M. Yamashita et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6417–6420
Table 2. Cytotoxic effect of racemate 1, (R)-1,1, and mitomycin
6419
References and notes
against human normal cell linesa,b
1. Gentry, A. H. Ann. Missouri Bot. Gard. 1973, 60, 945.
2. Hashimoto, G. Brazil Shokubutu-ki. Teikoku Shoin,
Tokyo, 1962; 193 pp.
Compound
EC50 (lM)
MPC-5
Fb
Hc
IE
Racemate 1
(R)-1
45.4
39.7
11.1
89.3
29.8
11.1
89.3
65.9
29.7
2.1
158
3. (a) Hartwell, J. L. Lloydia 1968, 31, 71; (b) Rao, M. M.;
Kingston, D. G. I. J. Nat. Prod. 1982, 45, 600.
4. (a) Ueda, S.; Tokuda, H. Planta Med. 1990, 56, 669;
(b) Zani, C. L.; O1iveira, A. B.; O1iveira, G. G.
Phytochemistry 1991, 30, 2379.
5. Wagner, H.; Kreher, B.; Lotter, H.; Hamburger, M. O.;
Cordell, G. A. Helv. Chim. Acta 1989, 72, 659.
6. (a) Ueda, S.; Tokuda, H.; Hirai, K. JP Patent 2669762,
1997; (b) Saizarbitoria T. C.; Anderson J. E.; McLaughlin
J. L. Abstr Pap 33rd Annu Meet Am Soc Phamacognogy,
Williamsburg, VA, 1992, P-22.
7. Ueda, S.; Umemura, T.; Dohguchi, K.; Matsuzaki, T.;
Tokuda, H.; Nishino, H.; Iwashima, A. . Phytochemistry
1994, 36, 323.
8. Ueda, S.; Tokuda, H.; Hirai, K.; Hatanaka, H. Chem.
Abstr 1994, 121, 50088, U.S. Patent 566319, 1977.
9. Ravelo, A. G.; Braun, A. E.; Sacau, E. P.. In Studies in
Natural Products Chemistry; Rahman, A. U., Ed.; Else-
vier: Amsterdam, 2003; Vol. 29, p 719.
39.7
54.5
1.46
1
Mitomycin
0.93
1.46
a Cell line: Fb, skin; Hc, liver; MPC-5, lung; IE, colon.
b Cell viability was evaluated by the Trypan blue staining method.
Table 3. Inhibitory effects on TPA-induced EBV-EA activation
Compound
EBV-EA positive cells (% viability)a
Compoundconcentration(molratio/32 pmolTPA)
c
1000
500
6.2 (70) 20.7 52.9
9.7 24.7 59.4
4.4 (60) 16.9 50.0
100
10
IC50 (lM)
Racemate 1
(R)-1
0 (60)b
0 (70)
0 (60)
34.9
38.9
33.2
1
b-Lapachone 4.7 (50) 21.7 50.4 73.1 210.3
Lapachol 8.9 (50) 32.8 (60) 65.2 86.6 311.4
a Values represent relative percentage to the positive control value
(100%).
b Values in parentheses represent viability percentages of Raji cells
measured through Trypan blue staining; unless otherwise stated, the
viability percentage of Raji cells was more than 80%.
c IC50 value of curcumin, a positive control substance, was 345 lM.
10. (a) Fujimoto, Y.; Eguchi, T.; Murasaki, C.; Ohashi, Y.;
Kakinuma, K.; Takagaki, H.; Abe, M.; Inazawa, K.;
Yamazaki, K.; Ikekawa, N.; Yoshikawa, O.; Ikekawa, T.
J. Chem. Soc. Perkin Trans. 1991, 2323; (b) Hagiwara, H.;
Sato, K.; Nishino, D.; Hoshi, T.; Suzuki, T.; Ando, M.
J. Chem. Soc. Perkin Trans. I 2001, 2946.
11. Tietze, L. F.; Guntner, C.; Gericke, K. M.; Schuberth, I.;
¨
Bunkoczi, G. Eur. J. Org. Chem 2005, 2459.
12. (a) Chaker, L.; Pautet, F.; Fillion, H. Chem. Pharm.
Bull. 1994, 42(11), 2238; (b) de Oliveira, A. B.;
Ferreira, D. T.; Raslan, D. S. Tetrahedron Lett. 1988,
29(2), 155.
cytotoxicity against the normal cell lines (0.93–
1.46 lM). These results suggest that 1 could be a prom-
ising candidate for the development of anticancer drugs.
13. Synthesis of racemate 1. Reagents and conditions: Reduc-
tion of 10 with NaBH4 in CH2Cl2 at 0 ꢁC provided
racemate 1 in 79% yield.
14. The absolute stereochemistry of synthetic 1 was confirmed
as S by comparing its specific rotation with the previously
reported one.10a
Compound 1 has already been known to act as a cancer
chemopreventive agent.8 In order to compare in vitro
cancer chemopreventing activity of (R)-1 with that of
1, 1 and (R)-1 were evaluated for their inhibitory effects
on EBV-EA activation induced by TPA in Raji cells as a
primary screening test for antitumor promoters (Table 3).
In this assay, both 1 and (R)-1 showed potent inhibition
on EBV-EA activation without cytotoxicity against Raji
cells dose-dependently (100%, 90–95%, 75–83%, 41–50%
inhibition at 1000, 500, 100, and 10 mol ratio/TPA,
respectively). In particular, 1 exhibited significantly po-
tent inhibitory effects on EBV-EA activation. The inhib-
itory activities of these compounds were greater than
those of b-lapachone and lapachol, which are known
as congeners of 1 in T. avellanedae.
15. (a) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.;
Noyori, R. J. Am. Chem. Soc 1996, 118, 2521; (b) Noyori,
R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97.
16. General experiment procedures: to a flask were added
ketone 10 (128 mg, 0.5 mmol), Noyori asymmetric transfer
hydrogenation catalyst Ru [(S,S)-Tsdpen](p-cymene)
(15 mg, 0.025 mmol, 5 mol %), CH2Cl2 (5.0 mL), and
formic acid/Et3N (5:2, 1.3 ml). The resulting solution was
stirred at room temperature for 24 h. The reaction mixture
was diluted by addition of H2O and 10% HCl aq, and
extracted with CHCl3. The organic extracts were washed
with brine and then dried over Na2SO4. Concentration
and column chromatography (hexane/EtOAc = 2/1) gave
1 (115 mg, 89% yield, 96% ee) as yellow needles of mp
In conclusion, the concise stereoselective synthesis of 1
was completed by using Noyori reduction as a key step.
Compound 1 showed potent cytotoxicity and cancer
chemopreventive activity. Future progress on related
series will be reported in due course.
24
171–172 ꢁC. ½aꢁD ꢀ 22.7 (c 0.58, CH3OH), 96% ee (HPLC,
SUMICHIRAL, OA-4500 (4.6 mm/ · 250 mm), hexane/i-
PrOH/MeOH = 95/4/1, 1 mL/min, 254 nm, minor 37.9 min
and major 40.9 min). 1H NMR (CDCl3): 1.66 (3H, d,
J = 6.8 Hz), 2.31 (1H, brs), 5.05 (1H, m), 6.84 (1H, s), 7.27
(1H, dd, J = 1.0, 8.3 Hz), 7.75 (1H, dd, J = 0.9, 8.0 Hz),
12.18 (1H, s). 13C NMR (CDCl3): 21.5, 63.83, 103.4,
115.2, 120.0, 125.3, 131.0, 132.6, 136.3, 152.0, 162.3, 165.4,
172.7, 186.5.
Acknowledgments
The authors thank Taheebo Japan Co. Ltd. (Osaka, Ja-
pan) for generously providing the powdered inner bark
of Tabebuia avellanedae.
17. Tsdpen = N-(p-toluenesulfonyl)-1,2-diphenylethanediamine,
Msdpen = N-(methanesulfonyl)-1,2-diphenylethanediamine.
18. Enantiomerically pure 1 and (R)-1 (>99% ee) used for
biological evaluation were prepared from racemate 1