o-Quinone Methides of Bis-naphthalene and Perylene as Alkylating Agents of Selected Peptides

1. o-Quinone Methides of Bis-naphthalene and Perylene as Alkylating Agents of Selected Peptides 2A. Saravanos, 1Y. Sarigiannis, 1G. Stavropoulos, 2P. Tsoungas and 2P. Cordopatis 1Department of Chemistry and 2Department of Pharmacy, University of Patras, 265 00 Patras, Greece, University of Patras Introduction o-Quinone methides (o-QMs) 1 are highly reactive and ephemeral intermediates extensive harnessed by nature. A variety of plants, animals and insects capitalize upon them as a means of defense. Their significance in organic synthesis emanates from their versatile reactivity towards electrophiles, nucleophiles or (hetero) Diels – Alder cycloadditions [1]. The driving force inherent in these transformations and the propensity of 1 to “revert to type” (i.e. restore its aromaticity). Either acting as a highly polarized species or as heterodiene, 1 has been the prototype for the construction of diverse heterocyclic frameworks of varying complexity. In biology, on the other hand, the significance of 1 rests upon its mode of action being the reactive site of various structures on cellular macromolecules such us DNA or proteins. Alkylation or cross – linking are among the major biochemical processes taking place [3-7]. It has been observed at very low temperatures [8] or when highly hindered [9] and has been isolated only when metal stabilized [9,10]. Under ordinary conditions, the intermediacy of 1 is inferred by trapping reactions. A plethora of methods have been developed for its generation, mainly as a precursor to various heterocycles, natural products among them. The activity in the field has been reflected on a number of reviews, which have subsequently appeared, as early as mid 60’s right through to the present days [1]. There has been a resurgence of interest in the chemistry and biology of 1, recently. This has focused primarily on its photogeneration, metal complexation and its effect on biomacromolecules. o-QMs of types 5 and 8, prepared by coupling of an appropriately substituted naphthol 3, are useful intermediates for alkylation / X-linking of simple amino acids right through to cellular macromolecules such as DNA, proteins and peptides. This reaction is already known to be responsible for a broad spectrum of activity of these molecules. Scheme: Part of the Synthetic Route for the preparation of o-Quinone methides • References • Van De Water, R.W. and Pettus, T.R.R., Tetrahedron 2002, 58, 5367 and references cited therein. • Boger, D.L., Nishi, T. and Teergarden, B.R., J. Org. Chem. 1994, 59, 4943 • (a) Chatterjee, M. and Rokita, S.E., J. Am. Chem. Soc. 1994, 116, 1690. (b) Zeng, Q, and Rokita, S.E., J Org. Chem. 1996, 61, 90 • (a) Skibo, E.B., J Org. Chem. 1992, 57, 587. (b) Quyang, A., and Skibo, E.B. ibid 1998, 63, 1983 • Nikolaou, K.C., Dai, W., J Am. Chem. Soc. 1992, 114, 8908 • Bolton, J.L., Sevestre, H., Ibe, B.O. and Thompsom, J.A. Chem. Res. Toxicol. 1990, 3, 65 • (a) Gaudiano G., Frigerio M., Bravo, P., and Koch, T., J. Am. Chem. Soc. 1990, J Org. Chem. 1996, 61, 90, 6704. (b) Angle, S.R. and Yong, W. J. Am. Chem. Soc. 1990, 112, 4524 • (a) Tomioka, H., Pure Appl Chem, 1997, 69, 837. (b) Qiao, G.G., Lenghaus, K., Solomon, D.H. Reisinger, A, Bytheway, I. and Wentriep, C. J. Org Chem., 1998, 63, 9806 • Kopach, M.E., and Harman, W.D., J. Am. Chem. Soc. 1994, 116, 6581. (b) Vigalok, A., and Milstein, D., ibid 1997, 119, 7873 • (a) Amouri, H., Besace, Y. and Le Bras, J., J. Am. Chem. Soc. 1998, 120, 6171. (b) Amouri, H. and Vaissermann, J., Organometallics, 2000, 19, 5143. (c) Amouri, H., and Vaissermann, J., Rager, M.N. and Grotjiahn, D.B. ibid 2000, 19, 1740. (d) Vigalok, A. and Milstein, D., Acc. Chem. Res., 2001, 34, 798 Aknowledgements We thank the European Social Fund (ESF), Operational Program for Educational and Vocational Training II (EPEAEK II) and particularly the Program PYTHAGORAS II for funding the above work.