Abstract
Luliberin analogues modified at the N-terminus were synthesized to search for drugs exerting a cytotoxic effect on cells of hormone-dependent tumors. A synthetic scheme effective in the preparation of analogues containing fatty acid residues was proposed. The cytotoxic effect of the peptides was studied on a number of cell lines of human tumors in vitro. The dependence of the antitumor effect on the length of peptide chain, amino acid sequence, and structure of the N-terminal group was demonstrated. Modification with palmitic acid was found to result in highly active compounds in the case of analogues containing more than ten aa, whereas modifications with lauric, caproic, or trimethylacetic acid led to compounds with significantly lower activities. Analogues of luliberin containing a palmitic acid residue and effectively inhibiting the growth of tumor cells in vitro were synthesized.
Similar content being viewed by others
Abbreviations
- ATCC:
-
American Type Cultures Collection
- Bzl(Cl2):
-
2,6-dichlorobenzyl
- Cpa:
-
4-chlorophenylalanine
- DGlu (AA):
-
4-(p-methoxybenzoil)-D-2-aminobutyric acid
- hArg:
-
homoarginine
- Hcit:
-
homocitrulline
- GnRH:
-
luliberin (gonadotropin-releasing hormone)
- Hx:
-
hexanoyl
- Lau:
-
lauryl
- MTS:
-
mesitylenesulfonyl
- Nal:
-
3-(2-naphthyl)alanine
- Nic:
-
nicotinoyl
- Pal:
-
3-(3-pyridyl)alanine
- Pam:
-
palmitoyl
- Piv:
-
pivaloyl
- Z(Cl):
-
2-chlorobenzyloxycarbonyl
References
Corbin, A., Yale J. Biol. Med., 1982, vol. 55, no. (1), pp. 27–47.
Redding, T.W., Coy, D.H., and Schally, A.V., Proc. Natl. Acad. Sci. USA, 1982, vol. 79, pp. 1273–1276.
Tolis, G., Ackman, D., Stellos, A., Mehta, A., Labrie, F., Fazekas, A.T., Comaru-Schally, A.M., and Schally, A.V., Proc. Natl. Acad. Sci. USA, 1982, vol. 79, pp. 1658–1662.
Qayum, A., Gullick, W., Clayton, R.C., Sikora, K., and Waxman, J., Br. J. Cancer, 1990, vol. 62, pp. 96–99.
Imai, A., Ohno, T., Lida, K., Fuseya, T., Furui, T., and Tamaya, T., Gynecol. Oncol., 1994, vol. 55, pp. 144–148.
Nechushtan, A., Yarkoni, S., Marianovsky, I., and Lorberboum-Galski, H., J. Biol. Chem., 1997, vol. 272, pp. 11597–11603.
Chien, C.-H., Chen, C.-H., Lee, C.-Y.G., Chang, T.-C., Chen, R.-J., and Chow, S.-N., Int. J. Gynecol. Cancer, 2004, vol. 14, pp. 451–458.
Gründker, C., Nia, A.H., and Emons, G., Mol. Cancer Ther., 2005, vol. 4, pp. 225–231.
Palyi, I., Vincze, B., Lovas, S., Mezo, I., Pato, J., Kalnay, A., Turi, G., Gaal, D., Mihalik, R., Peter, I., Teplan, I., and Murphy, R.F., Proc. Natl. Acad. Sci. USA, 1999, vol. 96, pp. 2361–2366.
Schally, A.V. and Nagy, A., Eur. J. Endocrinol., 1999, vol. 141, pp. 1–14.
Yang, W.-H., Wieczorck, M., Allen, M.C., and Nett, T.M., Endocrinology, 2003, vol. 144, pp. 1456–1463.
Freidinger, R.M., Veber, D.F., Perlow, D.S., Grooks, J.R., and Saperstein, R., Science, 1980, vol. 210, pp. 656–658.
Monahan, M.W., Amoss, M.S., Andersson, H.A., and Vale, W., Biochemistry, 1973, vol. 12, pp. 4616–4620.
Yardley, J.P., Foell, T.J., Beattie, C.W., and Grant, N.H., J. Med. Chem., 1975, vol. 18, pp. 1244–1247.
Emons, G. and Schally, A.V., Hum. Reprod., 1994, vol. 9, pp. 1364–1378.
Harrison, G.S., Wierman, M.E., Nett, T.M., and Glode, L.M., Endocrine-Related Cancer, 2004, vol. 11, pp. 725–748.
Chester, A.E., Fairchild, D.G., and Depass, L.R., Fundam. Appl. Toxicol., 1991, vol. 17, pp. 505–518.
Schmidt, F., Sunaram, K., Thau, R.B., and Bardin, C.W., Contraception, 1984, vol. 29, pp. 283–289.
Vlasov, G.P., Burov, S.V., and Semko, T.V., RF Patent 2084458, 1993.
Yablokova, T.V., Syntesis of Lyuliberin Analogues Bearing Cytotoxic Groupings, Cand. Sci. (Chem.) Dissertation, St Petersburg: Institute of High-Molecular Compounds, Russian Academy of Sciences, 1997, pp. 68, 73.
Applied Biosystems. Introduction to Cleavage Technique, 2nd ed., Foster City, 1995.
Keisari, Y., J. Immunol. Methods, 1992, vol. 146, pp. 155–161.
Coy, D.H., Labrie, F., Savary, M., Coy, E.J., and Schally, A.V., Mol. Cell Endocrinol., 1976, vol. 5, pp. 201–208.
Wasiak, T., Humphries, J., Folkers, K., and Bowers, C.Y., Biochem. Biophys. Res. Commun., 1979, vol. 86, pp. 843–848.
Momany, F.A., J. Med. Chem., 1978, vol. 21, pp. 63–68.
Bowers, C.Y., Humphries, J., Wasiak, T., Folkers, K., Reynolds, G.A., and Reichert, L.E., Jr, Endocrinology, 1980, vol. 106, pp. 674–683.
Bajusz, S., Csernus, V.J., Janaky, T., Bokser, L., Fekete, M., and Schally, A.V., Int. J. Pept. Protein Res., 1988, vol. 32, pp. 425–435.
De Pablo, M.A., Susin, S.A., Jacotot, E., Larochette, N., Costantini, P., Ravagnan, L., Zamzami, N., and Kroemer, G., Apoptosis, 1999, vol. 4, pp. 81–87.
Mu, Y.-M., Yanase, T., Nishi, Y., Tanaka, A., Saito, M., Jin, C.-H., Mukasa, C., Okabe, T., Nomura, M., Goto, K., and Nawata, H., Endocrinology, 2001, vol. 142, pp. 3590–3597.
Harada, H., Yamashita, U., Kurihara, H., Fukushi, E., Kawabata, J., and Kamei, Y., Anticancer Res., 2002, vol. 22, pp. 2587–2590.
Gisin, B.F., Helv. Chim. Acta, 1973, vol. 56, pp. 1476–1482.
Author information
Authors and Affiliations
Corresponding author
Additional information
Original Russian Text © S.V. Burov, T.V. Yablokova, M.Yu. Dorosh, Z.P. Shkarubskaya, M. Blank, N. Epstein, M. Fridkin, 2006, published in Bioorganicheskaya Khimiya, 2006, Vol. 32, No. 5, pp. 459–466.
Rights and permissions
About this article
Cite this article
Burov, S.V., Yablokova, T.V., Dorosh, M.Y. et al. Luliberin analogues exhibiting a cytotoxic effect on tumor cells in vitro. Russ J Bioorg Chem 32, 413–419 (2006). https://doi.org/10.1134/S1068162006050037
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1134/S1068162006050037