T. Devji et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5770–5773
5773
tetrahydrofuran was added dropwise via syringe. The suspension was
allowed to warm to 0 °C and was subsequently allowed to stir at 0 °C for 1 h.
The reaction mixture was poured into 8 mL of iced water and the aqueous layer
was extracted with ice-cold diethyl ether (3 Â 4 mL). The combined organic
extracts were washed with ice-cold saturated NaHCO3 (10 mL) and brine
(10 mL), and dried over anhydrous MgSO4. The organic layer was filtered and
concentrated in vacuo to give the crude geranylgeranyl bromide which was
then was used for the next reaction immediately without further purifications.
Synthesis of 7-((2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraenyl-
oxy)-2H-chromen-2-one (9): To an oven dried 50-mL round-bottom flask
equipped with a magnetic stirring bar, rubber septa and a nitrogen inlet,
umbelliferone (1) (19.3 mg, 0.12 mmol) and 10 mL of anhydrous DMF were
added. The solution was cooled to 0 °C and sodium hydride (4.2 mg of 60%
mineral oil suspension) was added. The reaction mixture was allowed to stir
for 25 min at 0 °C, and the crude geranylgeranyl bromide from the previous
step was dissolved anhydrous DMF (2 mL) and added dropwise to the reaction
flask via syringe. The reaction was allowed to slowly warm to room
temperature and was stirred overnight. The desired compound was isolated
via preparative thin layer chromatography using 3:7 ethyl acetate:hexanes
solvent system. 1H NMR (300 MHz, CDCl3): d 1.51–1.87 (m, 15H), 1.92–2.18 (m,
12H), 4.60 (d, J = 6.6 Hz, 2H), 5.10 (m, 3H), 5.47 (t, J = 6.3 Hz, 1H), 6.25 (d,
J = 9.5 Hz, 1H), 6.80–6.88 (m, 2H), 7.36 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 9.5 Hz,
1H). 13C NMR (75 MHz, CDCl3): d 16.1, 16.8, 17.7, 20.9, 26.6, 29.4, 29.7, 30.0,
39.5, 39.7, 39.8, 65.5, 101.6, 112.4, 113.0, 113.2, 118.4, 123.5, 124.4, 129.7,
131.3, 135.6, 136.2, 142.4, 143.5, 155.9, 161.3, 162.2. HRMS (EI) Calcd for
References and notes
1. Jemal, A.; Siegel, R.; Ward, E.; Murray, T.; Xu, J.; Thun, M. J. CA Cancer J. Clin.
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2. Eckel, F.; Schneider, G.; Schmid, R. M. Expert Opin. Investig. Drugs 2006, 15,
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3. Huguet, F.; Andre, T.; Hammel, P.; Artru, P.; Balosso, J.; Selle, F.; Deniaud-
Alexandre, E.; Ruszniewski, P.; Touboul, E.; Labianca, R.; de Gramont, A.;
Louvet, C. J. Clin. Oncol. 2007, 25, 326.
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6201.
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1263.
6. Esumi, H.; Izuishi, K.; Kato, K.; Hashimoto, K.; Kurashima, Y.; Kishimoto, A.;
Ogura, T.; Ozawa, T. J. Biol. Chem. 2002, 277, 32791.
7. Esumi, H.; Lu, J.; Kurashima, Y.; Hanaoka, T. Cancer Sci. 2004, 95, 685.
8. Awale, S.; Lu, J.; Kalauni, S. K.; Kurashima, Y.; Tezuka, Y.; Kadota, S.; Esumi, H.
Cancer Res. 2006, 66, 1751.
9. Awale, S.; Nakashima, E. M. N.; Kalauni, S. K.; Tezuka, Y.; Kurashima, Y.; Lu, J.;
Esumi, H.; Kadota, S. Bioorg. Med. Chem. Lett. 2006, 16, 581.
10. For examples of reviews, see: (a) Riveiro, M. E.; De Kimpe, N.; Moglioni, A.;
Vazquez, R.; Monczor, F.; Shayo, C.; Davio, C. Curr. Med. Chem. 2010, 17, 1325;
(b) Dighe, N. S.; Pattan, S. R.; Dengale, S. S.; Musmade, D. S.; Shelar, M.; Tambe,
V.; Hole, M. B. Arch. Appl. Sci. Res. 2010, 2, 65; (c) Bhatnagar, A.; Sharma, P. K.;
Kumar, N.; Dudhe, R. Pharmacia Lettre 2010, 2, 297; (d) Wu, L.; Wang, X.; Xu,
W.; Farzaneh, F.; Xu, R. Curr. Med. Chem. 2009, 16, 4236; (e) Borges, F.; Roleira,
F.; Milhazes, N.; Santana, L.; Uriarte, E. Curr. Med. Chem. 2005, 12, 887.
11. For examples, see: (a) Hamerski, D.; Schmitt, D.; Matern, U. Phytochemistry
1990, 29, 1131; (b) Rahalison, L.; Benathan, M.; Monod, M.; Frenk, E.; Gupta, M.
P.; Solis, P. N.; Fuzzati, N.; Hostettmann, K. Planta Med. 1995, 61, 360; (c) Zdero,
C.; Bohlmann, F.; Niemeyer, H. M. Phytochemistry 1990, 29, 326; (d) Kofinas, C.;
Chinou, I.; Loukis, A.; Harvala, C.; Roussakis, C.; Maillard, M.; Hostettmann, K.
Planta Med. 1998, 64, 174; (e) Fortin, H.; Tomasi, S.; Jaccard, P.; Robin, V.;
Boustie, J. Chem. Pharm. Bull. 2001, 49, 619; (f) Iranshahi, M.; Arfa, P.; Ramezani,
M.; Jaafari, M. R.; Sadeghian, H.; Bassarello, C.; Piacente, S.; Pizza, C.
Phytochemistry 2007, 68, 554; (g) Iranshahi, M.; Kalategi, F.; Rezaee, R.;
Shahverdi, A. R.; Ito, C.; Furukawa, H.; Tokuda, H.; Itoigawa, M. Planta Med.
2008, 74, 147; (h) Jabrane, A.; Ben, J. H.; Mighri, Z.; Mirjolet, J. F.; Duchamp, O.;
Harzallah-Skhiri, F.; Lacaille-Dubois, M. A. Chem. Biodivers. 2010, 7, 392; (i) Lee,
C. L.; Chiang, L. C.; Cheng, L. H.; Liaw, C. C.; El-Razek, M. H. A.; Chang, F. R.; Wu,
Y. C. J. Nat. Prod. 2009, 72, 1568.
C
29H38O3: 434.28210; found: 434.28330.
14. Synthesis of 7-hydroxy-8-iodo-2H-chromen-2-one (2): Umbelliferone (1)
(200 mg, 1.23 mmol) was dissolved in 20% NH4OH solution (5 mL) to
a
which a solution of I2 (313 mg, 1.23 mmol) dissolved in aqueous KI (5%, 10 mL)
was added dropwise. After 1.5 h, the reaction was quenched with 2.5 NÁH2SO4
until acidic and precipitation occurred. The solid was filtered and purified with
silica gel column chromatography using 5:95 ethyl acetate:dichloromethane to
afford the desired product as a yellow solid (318 mg, 90%). 1H NMR (300 MHz,
CD3OD): d 8.01 (d, J = 9 Hz, 1H), 7.66 (d, J = 6 Hz, 1H), 7.05 (d, J = 9 Hz, 1H), 6.41
(d, J = 9 Hz, 1H). 13C NMR (75 MHz, CD3OD): d 74.7, 112.4, 113.2, 130.0, 145.3,
156.3, 162.4, 162.6. HRMS (EI) Calcd for C9H5O3I: 287.92838; found:
287.92906.
15. In vitro preferential cytotoxicity and morphological change observation: PANC-1
cells were seeded in 96-well plates (2 Â 104 cells per well) and incubated in
fresh Dulbecco’s modified Eagle’s medium (DMEM; Nissui Pharmaceuticals;
Tokyo, Japan) at 37 °C under 5% CO2 and 95% air for 24 h. The cells were then
washed with PBS (Nissui Pharmaceuticals), followed by addition of serially
diluted test samples in DMEM or nutrient deprived medium (absence of
glucose, amino acid and serum), and incubated for 24 h incubation. Then, the
cell morphology was observed under the inverted microscope (TS100, Nikon)
and was photographed by digital camera (Degital Sight DS-L2, Nikon). The cells
were then washed again with PBS, and 100 ml of DMEM with 10% WST-8 cell
counting kit solution was added to each well. After 3 h incubation, absorbance
of the wells at 450 nm was measured. Cell viability was calculated from the
mean values of data from three wells by using the following equation: (%) Cell
viability = [{Abs(test sample)ÀAbs (blank)}/Abs(control)ÀAbs(blank)] Â 100.
12. (a) Kingsbury, J. S.; Corey, E. J. J. Am. Chem. Soc. 2005, 127, 13813; (b) Corey, E.
J.; Hahl, R. W. Tetrahedron Lett. 1989, 30, 3023.
13. Synthesis of geranylgeranyl bromide: To an oven-dried 25-mL round-bottom
flask equipped with a magnetic stirring bar, rubber septum and a nitrogen
inlet, 326.8 mg (1.125 mmol) of geranylgeraniol and 7.5 mL of anhydrous
tetrahydrofuran were added. The solution was stirred and cooled to À45 °C. To
the cold solution, methanesulfonyl chloride (167.5 mg, 113 lL, 1.46 mmol)
was slowly added to the reaction flask via syringe. To this solution,
triethylamine (227.7 mg, 313 L, 2.25 mmol) was then added via syringe
over 5 min and the resulting suspension was stirred at À45 °C for 45 minutes.
solution of lithium bromide (390.8 mg, 4.5 mmol) in 2.5 mL of
l
A