556
C. L. Arthurs et al. / Bioorg. Med. Chem. Lett. 17 (2007) 553–557
9. Hamilton, D. S.; Ding, Z.; Ganem, B.; Creighton, D. J.
Org. Lett. 2002, 4, 1209.
10. Zhang, Q.; Ding, Z.; Creighton, D. J.; Ganem, B.; Fabris,
D. Org. Lett. 2002, 4, 1459.
11. Joseph, E.; Eiseman, J. L.; Hamilton, D. S.; Wang, H.;
Tak, H.; Ding, Z.; Ganem, B.; Creighton, D. J. J. Med.
Chem. 2003, 46, 194.
12. Hamilton, D. S.; Zhang, X.; Ding, Z.; Hubatsch, I.;
Mannervik, B.; Houk, K. N.; Ganem, B.; Creighton, D. J.
J. Am. Chem. Soc. 2003, 125, 15049.
Mammalian GSTs generally display selectivity for lipo-
philic substrates and the reduced potency of diols 7 and
8 compared with the more hydrophobic compounds 2,
19, and 22 is consistent, therefore, with a GST mediated
mechanism for anti-cancer activity. Indeed, comparative
bioassays by Douglas and co-workers of COTC (1) and
COMC (2) against a range of cancer cell lines showed 2
to be more potent than 1 in almost all cases.3,32 In this
regard, the finding that the monohydroxylated com-
pound 6 is more potent than COMC (2) toward the
two lung cancer cell lines investigated here represents
an interesting conundrum. Further studies are under
way to investigate the influence of absolute stereochem-
istry, as well as the position and degree of hydroxylation
of the cyclohexenone ring, on the anti-cancer activity of
this intriguing class of compounds.
13. Joseph, E.; Ganem, B.; Eiseman, J. L.; Creighton, D. J.
J. Med. Chem. 2005, 48, 6549.
14. Zheng, Z.-B.; Zhu, G.; Tak, H.; Joseph, E.; Eiseman, J. L.;
Creighton, D. J. Bioconjugate Chem. 2005, 16, 598.
15. Kamiya, D.; Uchihata, Y.; Ichikawa, E.; Kato, K.;
Umezawa, K. Bioorg. Med. Chem. Lett. 2005, 15, 1111.
16. Ba¨ckvall, J.-E.; Bystro¨m, S. E.; Nordberg, R. E. J. Org.
Chem. 1984, 49, 4619.
17. Deardorff, D. R.; Matthews, A. J.; McMeekin, D. S.;
Craney, C. L. Tetrahedron Lett. 1986, 27, 1255.
18. Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport, A. T.;
Cuccia, L. A. J. Org. Chem. 1991, 56, 2656.
19. Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D.
J. Chem. Soc., Chem. Commun. 1987, 1625.
In conclusion, three analogues of the anti-tumor agent
COTC (1) have been prepared from either 1,3-cyclohex-
adiene (9) or (ꢁ)-quinic acid (14) as starting material.
The structures of these compounds differ from that of
1 with respect to the extent of hydroxylation of the
cyclohexenone ring. Bioassay of the target compounds
indicates that polar dihydroxylated compounds are only
weakly active against lung cancer cell lines, whereas the
most potent analogue bears a single hydroxyl group at
C4 and is racemic. The findings indicate that further
modification of the cyclohexenone core structure of
COTC analogues will allow fine-tuning of the anti-can-
cer activity of this structural class.
20. Audia, J. E.; Boisvert, L.; Patten, A. D.; Villalobos, A.;
Danishefsky, S. J. J. Am. Chem. Soc. 1989, 54, 3738.
21. Rezgui, F.; El Gaied, M. M. Tetrahedron Lett. 1998, 39,
5965.
22. Selected analytical data for compound 6. mmax (film)/cmꢁ1
3434br s (O–H), 1716s (C@O, ester), 1657s (C@O, enone);
dH (300 MHz; CDCl3) 1.93 (3H, dd,
J 6.9, 1.8,
CH3CH@CHC(@O)), 2.35–2.72 (4H, m, C(5)H2 and
C(6)H2), 4.62–4.69 (1H, m, C(4)H), 4.80–4.92 (2H, m,
CH2O(C@O)),
5.92
(1H,
dq,
J
15.3,
1.8,
CH3CH@CHC(@O)), 6.92–6.93 (1H, m, C(3)H), 7.06
(1H, dq, J 15.3, 6.9, CH3CH@CHC(@O)); dC (75 MHz;
CDCl3) 18.4 (CH3CH@CHC(@O)), 32.7 (C(5)H2 or
C(6)H2), 35.8 (C(5)H2 or C(6)H2), 60.7 (CH2O(C@O)),
66.7 (C(4)H), 122.4 (CH3CH@CHC(@O)), 134.5 (C(2)),
146.0 (C(3)H), 148.9 (CH3CH@CHC(@O)), 166.3
(CH3CH@CHC(@O)), 197.4 (C(1)O); m/z (CI/NH3) 228
([M+NH4]+, 50%) 211 ([M+H]+, 100) (Found 228.1239,
C11H18O4N ([M+H]+) requires 228.1230).
Acknowledgments
We acknowledge, with thanks, the EPSRC for funding
(C.L.A.) and the MRC for funding (I.J.S. [MRC Grant
G0500366] and N.S.W.). We are also very grateful to
Professor Gareth Morris of the School of Chemistry at
the University of Manchester for invaluable advice con-
cerning the NMR analysis of several of our target com-
pounds and also to Rehana Sung for expert assistance
with HPLC purification of compounds 7 and 8.
23. Gebauer, O.; Bruckner, R. Liebigs Ann. 1996, 1559.
¨
24. Zhong, Y.-L.; Shing, T. K. M. J. Org. Chem. 1997, 62,
2622.
18
25. Selected analytical data for compound 7. ½aꢀD +11.74 (c
2.5, CH2Cl2); mmax (film)/cmꢁ1 3402br s (O–H), 2963w
(C–H), 1719m (C@O, ester), 1678m (C@O, enone); dH
(300 MHz; CDCl3) 1.94 (3H, dd,
CH3CH@CHC(@O)), 2.52 (1H, dd,
J
6.9, 1.8,
16.5, 12.3,
References and notes
J
C(6)Hb), 2.92 (1H, dd, J 16.5, 4.8, C(6)Ha), 4.01 (1H,
ddd, J 12.3, 8.4, 4.8, C(5)H), 4.58 (1H, dq, J 8.4, 2.4,
C(4)H), 4.85 (2H, br s, CH2O(C@O)) 5.90 (1H, dq, J 15.6,
1.8, CH3CH@CHC(@O)), 6.84 (1H, d, J 2.4, C(3)H), 7.05
(1H, dq, J 15.6, 6.9, CH3CH@CHC(@O)); dC (75 MHz;
CDCl3) 18.4 (CH3CH@CHC(@O)), 44.8 (C(6)H2), 60.3
(CH2O(C@O)), 72.9 (C(5)H), 73.3 (C(4)H), 122.2
(CH3CH@CHC(@O)), 135.2 (C(2)), 146.4 (C(3)H), 146.8
(CH3CH@CHC(@O)), 166.4 (CH3CH@CHC(@O)), 195.8
(C(1)O); m/z (CI/NH3) 244 ([M+NH4]+, 90%), 227
([M+H]+, 20) (Found 244.1181, C11H18O5N ([M+NH4]+)
requires 244.1179).
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28. Selected analytical data for compound 8. ½aꢀD ꢁ4.41 (c 1.4,
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(C@O, ester), 1680s (C@O, enone); dH (400 MHz; CDCl3)
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