pronounced cytotoxicity, indicating the possibility to develop
further scaffolds for attachment to the taxol side chain.
Currently, more extensive biological evaluation is being
pursued and efforts are ongoing to identify and synthesise
further hybrids of these important anticancer agents.
Financial support was provided by the EPSRC and NIH
Grant no. R56 CA093455. We thank Dr J. Fernando Dıaz
´
(CSIC, Madrid) for providing AutoDock 3D structures, Dr
Stuart Mickel (Novartis) for chemicals, Professor Eiichi
Nakamura (University of Tokyo) for arranging a student
exchange (TF), and Tara Pitts and Pat Linley (HBOI) for
biological assays.
Notes and references
1 (a) M. S. Butler, Nat. Prod. Rep., 2005, 22, 162; (b) M. S. Butler,
Nat. Prod. Rep., 2008, 25, 475; (c) D. J. Newman and G. M. Cragg,
J. Nat. Prod., 2007, 70, 461; (d) I. Paterson and E. A. Anderson,
Science, 2005, 310, 451.
2 (a) G. M. L. Cragg, D. G. I. Kingston and D. J. Newman,
Anticancer Agents From Natural Products, Taylor & Francis
Group, Boca Raton, 2005; (b) K. H. Altmann and J. Gertsch,
Nat. Prod. Rep., 2007, 24, 327.
3 (a) K. C. Nicolaou, W. M. Dai and R. K. Guy, Angew. Chem., Int.
Ed., 1994, 33, 15; (b) F. Gueritte-Voegelein, D. Guenard,
F. Lavelle, M. T. Le Goff, L. Mangatal and P. Potier, J. Med.
Chem., 1991, 34, 992; (c) M. A. Jordan and L. Wilson, Nat. Rev.
Cancer, 2004, 4, 253.
4 E. ter Haar, R. J. Kowalski, E. Hamel, C. M. Lim, R. E. Longley,
S. P. Gunasekera, H. S. Rosenkranz and B. W. Day, Biochemistry,
1996, 35, 243.
Scheme 3 Completion of C7 methoxy analogues 18–20.
5 (a) G. R. Pettit, Z. A. Cichacz, F. Goa, M. R. Boyd and
J. M. Schmidt, J. Chem. Soc., Chem. Commun., 1994, 1111;
(b) R. A. Isbrucker, J. Cummins, S. A. Pomponi, R. E. Longley
and A. E. Wright, Biochem. Pharmacol., 2003, 66, 75;
(c) I. Paterson, R. Britton, O. Delgado and A. E. Wright, Chem.
Commun., 2004, 632.
6 (a) R. M. Buey, I. Barasoain, E. Jackson, A. Meyer,
P. Giannakakou, I. Paterson, S. Mooberry, J. M. Andreu and
J. F. Diaz, Chem. Biol., 2005, 12, 1269; (b) C. Madiraju,
M. C. Edler, E. Hamel, B. S. Raccor, R. Balachandran, G. Zhu,
K. A. Giuliano, A. Vogt, Y. Shin, J.-H. Fournier, Y. Fukui,
A. M. Bruckner, D. P. Curran and B. W. Day, Biochemistry,
¨
2005, 44, 15053.
7 A. Canales, R. Matesanz, N. M. Gardner, J. M. Andreu,
I. Paterson, J. F. Dıaz and J. Jimenez-Barbero, Chem.–Eur. J.,
´ ´
2008, 14, 7557.
8 I. Paterson, G. J. Naylor and A. E. Wright, Chem. Commun., 2008,
4628.
9 For other hybrids, see: (a) I. Paterson and N. M. Gardner, Chem.
Commun., 2007, 49; (b) Y. Shin, N. Choy, R. Balachandran,
C. Madiraju, B. W. Day and D. P. Curran, Org. Lett., 2002, 4,
4443.
10 Review: G. J. Florence, N. M. Gardner and I. Paterson, Nat. Prod.
Rep., 2008, 25, 342.
Fig. 2 The table shows human cancer cell growth inhibitory properties
of hybrids 9–12, 14–16, 18–20, relative to taxol (1), discodermolide
(3),8 dictyostatin (4) and dictyostatin–discodermolide hybrid (5).
Images: immunofluorescence images of PANC-1 cells stained with
anti-a-tubulin (green) and propidium iodide (red) and observed by
confocal microscopy. Cells were exposed to 100 nM concentrations of
dictyostatin (Image 1) and analogue 10 (Image 2). Dense microtubule
bundling (green) can be seen around the nuclei (red) in both images.
11 J. M. Andreu and I. Barasoain, Biochemistry, 2001, 40, 11975.
12 (a) I. Ojima, I. Habus, M. Zhao, M. Zucco, Y. H. Park, C. M. Sun
and T. Brigaud, Tetrahedron, 1992, 48, 6985; (b) I. Ojima,
C. M. Sun, M. Zucco, Y. H. Park, O. Duclos and S. Kuduk,
Tetrahedron Lett., 1993, 34, 4149; (c) R. A. Holton, Eur. Pat.
Appl., EP400 971 (Chem. Abstr., 1991, 114, 164568q).
13 Preparedw by adapting the method of Farina et al., see: V. Farina,
S. I. Hauck and D. G. Walker, Synlett, 1992, 761.
14 I. Paterson, N. M. Gardner, K. G. Poullennec and A. E. Wright,
Bioorg. Med. Chem. Lett., 2007, 17, 2443.
15 The methyl ether triple hybrids were stable in DMSO at ambient
temperature over several weeks; and the side chains were now
stable in methanol solution, implying that the neighbouring free
hydroxyl plays a critical role in the transesterification of hybrids
9–12.
In conclusion, we have designed and synthesised the first
triple hybrids of the anticancer natural products taxol,
dictyostatin and discodermolide. Significantly, we have
demonstrated that the polycyclic baccatin core of taxol can
be replaced with a macrolide template whilst maintaining
ꢀc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 261–263 | 263