[en] Cryptolepine and neocryptolepine are two indoloquinoline alkaloids isolated from the roots of the African plant Cryptolepis sanguinolenta. Both drugs have revealed antibacterial and antiparasitic activities and are strongly cytotoxic to tumour cells. We have recently shown that cryptolepine can intercalate into DNA and stimulates DNA cleavage by human topoisomerase II. In this study, we have investigated the mechanism of action and cytotoxicity of neocryptolepine, which differs from the parent isomer only by the orientation of the indole unit with respect to the quinoline moiety. The biochemical and physicochemical results presented here indicate that neocryptolepine also intercalates into DNA, preferentially at GC-rich sequences, but exhibits a reduced affinity for DNA compared with cryptolepine. The two alkaloids interfere with the catalytic activity of human topoisomerase II but the poisoning activity is slightly more pronounced with cryptolepine than with its isomer. The data provide a molecular basis to account for the reduced cytotoxicity of neocryptolepine compared with the parent drug.
De Pauw-Gillet, Marie-Claire ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Histologie - Cytologie - Département des sciences biomédicales et précliniques
Colson, Pierre ; Université de Liège - ULiège > Département de chimie (sciences) > Chimie physique biologique
Houssier, Claude ; Université de Liège - ULiège > Services généraux (Faculté des sciences) > Relations académiques et scientifiques (Sciences)
Cimanga, K.
Van Miert, S.
Vlietinck, A. J.
Pieters, L.
Language :
English
Title :
DNA intercalation, topoisomerase II inhibition and cytotoxic activity of the plant alkaloid cryptolepine
Ablordeppey S.Y., Fan P., Clark A., Nimrod A. (1999) Probing the N-5 region of the indoloquinoline alkaloid, cryptolepine for anticryptococcal activity. Bioorganic and Medicinal Chemistry 7:343.
Alajarin M., Molina P., Vidal A. (1997) Formal total synthesis of the alkaloid cryptotackieine (neocryptolepine). Journal of Natural Products 60:747.
Bailly C. (2000) Topoisomerase I poisons and suppressors as anticancer drugs. Current Medicinal Chemistry 7:39.
Bailly C., Waring M.J. (1995) Comparison of different foot-printing methodologies for detecting binding sites for a small ligand on DNA. Journal of Biomolecular Structure and Dynamics 12:869.
Bailly C., Ohuigin C., Rivalle C., Bisagni E., Henichart J.P., Waring M.J. (1990) Sequence-selective binding of an ellipticine derivative to DNA. Nucleic Acids Research 18:6283.
Bamgbose S.O.A., Noamesi B.K. (1981) Studies on cryptolepine. II. Inhibition of carragean induced oedema by cryptolepine. Planta Medica 41:392.
Boakye-Yiadom K., Heman-Ackah S.M. (1979) Cryptolepine hydrochloride effect on Staphylococcus aureus. Journal of Pharmaceutical Sciences 68:1510.
Bonjean K., De Pauw-Gillet M.C., Defresne M.P., Colson P., Houssier C., Dassonneville L., Bailly C., Wright C., Quetin-Leclercq J., Angenot L. (1997) Cryptolepine is a potent DNA intercalating agent which inhibits selectively DNA synthesis in B16 melanoma cells cultured in vitro. Anticancer Research 17:4068.
Bonjean K., De Pauw-Gillet M.-C., Defresne M.-P., Colson P., Houssier C., Dassonneville L., Bailly C., Greimers R., Wright C., Quetin-Leclercq J., Tits M., Angenot L. (1998) The DNA intercalating alkaloid cryptolepine interferes with topoisomerase II and inhibits primarily DNA synthesis in B 16 melanoma cells. Biochemistry 37:5136.
Bourdouxhe C., Colson P., Houssier C., Sun J.S., Montenay-Garestier T., Helene C., Rivalle C., Bisagni E., Waring M.J., Henichart J.P., Bailly C. (1992) Binding of a distamycinellipticine hybrid molecule to DNA and chromatin: Spectroscopic, biochemical and molecular modeling investigations. Biochemistry 31:12385.
Boye L.G., Oku-Ampofo O. (1990) Medicinal plants in Ghana., Economic and Medicinal Plant Research. Vol. 4. Plants and Traditional Medicine. Wagner and Fransworth N.R. (eds). Academic Press: London; 32.
Cantor C.R., Schimmel P.R., Biophysical Chemistry. W.H. Freeman and Co.: San Francisco, CA; 1980.
Cimanga K., De Bruyne T., Lasure A., Van Poel B., Pieters L., Claeys M., Vanden Berghe D., Kambu K., Tona L., Vlietinck A.J. (1996) In vitro biological activities of alkaloids from Cryptolepis sanguinolenta. Planta Medica 62:22.
Cimanga K., De Bruyne T., Pieters L., Claeys M., Vlietinck A.J. (1996) New alkaloids from Cryptolepis sanguinolenta. Tetrahedron Letters 37:1703.
Cimanga K., De Bruyne T., Pieters L., Vlietinck A.J. (1997) In vitro and in vivo antiplasmodial activity of cryptolepine and related alkaloids from Cryptolepis sanguinolenta. Journal of Natural Products 60:688.
Cimanga K., De Bruyne T., Pieters L., Totte J., Tona L., Kambu K., Vanden Berghe D., Vlietinck A.J. (1998) Antibacterial and antifungal activities of neocryptolepine, biscryptolepine and cryptoquindoline, alkaloids isolated from Cryptolepis sanguinolenta. Phytomedicine 5:209.
Colson P., Bailly C., Houssier C. (1996) Electric linear dichroism as a new tool to study sequence preference in drug binding to DNA. Biophysical Chemistry 58:125.
Dassonneville L., Bonjean K., De Pauw-Gillet M.C., Colson P., Houssier C., Quetin-Leclercq J., Angenot L., Bailly C. (1999) Stimulation of topoisomerase II-mediated DNA cleavage by three DNA-intercalating plant alkaloids. Cryptolepine, matadine and serpentine. Biochemistry 38:7719.
Grellier P., Ramiaramanana L., Millerioux V., Deharo E., Schrevel J., Frappier F., Trigalo F., Bodo B., Pousset J.L. (1996) Antimalarial activity of cryptolepine and isocryptolepine, alkaloids isolated from Cryptolepis sanguinolenta. Phytotherapy Research 10:317.
Houssier C. (1981) Investigating nucleic acids, nucleoproteins, polynucleotides, and their interactions with small ligands by electro-optical systems., Molecular Electro-Optics. Krause S. (ed.). Plenum Publishing Corp.: New York; 363.
Kirby G.C., Paine A., Warhurst D.C., Noamesi B.K., Phillipson J.D. (1995) In vitro and in vivo antimalarial activity of cryptolepine, a plant-derived indoloquinoline. Phytotherapy Research 9:359.
McGhee J.D., Von Hippel P.H. (1974) Theoretical aspects of DNA-protein interaction: Co-operative and non-cooperative binding of large ligands to a one-dimensional homogeneous lattice. Journal of Molecular Biology 86:469.
Molina P., Fresneda P.M., Delgado S. (1999) Iminophosphorane-mediated synthesis of the alkaloid cryptotackieine. Synthesis 2:326.
Noamesi B.K., Bamgbose S.O.A. (1980) The alpha-adrenoreceptor blocking properties of cryptolepine on the rat isolated vas deferens. Planta Medica 39:51.
Noamesi B.K., Bamgbose S.O.A. (1982) Preferential blockade of pre-synaptic alpha-adrenoreceptors on the rat isolated vas deferens by cryptolepine. Planta Medica 44:241.
Paulo A., Pimentel M., Viegas S., Pires I., Duarte A., Cabrita J., Gomes E.T. (1994) Cryptolepis sanguinolenta activity against diarrhoeal bacteria. Journal of Ethnopharmacology 44:73.
Paulo A., Duarte A., Gomes E.T. (1994) In vitro antibacterial screening of Cryptolepis sanguinolenta alkaloids. Journal of Ethnopharmacology 44:127.
Peczynska-Czoch W., Pognan F., Kaczmarek L., Boratynski J. (1994) Synthesis and structure-activity relationship of methyl-substituted indolo[2,3-b]quinolines: Novel cytotoxic, DNA topoisomerase II inhibitors. Journal of Medicinal Chemistry 37:3503.
Rauwald H.W., Kober M., Mutschler E., Lambrecht G. (1992) Cryptolepis sanginolenta: Antimuscarinic properties of cryptolepine and the alkaloid fraction at M1, M2 and M3 receptors. Planta Medica 58:486.
Waring M.J., Bailly C. (1994) DNA recognition by intercalators and hybrid molecules. Journal of Molecular Recognition 7:109.
Wright C.W., Phillipson J.D., Awe S.O., Kirby G.C., Warhurst D.C., Quetin-Leclercq J., Angenot L. (1996) Antimalarial activity of cryptolepine and some other anhydronium bases. Phytotherapy Research 10:361.