C. L. Arthurs et al. / Tetrahedron Letters 49 (2008) 2410–2413
2413
Table 1
Mannervik, B.; Houk, K. N.; Ganem, B.; Creighton, D. J. J. Am.
Chem. Soc. 2003, 125, 15049–15058; (f) Joseph, E.; Ganem, B.;
Eiseman, J. L.; Creighton, D. J. J. Med. Chem. 2005, 48, 6549–6552;
(g) Zheng, Z.-B.; Zhu, G.; Tak, H.; Joseph, E.; Eiseman, J. L.;
Creighton, D. J. Bioconjugate Chem. 2005, 16, 598–607.
Bioactivity of COTC analogues towards lung cancer cell lines
Compound
IC50 (lM)
A549
H460
COMC (2)5a
55
147
170
24
>200
18
40
158
158
10
>200
20
5. (a) Arthurs, C. L.; Wind, N. S.; Whitehead, R. C.; Stratford, I. J.
Bioorg. Med. Chem. Lett. 2007, 17, 553–557; (b) Arthurs, C. L.;
Raftery, J.; Whitby, H. L.; Whitehead, R. C.; Wind, N. S.; Stratford,
I. J. Bioorg. Med. Chem. Lett. 2007, 17, 5974–5977.
55a
65b
75a
9
6. Gebauer, O.; Bruckner, R. Liebigs Ann. 1996, 1559–1563.
¨
7. Rezgui, F.; El Gaied, M. M. Tetrahedron Lett. 1998, 39, 5965–5966.
8. Selected analytical data for compound 9: A clear oil; ½aꢁ2D2 +101.5 (c 1.3,
CH2Cl2); mmax (film)/cmꢀ1 3434 (br s, OH), 2099 (w, CH), 1644 (br s,
C@O); dH (300 MHz; CDCl3) 1.22 (1H, dd, J 8.4, 6.3, cyclopropyl
CHexo), 1.43 (1H, t, J 6.0, cyclopropyl CHendo), 1.91 (3H, dd, J 6.9,
1.8, CH3CH@CH), 2.05–2.11 (1H, m, C(3)H), 2.31 (1H, dd, J 18.0,
10.2, C(6)Hb), 2.35 (2H, br, 2 ꢂ OH), 2.82 (1H, dd, J 18.0, 5.7,
C(6)Ha), 3.79–3.87 (1H, m, C(5)H), 3.95 (1H, d, J 11.7, one of
CH2OC@O), 4.14 (1H, q, J 4.2, C(4)H), 4.73 (1H, d, J 11.7, one of
CH2OC@O), 5.86 (1H, dq, J 15.6, 1.8, CH3CH@CH), 7.00 (1H, dq, J
15.6, 6.9, CH3CH@CH); dC (75 MHz; CDCl3) 13.8 (cyclopropyl
CH2), 18.0 (CH3CH@CH), 26.5 (C(3)H), 34.8 (C(2)), 43.4 (C(6)H2),
64.7 (CH2OC@O), 68.4 (C(5)H), 70.4 (C(4)H), 122.2 (CH3CH@CH),
145.4 (CH3CH@CH), 166.3 (CH2OC@O), 222.1 (C(1)O); m/z (CI/
NH3) 258 (MNH4þ, 10%), 241 (MH+, 100); (Found: 241.2523,
C12H17O5 requires 241.2524).
10
11
17
11
the design and synthesis of compounds belonging to this
structural class with improved anti-cancer activity.
Acknowledgements
We acknowledge, with thanks, the EPSRC (C.L.A.),
BBSRC (M.P.) and the MRC (I.S. and N.S.W) for funding
and AstraZeneca for the generous provision of a vacation
bursary (K.F.L.).
9. Luo, S.; Wang, P. G.; Chen, J.-P. J. Org. Chem. 2004, 69, 555–558.
References and notes
20
10. Selected analytical data for compound 10: A clear oil; ½aꢁD ꢀ84.2 (c
0.57, CH2Cl2); mmax(film)/cmꢀ1 3424 (br, OH), 1713 (s, C@O), 1666 (s,
C@O); dH (300 MHz; CDCl3) 1.11–1.34 (2H, m, cyclopropyl CH2),
1.93 (3H, dd, J 6.0, 3.0, CH3CH@CH), 2.07–2.12 (2H, m, C(5)H and
C(6)H), 2.60 (1H, br, OH), 4.72–4.87 (2H, m, CH2OC@O), 4.96–4.98
(1H, m, C(4)H), 5.90 (1H, dq, J 15.0, 3.0, CH3CH@CH), 6.35–6.36
(1H, m, C(3)H), 7.05 (1H, dq, J 15.0, 6.0, CH3CH@CH); dC (75 MHz;
CDCl3) 11.3 (cyclopropyl CH2), 18.4 (CH3CH@CH), 18.9 (C(5)H or
C(6)H), 24.3 (C(5)H or C(6)H), 60.7 (CH2OC@O), 64.9 (C(4)H),
122.3 (CH3CH@CH), 130.7 (C(2)), 141.9 (C(3)H), 146.1
(CH3CH@CH), 166.3 (CH2OC@O), 195.6 (C(1)O); m/z (CI/NH3)
240 (MNH4þ, 15%), 223 (MH+, 100); (Found: 223.0969, C12H15O4
requires 223.0965).
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