S. J. Gregson et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2859–2862
2861
Scheme 2. (a) (EtO)2P(O)CH2CO2Me, NaH, THF, 0 ꢀC, 16 h, 79%; (b) Ph3PCH3Br, KOtBu, THF, 0 ꢀC, 2.5 h, 51%; (c) AcOH/THF/H2O (3:1:1),
16 h, 94%; (d) HF–pyridine complex, THF, 0 ꢀC, 1.5 h, 99%; (e) (COCl)2, DMSO, TEA, CH2Cl2, ꢁ45 ꢀC, 78% for 14, 77% for 15; (f) Pd(PPh3)4,
PPh3, pyrrolidine, CH2Cl2, 1.5 h, 66% for 16, 77% for 1.
4. Thurston, D. E.; Bose, D. S.; Thompson, A. S.; Howard,
Interestingly, no similar trends are obvious for the
structurally analogous series of 7,8-dimethoxy-PBD
P. W.; Leoni, A.; Croker, S. J.; Jenkins, T. C.; Neidle, S.;
Hartley, J. A.; Hurley, L. H. J. Org. Chem. 1996, 61, 8141.
monomers (results given in parentheses in Table 1;
5. Gregson, S. J.; Howard, P. W.; Jenkins, T. C.; Kelland,
L. R.; Thurston, D. E. J. Chem. Soc., Chem. Commun. 1999,
797.
6. Bose, D. S.; Thompson, A. S.; Ching, J. S.; Hartley, J. A.;
Berardini, M. D.; Jenkins, T. C.; Neidle, S.; Hurley, L. H.;
Thurston, D. E. J. Am. Chem. Soc. 1992, 114, 4939.
7. Gregson, S. J.; Howard, P. W.; Hartley, J. A.; Brooks,
N. A.; Adams, L. J.; Jenkins, T. C.; Kelland, L. R.; Thurston,
D. E. J. Med. Chem. 2001, 44, 737.
8. Mountzouris, J. A.; Wang, J. J.; Thurston, D. E.; Hurley,
L . H.J. Med. Chem. 1994, 37, 3132.
9. Jenkins, T. C.; Hurley, L. H.; Neidle, S.; Thurston, D. E. J.
Med. Chem. 1994, 37, 4529.
structures not shown), presumably reflecting the different
mechanism of action of the two series of compounds (i.e.,
monoalkylation for PBD monomers versus cross-linking
for PBD dimers).
In summary, we have developed a versatile and efficient
synthetic route to C-ring unsaturated PBD dimers of
types 1 and 16. This has enabled the preparation of
gram quantities of the clinical candidate 1 and should
allow the synthesis of more structurally diverse PBD
dimer analogues. Furthermore, it has been established
that C2-exo-unsaturation enhances both cytotoxicity
and DNA-binding affinity to a greater degree than C2-
C3-endo-unsaturation in A-ring-linked PBD dimers.
10. Thurston, D. E.; Howard, P. W. International Patent
Application, No. WO 00/12508, UK, 2000.
11. Gregson, S. J.; Howard, P. W.; Corcoran, K. E.; Barcella,
S.; Yasin, M. M.; Hurst, A. A.; Jenkins, T. C.; Kelland, L. R.;
Thurston, D. E. Bioorg. Med. Chem. Lett. 2000, 10, 1845.
12. Gregson, S. J.; Howard, P. W.; Barcella, S.; Nakamya, A.;
Jenkins, T. C.; Kelland, L. R.; Thurston, D. E. Bioorg. Med.
Chem. Lett. 2000, 10, 1849.
Acknowledgements
This work was supported in part by the Cancer
Research Campaign UK (Grant numbers: SP1938/0301
to D.E.T. & T.C.J.; SP1938/0401 to D.E.T.; SP/DC/
STU2330/0201 to L.R.K.) and Yorkshire Cancer
Research (to T.C.J.).
13. Leimgruber, W.; Batcho, A. D.; Czajkowski, R. C. J. Am.
Chem. Soc. 1968, 90, 5641.
14. Kaneko, T.; Wong, H.; Doyle, T. W.; Rose, W. C.; Brad-
ner, W. T. J. Med. Chem. 1985, 28, 388.
15. Fukuyama, T.; Liu, G.; Linton, S. D.; Lin, S. C.; Nishino,
H. Tetrahedron Lett. 1993, 34, 2577.
16. Experimental procedure for Scheme 2 step (e): A solution
of DMSO (0.55 mL, 7.75 mmol) in dry CH2Cl2 (10 mL) was
added drop-wise over a 15 min period to a stirred solution of
oxalyl chloride (0.32 mL, 3.67 mmol) in CH2Cl2 (10 mL) at
ꢁ45 ꢀC under a nitrogen atmosphere. The reaction mixture
was allowed to stir for 35 min at ꢁ45 ꢀC followed by addition
of the bis-alcohol 13 (1.01 g, 1.32 mmol) in CH2Cl2 (10 mL) at
the same temperature over 15 min. After a further 45 min a
solution of triethylamine (1.50 mL, 10.76 mmol) in CH2Cl2 (10
mL) was added over a period of 15 min. The reaction mixture
References and Notes
1. Thurston, D. E. Br. J. Cancer 1999, 80, 65.
2. Kamal, A.; Laxman, N.; Ramesh, G.; Neelima, K.; Kon-
dapi, A. K. J. Chem. Soc., Chem. Commun. 2001, 437.
3. Reddy, B. S. P.; Damayanthi, Y.; Reddy, B. S. N.; Lown,
J. W. Anti-Cancer Drug Des. 2000, 15, 225.