)
(390 mg) in acetone (3.5 ml) and the whole was stirred at ꢀ10 °C for 30 min.
acid were purchased from Wako Pure Chemical Industries, Ltd.
The EtOAc extract was worked up in the usual manner to give a product
Non-8-ynol (9) To a solution of propargyl alcohol (7, 1.96 g, 35.0
(376 mg). Purification of the product by silica gel column chromatography
mmol) in tetrahydrofuran (THF, 32 ml) and hexamethylphosphoric triamide (SiO 30 g, hexane : EtOAcꢁ3 : 1) gave hexadec-10-ynoic acid (3, 310 mg,
2
(
ꢀ
HMPA, 18 ml) was added n-BuLi (1.6 M in hexane, 43.8 ml, 70.0 mmol) at
78 °C. After the reaction temperature allowed to reach at ꢀ30 °C, 1-bro-
1.23 mmol, 62% yield from 12), which physicochemical properties were
identical with those in the literature.
4)
mohexane (8, 6.36 g, 38.5 mmol) was added to the mixture and stirred at
room temperature for 12 h. The reaction mixture was treated with aqueous
Hexadeca-8,10-diynoic Acid (4) To a solution of 1-pentyne (14, 960
mg, 10.0 mmol) in THF (8.0 ml) was added n-BuLi (1.6 M in hexane, 6.25
saturated NH Cl and extracted with Et O. The Et O extract was washed with ml, 10.0 mmol) at ꢀ78 °C. Then, iodine (2.79 g, 11.0 mmol) in THF (5 ml)
4
2
2
brine and dried over MgSO . Removal of the solvent gave a product (6.8 g), was added to the reaction mixture at ꢀ30 °C and stirred at room temperature
4
which was purified by silica gel column chromatography (SiO2 200 g,
hexane : EtOAcꢁ5 : 1) to afford non-2-ynol (4.17 g, 29.8 mmol), which was and the whole was extracted with Et O. The Et O extract was washed with
for 30 min. The reaction mixture was poured into aqueous saturated NH Cl
4
2
2
6)
treated with the KAPA reagent [prepared from 1,3-diaminopropane (100
aqueous Na S O and brine, and dried over MgSO . Removal of the solvent
2
2
3
4
ml), Li (1.40 g) and potassium t-butoxide (13.4 g)]. After stirring at room
furnished 1-iodopent-1-yne (15, 2.15 g). CuI (47.5 mg, 0.25 mmol) was
temperature for 30 min, the reaction mixture was poured into ice-water and added to a solution of 9 (350 mg, 2.5 mmol) and 15 (610 mg) in pyrrolidine
extracted with CHCl . The CHCl extract was washed with 5% aqueous HCl (4.0 ml), and the whole mixture was stirred at room temperature for 30 min.
3
3
and brine, then dried over MgSO . Removal of the solvent gave a product The reaction mixture was treated with aqueous saturated NH Cl and ex-
4
4
(
4.20 g), which was purified by silica gel column chromatography (SiO 150
tracted with EtOAc. The EtOAc extract was worked up in the usual manner
2
g, hexane : EtOAcꢁ3 : 1) to give non-8-ynol (9, 3.94 g, 28.1 mmol, 80%
to give a product (620 mg). Purification of the product by silica gel column
yield from 7), which physicochemical properties were identical with those in chromatography (SiO2 100 g, hexane : EtOAcꢁ5 : 1) afforded hexadeca-
7)
the literature.
8,10-diynol (503 mg, 2.15 mmol). To a solution of hexadeca-8,10-diynol
Hexadec-8-ynoic Acid (2) To a solution of 9 (280 mg, 2.0 mmol) in
THF (2.0 ml) and HMPA (1.0 ml) was added n-BuLi (1.6 M in hexane, 2.5
ml, 4.0 mmol) at ꢀ78 °C and the reaction temperature allowed to ꢀ30 °C.
Then, 1-bromoheptane (10, 394 mg, 2.2 mmol) was added to the mixture at
(400 mg, 1.71 mmol) in acetone (4.0 ml) was added the chromic acid
8)
reagent (1.70 ml, 3.4 mmol) and the whole was stirred at ꢀ10 °C for 15
min, then treated with 2-propanol and extracted with EtOAc. The EtOAc ex-
tract was worked up in the usual manner to give a product (430 mg). Purifi-
cation of the product by silica gel column chromatography (SiO2 30 g,
ꢀ30 °C and stirred at room temperature for 12 h. After treating the reaction
mixture with aqueous saturated NH Cl, the whole was extracted with hexane : EtOAcꢁ5 : 2) and HPLC (Wakosil 5 SIL, hexane : EtOAcꢁ4 : 1) af-
4
EtOAc. The EtOAc extract was worked up in the usual manner to give a forded hexadeca-8,10-diynoic acid (4, 317 mg, 1.28 mmol, 57% from 14).
1
13
product (604 mg), which was purified by silica gel column chromatography
SiO 60 g, hexane : EtOAcꢁ5 : 1) to furnish hexadec-8-ynol (400 mg, 1.68
H- and C-NMR data of 4 are given here, since the spectra have not been
5)
(
reported in the literature.
2
1
mmol). To a solution of hexadec-8-ynol (400 mg, 1.68 mmol) in acetone (4.0
4: H-NMR (300 MHz, CDCl ) d: 0.89 (3H, t, Jꢁ7.1 Hz), 1.25—1.42
3
8)
ml) was added 1.7 ml of the chromic acid reagent [prepared from CrO (10
(8H), 1.47—1.55 (4H), 1.64 (2H, quintet, Jꢁ7.3 Hz), 2.22—2.27 (4H), 2.35
3
1
3
g), H SO (16 g) and H O (50 ml)] and the whole was stirred at ꢀ10 °C for
(2H, t, Jꢁ7.4 Hz). C-NMR (75 MHz, CDCl ) dc: 179.7, 77.7, 68.3, 65.4,
2
4
2
3
1
5 min. The reaction mixture was treated with 2-propanol and extracted with 65.2, 33.9, 31.0, 28.5, 28.4, 28.1, 28.0, 24.5, 22.2, 19.2, 19.1, 13.9.
EtOAc. The EtOAc extract was worked up in the usual manner to give a
product (311 mg). Purification of the product by silica gel column chro-
Hept-6-ynol (17) n-BuLi (1.6 M in hexane, 15.6 ml, 25.0 mmol) was
added to a solution of 7 (700 mg, 12.5 mmol) in THF (10 ml) and HMPA
matography (SiO2 20 g, hexane : EtOAcꢁ3 : 1) afforded hexadec-8-ynoic (6.5 ml) at ꢀ78 °C and then the reaction temperature allowed to ꢀ30 °C. 1-
acid (2, 304 mg, 1.21 mmol, 61% yield from 9). Physicochemical properties Bromobutane (16, 1.89 g, 13.8 mmol) was added to the solution and stirred
3
)
of 2 are given here, since they have not been reported in the literature.
: An amorphous solid. mp 34—35 °C (from MeOH). IR (film) cm
at room temperature. After 12 h, the reaction mixture was poured into aque-
ꢀ1
2
:
ous saturated NH Cl and the whole was extracted with Et O. The Et O ex-
4
2
2
1
3
300—2500 (br), 1710. H-NMR (300 MHz, CDCl ) d: 0.88 (3H, t, Jꢁ6.8
Hz), 1.20—1.55 (16H), 1.65 (2H, qu, Jꢁ7.4 Hz), 2.10—2.20 (4H), 2.35
2H, t, Jꢁ7.4 Hz). C-NMR (75 MHz, CDCl ) dc: 180.0, 80.5, 79.9, 34.0,
1.8, 29.2, 28.9, 28.8, 28.8, 28.6, 28.4, 24.6, 22.6, 18.8, 18.7, 14.1. EI-MS the KAPA reagent [prepared from 1,3-diaminopropane (35 ml), Li (294 mg,
tract was worked up in the usual manner to give a product (2.5 g). Purifica-
3
tion of the product by silica gel column chromatography (SiO 150 g, hexane :
2
13
(
EtOAcꢁ8 : 1) gave hept-2-ynol (1.18 g, 10.5 mmol), which was treated with
3
6)
3
ꢂ
m/z (%): 252 (M , 0.01), 67 (100). High-resolution EI-MS m/z: Calcd for 42.0 mmol) and potassium t-butoxide (4.60 g, 41.1 mmol)]. The whole mix-
ꢂ
C H O : 252.2089. Found: 252.2073 [M ].
ture was stirred at room temperature for 1 h. The mixture was poured into
16
28
2
Undec-10-ynol (12) To a solution of 7 (840 mg, 15.0 mmol) in THF (14
ice-water and the whole was extracted with CHCl . The CHCl extract was
3
3
ml) and HMPA (7.0 ml) was added n-BuLi (1.6 M in hexane, 18.8 ml, 30.0
mmol) at ꢀ78 °C and the reaction temperature allowed to ꢀ30 °C. 1-Bro-
worked up in the usual manner to affored a product (1.24 g). Purification of
the product by silica gel column chromatography (SiO2 50 g, hexane :

466
Vol. 51, No. 4
ꢂ
EtOAcꢁ9 : 1) afforded hept-6-ynol (17, 1.09 g, 9.73 mmol, 78% yield from
).
To a solution of 17 (900 mg, 8.0 mmol) in THF (6.0 ml) was added n-BuLi
1.6 M in hexane, 10.0 ml, 16.0 mmol) at ꢀ78 °C. I (2.24 g, 8.8 mmol) in
27.4, 23.8, 22.7, 19.4, 19.2, 13.9. EI-MS m/z (%): 244 (M , 3), 128 (100).
7
High-resolution EI-MS m/z: Calcd for
C
16
H
20
O
2
:
244.1463. Found:
ꢂ
244.1471 [M ].
(
Hexadeca-8,10,12-triynoic Acid (6) To a solution of undeca-8,10-
diynol (21, 50 mg, 0.305 mmol) and 1-iodopent-1-yne (22, 71 mg) in pyrroli-
2
THF (3 ml) was added to the mixture at ꢀ30 °C and stirred at room temper-
ature for 30 min. The reaction mixture was treated with aqueous saturated dine (1.0 ml) was added CuI (5.8 mg, 0.031 mmol) and the whole was stirred
NH Cl and extracted with Et O. The Et O extract was worked up in the at room temperature for 30 min. The reaction mixture was treated with aque-
4
2
2
usual manner to give 7-iodohept-6-ynol (1.83 g). To a solution of 7-
iodohept-6-ynol (1.83 g) and 3-methyl-1-pentyn-3-ol (18, 967 mg, 9.6 mmol) washed with brine and dried over MgSO
in pyrrolidine (8.0 ml) was added CuI (152 mg, 0.80 mmol) and the whole hexadeca-8,10,12-triynol (85 mg), which was purified by silica gel column
was stirred at room temperature for 30 min. The reaction mixture was treated
chromatography (SiO 10 g, hexane : EtOAcꢁ2 : 1) to afford hexadeca-8,10,12-
with aqueous saturated NH Cl and the whole was extracted with EtOAc. The triynol (63 mg, 0.27 mmol). To a solution of hexadeca-8,10,12-triynol (63
ous saturated NH
4
Cl and extracted with EtOAc. The EtOAc extract was
. Removal of the solvent gave
4
2
4
8)
EtOAc extract was worked up in the usual manner to give a product (2.23 g), mg, 0.27 mmol) in acetone (1.0 ml) was added the chromic acid reagent
which was purified by silica gel column chromatography (SiO2 200 g,
(0.28 ml, 0.55 mmol) and stirred at ꢀ10 °C for 15 min. The solution mixture
hexane : EtOAcꢁ2 : 1) to afford 10-hydroxy-10-methyldodeca-6,8-diynol was treated with 2-propanol and extracted with EtOAc. The EtOAc extract
(
19, 1.60 g, 6.8 mmol, 85% yield from 17).
was worked up in the usual manner to give a product (73 mg). Purification of
the product by silica gel column chromatography (SiO 10 g, CHCl
MeOHꢁ30 : 1) and HPLC (Wakosil 5 SIL, hexane : EtOAcꢁ4 : 1) afforded
ꢀ1
19: Colorless oil. IR (film) cm : 3600—3100 (br), 2253. UV l
2
:
3
max
1
(EtOH) nm (e): 214 (327), 228 (327), 240 (333), 254 (216), 282 (38). H-
NMR (300 MHz, CDCl ) d: 1.03 (3H, t, Jꢁ7.4 Hz), 1.47 (3H, s), 1.40—1.63 hexadeca-8,10,12-triynoic acid (6, 49 mg, 0.201 mmol, 66% yield from 21).
3
ꢀ1
(
7H), 1.70 (2H, ddd, Jꢁ2.1, 7.4, 14.9 Hz), 2.31 (2H, t, Jꢁ6.8 Hz), 3.65 (2H,
6: Colorless needles. mp 70—72 °C (from ether). IR (film) cm : 3300—
13
1
t, Jꢁ6.3 Hz). C-NMR (75 MHz, CDCl ) dc: 81.2, 79.2, 69.1, 68.3, 64.6, 2500 (br), 2216, 1695. H-NMR (300 MHz, CDCl
) d: 0.99 (3H, t, Jꢁ7.3
3
3
6
(
2.7, 36.4, 32.1, 29.1, 28.0, 25.0, 19.3, 8.9. EI-MS m/z (%): 190 (0.2), 179
19), 91 (100). High-resolution EI-MS m/z: Calcd for C H O: 190.1358, Jꢁ7.0 Hz), 2.36 (2H, t, Jꢁ7.4 Hz). C-NMR (75 MHz, CDCl ) dc: 179.1,
3
Hz), 1.30—1.47 (4H), 1.50—1.65 (6H), 2.26 (2H, t, Jꢁ7.0 Hz), 2.29 (2H, t,
1
3
1
3
18
ꢂ
and for C H O : 179.1072. Found: 190.1366 [M ꢀH O] and 179.1091 79.3, 79.0, 65.9, 65.8, 60.5, 60.3, 33.8, 28.5, 28.4, 27.8, 24.5, 21.6, 21.4,
11
15
2
2
ꢂ
ꢂ
[M ꢀC H ].
19.3, 13.5. EI-MS m/z (%): 244 (M , 2.4), 128 (100). High-resolution EI-
2
5
ꢂ
Nona-6,8-diynol (20) To a solution of 19 (700 mg, 3.37 mmol) in xy-
MS m/z: Calcd for C16
H
20
O
2
244.1463. Found: 244.1462 [M ].
lene (4.0 ml) was added NaOH (40 mg, 1.00 mmol) and the whole was
stirred under reflux for 10 min. After cooling, the mixture was poured into
ice-water and the whole was extracted with EtOAc. The EtOAc extract was
worked up in the usual manner to give a product (809 mg). Purification of
the product by silica gel column chromatography (SiO2 100 g, hexane :
EtOAcꢁ2 : 1) and HPLC (Wakosil 5 SIL, hexane : EtOAcꢁ4 : 1) afforded
nona-6,8-diynol (20, 380 mg, 2.79 mmol, 83% yield), which physicochemi-
The detail of invasion assay procedure was described in our previous
paper.
1)
References
1) Part XXV: Ohashi K., Winarno H., Mukai M., Inoue M., Prana M. S.,
Simanjuntak P., Shibuya H., Chem. Pharm. Bull. 51, 343—345 (2003).
2) Akedo H., Shinkai K., Mukai M., Mori Y., Tateishi R., Tanaka K.,
Yamamoto R., Morishita T., Cancer Res., 46, 2416—2422 (1986).
3) Van De Ven M., Van Langen H., Verwer W., Levine Y. K., Chem. Phys.
Lipids, 34, 185—200 (1984).
10)
cal properties were identical with those in the literature.
Hexadeca-6,8,10-triynoic Acid (5) To a solution of 15 (100 mg) and 20
(50 mg, 0.368 mmol) in pyrrolidine (1.0 ml) was added CuI (7.0 mg, 0.037
mmol) and the whole was stirred at room temperature for 30 min. The reac-
4) Arsequell G., Fabrias G., Gosalbo L., Camps F., Chem. Phys. Lipids,
63, 149—158 (1992).
tion mixture was treated with aqueous saturated NH Cl and extracted with
4
EtOAc. The EtOAc extract was worked up in the usual manner to afford a
product (122 mg), which was purified by silica gel column chromatography
5) Gunstone F. D., Sykes P. J., J. Chem. Soc., 1962, 3055—3058 (1962).
6) Abrams S. R., Can. J. Chem., 62, 1333—1334 (1984).
7) Poleschner H., Heydenreich M., Magn. Reson. Chem., 33, 917—921
(1995).
8) Heilbron I., Jones E. R. H., Sondheimer F., J. Chem. Soc., 1949, 604—
607 (1949).
9) Alami M., Ferri F., Tetrahedron Lett., 37, 2763—2766 (1996).
10) Okada S., Doi T., Mito A., Hayamizu K., Ticktin A., Matsuda H.,
Kikuchi N., Masaki A., Minami N., Hass K.-H., Nakanishi H., Nonlin-
ear Optics, 8, 121—132 (1994).
11) Zeni G., Panatieri R. B., Lissner E., Menezes P. H., Braga A. L., Ste-
fani H. A., Org. Lett., 3, 819—821 (2001).
(SiO2 10 g, hexane : EtOAcꢁ2 : 1) to give hexadeca-6,8,10-triynol (81 mg,
0
.352 mmol). To a solution of hexadeca-6,8,10-triynol (81 mg) in acetone
8)
(1.0 ml) was added the chromic acid reagent (0.350 ml, 0.70 mmol) and
stirred at ꢀ10 °C for 15 min. The reaction mixture was treated with 2-
propanol and extracted with EtOAc. The EtOAc phase was worked up in the
usual manner to give a product (76 mg). Purification of the product by silica
gel column chromatography (SiO 10 g, CHCl : MeOHꢁ30 : 1) and HPLC
2
3
(
Wakosil 5 SIL, hexane : EtOAcꢁ4 : 1) afforded hexadeca-6,8,10-triynoic
acid (5, 59 mg, 0.242 mmol, 66% yield from 20).
: Colorless needles. mp 86—88 °C (from ether). IR (film) cm : 3300—
ꢀ
1
5
1
2
500 (br), 2216, 1697. H-NMR (300 MHz, CDCl ) d: 0.90 (3H, t, Jꢁ7.1
Hz), 1.22—1.40 (4H), 1.45—1.68 (4H), 1.68—1.80 (2H), 2.28 (2H, t,
Jꢁ7.1 Hz), 2.33 (2H, t, Jꢁ7.0 Hz), 2.38 (2H, t, Jꢁ7.2 Hz). C-NMR (75
12) Imamura F., Shinkai K., Mukai M., Yoshioka K., Komagome R.,
Iwasaki T., Akedo H., Int. J. Cancer, 65, 627—632 (1996).
13) Shinkai K., Akedo H., Mukai M., Imamura F., Isoai A., Kobayashi M.,
Kitagawa I., Jpn. J. Cancer Res., 87, 357—362 (1996).
3
1
3
MHz, CDCl ) dc: 178.7, 79.6, 78.2, 66.2, 65.6, 60.7, 60.2, 33.3, 31.0, 27.8,
3