M. Gordaliza et al. / Il Farmaco 56 (2001) 297–304
303
nation of the dioxol grouping and opening of the
g-lactone ring, with simultaneous formation of a fused
isoxazol heterocycle seem to be adequate transforma-
tions for retaining, or even increasing, the immunosup-
pressive activity of cyclolignan.
CICYT (SAF 98-96), DGICYT (PB 96-1275) and Junta
de Castilla y Leo´n (Consejer´ıa de Educacio´n y Cultura
SA-26/97).
References
3.4. Conformational study
[1] D.C. Ayres, J.D. Loike, Lignans. Chemical, Biological and
Clinical Properties, Cambridge University Press, Cambridge,
1990 (chaps 3 and 4).
[2] (a) R.S. Ward, Nat. Prod. Rep. 16 (1999) 75. (b) Y. Damayan-
thi, J.W. Lown, Curr. Med. Chem. 5 (1998) 205. (c) I. Jardin, in:
J.M. Cassady, J.D. Douros (Eds.), Podophyllotoxins in Anti-
cancer Agents based on Natural Product Models, Academic
Press, New York, 1980.
[3] (a) C.P. Belani, L.A. Doyle, J. Aisner, Etoposide: current status
and future perspectives in the management of malignant neo-
plasms, Cancer Chemoter. Pharmacol. 34 (Suppl.) (1994) S118.
(b) F.M. Muggia, Cancer Chemoter. Pharmacol. 34 (Suppl.)
(1994) S127.
[4] A.H. Witterland, C.H. Koks, J.H. Beijnen, Pharmacy World Sci.
18 (1996) 163.
[5] J.D. Loike, C.F. Brewer, H. Sternlicht, W.J. Gensler, S.B. Hor-
witz, Cancer Res. 38 (1978) 2688.
[6] J.D. Loike, S.B. Horwitz, Biochemistry 15 (1976) 5435.
[7] (a) B.H. Long, S.T. Musial, M.B. Brattain, Biochemistry 23
(1984) 1183. (b) R. Ross, T. Rowe, B. Glisson, J. Yalowich, F.
Liu, Cancer Res. 44 (1984) 2857.
[8] S.J. Cho, Y. Kashiwada, K.F. Bastow, Y.C. Cheng, K.H. Lee, J.
Med. Chem. 39 (1996) 1396.
Antineoplastic and antiviral activities are greatly se-
lective to certain classes of lignans, the trans and cis-te-
tralinelactones being much more active than those of
naphtalene and non-lactonic cyclolignan classes. The
differences in activity for both types of tetralinelactones
could be explained in terms of their differences in
conformation, induced by the change of configuration
at C-8%. Trans-lactones are rigid, almost planar in the
tetracyclic moiety, and display the aryl substituent at
C-7% in a free rotating pseudoaxial disposition, whereas
cis-lactones are more flexible, with conformations rang-
ing, depending on the nature of their substituents,
between various folded dispositions of the fused four
rings system with the 7a-aryl group axial and an ex-
tended, more planar disposition, with the 7a-aryl group
being practically equatorial [11,13]
One other possibility for explaining the difference in
potency for cis and trans-tetraline- lactones lies in the
relative stability of both types of lactones. Trans com-
pounds are more strained than the cis ones and hence
they could be more reactive, thus showing a greater
capacity to make covalent bonds with the target
biomolecule in the biological system.
[9] (a) M.A. Castro, M. Gordaliza, J.M. Miguel del Corral, A. San
Feliciano, Phytochemistry 41 (1996) 995. (b) A. San Feliciano,
J.M. Miguel del Corral, M. Gordaliza, M.A. Castro, Phyto-
chemistry 28 (1989) 659. (c) A. San Feliciano, J.M. Miguel del
Corral, M. Gordaliza, M.A. Castro, Phytochemistry 29 (1990)
1335. (d) A. San Feliciano, J.M. Miguel del Corral, M. Gordal-
iza, M.A. Castro, Phytochemistry 30 (1991) 3483.
[10] A. San Feliciano, J.M. Miguel del Corral, M. Gordaliza, M.A.
Castro, An. Quim. 88 (1992) 256.
4. Conclusions
[11] A. San Feliciano, M. Gordaliza, J.M. Miguel del Corral, M.A.
Castro, M.D. Garc´ıa-Gra´valos, P. Ruiz-La´zaro, Planta Med. 59
(1993) 246.
[12] A. San Feliciano, J.M. Miguel del Corral, M. Gordaliza, M.A.
Castro, Magn. Reson. Chem. 31 (1993) 868.
[13] M. Gordaliza, M.A. Castro, M.D. Garc´ıa-Gra´valos, P. Ruiz-
La´zaro, J.M. Miguel del Corral, A. San Feliciano, Arch. Pharm.
(Weinheim) 327 (1994) 175.
[14] M.A. Castro, M. Gordaliza, J.M. Miguel del Corral, A. San
Feliciano, Org. Prep. Proced. Int. 26 (1994) 539.
[15] M. Gordaliza, J.M. Miguel del Corral, M.A. Castro, M.L.
Lo´pez-Va´zquez, P.A. Garc´ıa, A. San Feliciano, M.D. Garc´ıa-
Gra´valos, Bioorg. Med. Chem. Lett. 5 (1995) 2465.
[16] M. Gordaliza, J.M. Miguel del Corral, M.A. Castro, M.L.
Lo´pez-Va´zquez, A. San Feliciano, A. M.D. Garc´ıa-Gra´valos, A.
Carpy, Bioorg. Med. Chem. 3 (1995) 1203.
[17] J.M. Miguel del Corral, M. Gordaliza, M.A. Castro, L.J.
Morales, J.L. Lo´pez, A. San Feliciano, J. Nat. Prod. 58 (1995)
870.
[18] J.M. Miguel del Corral, M. Gordaliza, J.L. Lo´pez, E. del Olmo,
M.A. Castro, M.L. Lo´pez-Va´zquez, Helv. Chim. Acta 78 (1995)
1793.
It has been possible to deduce that the biochemical
mechanism of the anchoring of cyclolignans to DNA or
topoisomerase II would not involve the nucleophilic
attack of part of the biomolecule on the lactonic car-
bonyl at position 9%, but rather on the lactonic methyl-
ene at position 9, thus leading to breakage of the
strongly strained g-lactone and hence irreversible block-
ade of the biological substrate. Furthermore, interpreta-
tion of the results from the assays that have been
carried out to date has allowed us to deduce the
structural fragments that are most important for anti-
neoplastic activity and the pathways permitting de-
creases in cellular toxicity and increases in selectivity
have been established. This will lead to new proposals
regarding possible improvements to the therapeutic in-
dices of these types of compounds.
Acknowledgements
[19] M. Gordaliza, M.A. Castro, A. San Feliciano, J.M. Miguel del
Corral, M.L. Lo´pez-Vazquez, G.T. Faircloth, Patent EP 711765
A1.
Financial support for this work came from Spanish