F. Saito et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1975–1977
1977
In conclusion, we have found that synthetic (Æ)-unte-
none A (1) and (Æ)-manzamenone A (2) inhibited
mammalian DNA polymerases a and b, and human
terminal deoxynucleotidyl transferase (TdT). We also
found that untenone A was a relatively selective inhi-
bitor of DNA polymerase a. In order to examine the
structure–activity function relationships of untenone A,
we synthesized untenone derivatives 12, 14, 15 and 16
and investigated the inhibitory activities for each
enzyme.11 And we found that the b-ketoester moiety
was essential for these activities. The substituents at the
4-position influenced the inhibitory activity of DNA
polymerases a and b, and TdT as well as selective inhi-
bition of DNA polymerase a.
S.; Kuramochi, K.; Nagata, S.; Sugawara, F.; Sakaguchi,
K. Biochem. Biophys. Res. Commun. 2000, 273, 784.
6. Miyaoka, H.; Watanuki, T.; Saka, Y.; Yamada, Y. Tetra-
hedron 1995, 51, 8749.
7. Kaneko, C.; Sugimoto, A.; Tanaka, S. Synth. Commun.
1974, 876.
8. Reduction of the double bond of compound (Æ)-12 was
unsuccessful by both hydrogenation and 1,4-reduction.
Hydrogenation of 12 using catalytic Rh-Al2O3 and PtO2-
C gave (Æ)-16. The use of other reductants (NaBH4 in
MeOH, Mg in MeOH and CuCl, PhMe2SiH in DMF, etc)
gave complex mixture.
9. The NOESY correlation was observed for H-5/H-6.
10. (a) Mizushina, Y.; Tanaka, N.; Yagi, H.; Kurosawa, T.;
Onoue, M.; Seto, H.; Horie, T.; Aoyagi, N.; Yamaoka,
M.; Matsukage, A.; Yoshida, S.; Sakaguchi, K. Biochim.
Biophys. Acta 1996, 1308, 256. (b) Mizushina, Y.; Yagi,
H.; Tanaka, N.; Kurosawa, T.; Seto, H.; Katsumi, K.;
Onoue, M.; Ishida, H.; Iseki, A.; Nara, T.; Morohashi,
K.; Horie, T.; Onomura, Y.; Narusawa, M.; Aoyagi, N.;
Takami, K.; Yamaoka, M.; Inoue, Y.; Matsukage, A.;
Yoshida, S.; Sakaguchi, K. J. Antibiot. (Tokyo) 1996, 49,
491. (c) Mizushina, Y.; Yoshida, S.; Matsukage, A.;
Sakaguchi, K. Biochim. Biophys. Acta 1997, 1336, 509.
11. All new compounds were fully characterized by 1H NMR,
13C NMR, IR spectra and satisfactory high-resolution
MS were obtained. 14: mp=44–49 ꢀC. IR (film) 3418,
3017, 2925, 2854, 1715, 1589, 1465, 1404, 1339, 1215,
Acknowledgements
We are grateful to Dr. S. Yoshida and Dr. M. Take-
mura of Nagoya University School of Medicine for
preparing calf DNA polymerase a.
References and notes
1
1. (a) Ishibashi, M.; Takeuchi, S.; Kobayashi, J. Tetrahedron
Lett. 1993, 34, 3749. (b) Kobayashi, J. Kagaku To
Seibutsu 1993, 31, 659. (c) First total synthesis: Takeda,
K.; Nakayama, I.; Yoshii, E. Synlett 1994, 178.
2. Tsukamoto, S.; Takeuchi, S.; Ishibashi, M.; Kobayashi, J.
J. Org. Chem. 1992, 57, 5255.
3. (a) Al-Busafi, S.; Drew, M. G. B.; Sanders, T.; Whitehead,
R. C. Tetrahedron Lett. 1998, 39, 1647. (b) Al-Busafi, S.;
Whitehead, R. C. Tetrahedron Lett. 2000, 41, 3467. (c) Al-
Busafi, S.; Doncaster, J. R.; Drew, M. G. B.; Regan, A. C.;
Whitehead, R. C. J. Chem. Soc., Perkin Trans. 1 2002,
476.
4. Tsuda, M.; Endo, T.; Perpelescu, M.; Yoshida, S.;
Watanabe, K.; Fromont, J.; Mikami, Y.; Kobayashi, J.
Tetrahedron 2003, 59, 1137.
5. (a) Sakaguchi, K.; Sugawara, F.; Mizushina, Y. Seika-
gaku 2002, 74, 244. (b) Mizushina, Y.; Kamisuki, S.;
Mizuno, T.; Takemura, M.; Asahara, H.; Linn, S.;
Yamaguchi, T.; Matsukage, A.; Hanaoka, F.; Yohida, S.;
Saneyoshi, M.; Sugawara, F.; Sakaguchi, K. J. Biol.
Chem. 2000, 275, 33957. (c) Mizushina, Y.; Kamisuki,
S.; Kasai, N.; Shimazaki, N.; Takemura, M.; Asahara,
H.; Linn, S.; Yohida, S.; Matsukage, A.; Koiwai, O.;
Sugawara, F.; Yoshida, H.; Sakaguchi, K. J. Biol. Chem.
2002, 277, 630. (d) Hanashima, S.; Muzushina, Y.; Ohta,
K.; Yamazaki, T.; Sugawara, F.; Sakaguchi, K. Jpn. J.
Cancer Res. 2000, 91, 1073. (e) Mizushina, Y.; Kobayashi,
1067, 801, 759, 668 cmÀ1. H NMR (400 MHz, CDCl3) d
0.88 (3H, t, J=6.8 Hz), 1.19–1.27 (28H, brm), 1.74 (2H,
m), 1.80 (1H, brs), 2.44 (1H, d, J=18.3Hz), 2.56 (1H, d,
J=18.3Hz), 6.13(1H, d, J=5.6 Hz), 7.41 (1H, d, J=5.6
Hz). 13C NMR (100 MHz, CDCl3) d 14.1, 22.7, 24.2, 29.3,
29.4, 29.5, 29.6, 29.6, 29.7 (Â5), 29.8, 31.9, 40.3, 48.8,
79.2, 133.3, 165.8, 206.9. HRMS calcd for C21H38O2Na
(M+Na+) 345.2764, found 345.2765. 15: IR (film) 3020,
2926, 2854, 1739, 1714, 1620, 1465, 1437, 1361, 1295,
1259, 1216, 1155, 1026, 758, 667 cmÀ1
.
1H NMR
(600 MHz, CDCl3) d 0.88 (3H, t, J=7.0 Hz), 1.26–1.32
(23H, brm), 1.36 (1H, m), 1.57 (4H, m), 2.49 (2H, m), 2.68
(2H, m), 2.76 (2H, t, J=7.9 Hz), 3.84 (3H, s). 13C NMR
(100 MHz, CDCl3) d 14.1, 22.7, 27.7, 29.3, 29.4, 29.5,
29.6, 29.6, 29.7 (Â7), 30.4, 31.9, 32.7, 34.9, 51.8, 163.8,
189.0, 203.8. HRMS calcd for C23H40O3Na (M+Na+)
387.2869, found 387.2868. 16: mp=38–41 ꢀC. IR (film)
3021, 2927, 2855, 1754, 1726, 1463, 1439, 1216, 1129, 927,
759, 669 cmÀ1. 1H NMR (600 MHz, CDCl3) d 0.88 (3H, t,
J=6.9 Hz), 1.23–1.31 (27H, brm), 1.36 (1H, m), 1.43 (1H,
m), 1.47 (1H, m), 1.54 (1H, m), 2.23(1H, m), 2.32 (1H,
m), 2.42 (1H, dd, J=8.3Hz, 18.7 Hz), 2.57 (1H, m), 2.83
(1H, d, J=11.2 Hz), 3.76 (3H, s). 13C NMR (100 MHz,
CDCl3) d 14.1, 22.7, 27.2, 27.4, 29.4, 29.5, 29.6, 29.6, 29.7
(x 7), 31.9, 35.0, 38.5, 41.5, 52.4, 61.9, 170.1, 212.1.
HRMS calcd for C23H42O3Na (M+Na+) 389.3026,
found 389.3039.