1466
F. M. Perron-Sierra et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1463–1466
showed a T/C13 determined day 13 of 40% and 57%,
respectively, while 1b at 30 mg/kg showed a T/C of
22%. These results point out that the in vitro CAM
antiangiogenic test is not sufficient to predict anti-
tumoral activity in vivo (Table 2). However, the relative
low stability of the derivatives described here, t1/2
<30 min, could explain the discrepancy between their in
vitro and in vivo pharmacological activity.
Future 1993, 18, 239. (d) Billington, D. C. Drugs Design
Discov. 1991, 8, 3. (e) Jiang, W. G.; Mansel, R. E. Int. J.
Oncol. 1996, 9, 1013. (f) Teicher, B. A. Cancer Metastasis Rev.
1996, 15, 247. (g) Gasparini, G.; Presta, M. Ann. Oncol. 1996,
7, 441. (h) Voest, E. E. Anti-Cancer Drugs 1996, 7, 723.
2. Drugs Future 2000, 25, 1174; Drugs Future 1995, 20, 1176;
Drugs Future 1994, 19, 981; Annual Drug Data Report 1992,
835.
3. Marui, S.; Yamamoto, T.; Sudo, K.; Akimoto, H.; Kishi-
moto, S. Chem. Pharm. Bull. 1995, 43, 588. Marui, S.; Itoh, F.;
Kozai, Y.; Sudo, K.; Kishimoto, S. Chem. Pharm. Bull. 1992,
40, 96. Marui, S.; Kishimoto, S. Chem. Pharm. Bull. 1992, 40,
575.
4. Ingber, D.; Fujita, T.; Kishimoto, S.; Sudo, K.; Kama-
maru, T.; Brem, H.; Folkman, J. Nature 1990, 348, 555.
5. (a) Corey, E. J.; Snider, B. B. J. Am. Chem. Soc. 1972, 94,
2549. (b) Taber, D. F.; Christos, T. E.; Rheingold, A. L.;
Guzei, I. A. J. Am. Chem. Soc. 1999, 121, 5589.
6. Dorey, G.; Leon, P.; Sciberras, S.; Leonce, S.; Guilbaud,
N.; Pierre, A.; Atassi, G.; Billington, D. C. Bioorg. Med.
Chem. Lett. 1996, 6, 3045.
7. Billington, D. C.; Perron-Sierra, F.; Atassi, G.; Pierre A.;
Burbridge, M.; Guilbaud, N. PCT WO96/33999; FR95/0505.
8. (a) Perron, F.; Albizati, K. F. J. Org. Chem. 1989, 54, 2044.
(b) Georgiadis, M. P.; Albizati, K. F. Org. Prep. Proc. Int.
1992, 24, 95. (c) Kobayashi, Y.; Kusakabe, M.; Kitano, Y.;
Sato, F. J. Org. Chem. 1989, 54, 2085. (d) Kobayashi, X.;
Jusakabe, M.; Kitano, Y.; Sato, F. J. Org. Chem. 1988, 53,
1586.
9. All synthetic intermediates and final compounds gave
satisfactory 1H NMR, 13C NMR, mass spectral, and elemental
analysis data, in full agreement with their assigned structures
and stereochemistries. Experimental procedures and analytical
data have been described in ref 7.
A versatile synthetic route leading to pyran analogues
of 1b has been developed, where a stereocontrolled
oxidation-rearrangement of 2-furyl-carbinols led to
the formation of a series of original tetrahydro-
pyrano[3,2-d]oxazolones.7
Key structural features for antiangiogenic activity of the
pyran analogues of 1b have been identified. Epoxide
functionalities at C1 and C2 are not required for anti-
angiogenic activity and a large variety of lipophilic
chains can be introduced at C2 with the relative stereo-
chemistry of 1b (trans stereochemistry between C2 and C4).
Although the mechanism of action of 1b and its analo-
gues remains uncertain, it appears that for the most
active compounds, the spatial arrangements occupied
by the lipophilic chain with respect to the alkylating
functionality can be superimposed, suggesting a highly
stereospecific mechanism of action.
Acknowledgements
10. Evaluation of the percentage of eggs with an avascular
zone, allows the identification of specific antiangiogenic deri-
vatives devoid of toxicity. Compounds showing local hemor-
rhage, marked distortion of large preexisting vessels and/or
death of the embryo were not selected as potential anti-
angiogenic drugs.
The authors wish to thank Dr. Patrick Casara for cor-
rections and relevant comments in the preparation of
this manuscript.
11. Crum, R.; Szabo, S.; Folkman, J. Science 1985, 230, 1375.
12. For related methodology, see: Pierre, A.; Kraus-Berthier,
L.; Atassi, G.; Cros, S.; Poupon, M. F.; Lavielle, G.; Berlion,
M.; Bizzani, J. P. Cancer Res. 1991, 51, 2312.
References and Notes
1. (a) Polverini, P. J. Crit. Rev. Oral Biol. Med. 1995, 5, 230.
(b) Fan, T. P. D.; Jaggar, R.; Bicknell, R. Trends Pharmacol.
Sci. 1995, 16, 57. (c) Terano, H.; Shibata, T.; Otsuka, T. Drugs
13. T/C: Test/Control tumor volume.