The intercalation of imidazoacridinones into DNA induces conformational changes in their side chain.
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Imidazoacridinones (IAs) are a new group of highly active antitumor compounds. The intercalation of the IA molecule into DNA is the preliminary step in the mode of action of these compounds. There are no experimental data about the structure of an intercalation complex formed by imidazoacridinones. Therefore the design of new potentially better compounds of this group should employ the molecular modelling techniques. The results of molecular dynamics simulations performed for four IA analogues are presented. Each of the compounds was studied in two systems: i) in water, and ii) in the intercalation complex with dodecamer duplex d(GCGCGCGCGCGC)2. Significant differences in the conformation of the side chain in the two environments were observed for all studied IAs. These changes were induced by electrostatic as well as van der Waals interactions between the intercalator and DNA. Moreover, the results showed that the geometry of the intercalation complex depends on: i) the chemical constitution of the side chain, and ii) the substituent in position 8 of the ring system.
- 1. Cholody, M.W., Martelli, S., Łukowicz, J. & Konopa, J. (1990) 5-[(Aminoalkyl)amino]-imidazo[4,5,1-de]acridin-6-ones as a novel class of antineoplastic agents. Synthesis and biological activity. J. Med. Chem. 33, 49-52.
- 2. Cholody, M.W., Martelli, S. & Konopa, J. (1992) Chromophore-modified antineoplastic imidazoacridinones. Synthesis and activity against murine leukemias. J. Med. Chem. 35, 378-382.
- 3. Cholody, M.W., Horowska, B., Paradziej- Łukowicz, J., Martelli, S. & Konopa, J. (1996) Structure-activity relationship for antineoplastic imidazoacridinones. Synthesis and antileukemic activity in vitro. J. Med. Chem. 39, 1028-1032.
- 4. Mazerska, Z., Augustin, E., Składanowski, A., Bibby, M.C., Double, J.A. & Konopa, J. (1998) C-1311. Drugs Future 23, 702-706.
- 5. Burger, A.M., Double, J.A., Konopa, J. & Bibby, M.C. (1996) Preclinical evaluation of novel imidazoacridinone derivatives with potent activity against experimental colorectal cancer. Brit. J. Cancer 74, 1369-1374.
- 6. Dzięgielewski, J., Składanowski, A. & Konopa, J. (1996) Noncovalent binding of potent antitumor imidazoacridinones to DNA. Ann. Oncol. 7 (Suppl. 1), 56.
- 7. Dzięgielewski, J. & Konopa, J. (1996) Interstrand crosslinking of DNA induced in tumor cells by a new group of antitumor imidazoacridinones. Proc. Amer. Assoc. Cancer Res. 37, Abstract 2800.
- 8. Dzięgielewski, J., Mazerska, Z. & Konopa, J. (1998) Enzymatic activation of antitumor imidazoacridinone drug, C-1311, in relation to its DNA interaction. Exp. Toxicol. Pathol. 50, 101.
- 9. Cieplak, P., Rao, S.N., Grootenhuis, P.D.J. & Kollman, P.A. (1990) Free energy calculations on base specificity of drug-DNA interactions: Application to daunomycin and acridine intercalation into DNA. Biopolymers 29, 717-727.
- 10. Swaminathan, S., Beveridge, D.L. & Berman, H.H. (1990) Molecular dynamics simulation of a deoxynucleotid-drug complex: d(CpG)/ proflavine. J. Phys. Chem. 94, 4660-4665.
- 11. Langley, D.R., Dolye, T.W. & Beveridge, D.L. (1991) The dyneimicin-DNA intercalation complex. A model based on DNA affinity cleavage and molecular dynamics simulations. J. Am. Chem. Soc. 113, 4395-4403.
- 12. Herzyk, P., Neidle, S. & Goodfellow, J.M. (1992) Conformation and dynamics of drug-DNA intercalation. J. Biomol. Struct. Dyn. 10, 97-139.
- 13. Gallego, J., Ortiz, A.R. & Gago, F. (1993) A molecular dynamics study of the bis-intercalation complex of echinomycin with d(ACGT)2 and d(TCGA)2: Rationale for sequence-specific Hoogsteen base pairing. J. Med. Chem. 36, 1548-1561.
- 14. Denny, B.J., Wheelhouse, R.T., Stevens, M.F.G., Tsang, L.L.H. & Slack, J.A. (1994) NMR and molecular modeling investigation of the mechanism of activation of the antitumor drug Temozolomide and its interaction with DNA. Biochemistry 33, 9045-9051.
- 15. Van Garderen, C.J. & Van Houte, L.P.A. (1994) The solution structure of a DNA duplex containing the cis-Pt(NH3)2[d(-GTG-)-N7(G)] adduct, as determined with high-field NMR and molecular mechanics/dynamics. Eur. J. Biochem. 225, 1169-1179.
- 16. Bear, B. & Remers, W.A. (1996) Computer simulation of the binding of amonafide and azonafide to DNA. J. Comput.-Aided Molec. Design 10, 165-175.
- 17. Mazerski, J., Martelli, S. & Borowski, E. (1998) The geometry of intercalation complex of antitumor mitoxantrone and ametantrone with DNA: Molecular dynamics simulations. Acta Biochim. Polon. 45, 1-11.
- 18. VanGusteren, W.F., Billeter, S.R., Eising, A.A., Hunenberger, P.H., Kruger, P., Mark, E.A., Scott, W.R.P. & Tiron, I.G. (1996) Biomolecular Simulation: GROMOS96 Manual and User Guide. vdf Hochschulverlag AG, Zurich.
- 19. Ryckeart, J.P., Ciccotti, G. & Berendsen, J.H.C. (1977) Numerical integration of the cartesian equations of motion of a system with constraints: Molecular dynamics of n-alkanes. J. Comput. Phys. 23, 327-341.
- 20. Subraminian, P.S., Ravishanker, G. & Beveridge, D.L. (1991) Molecular dynamics of B-DNA including water and counterions. A 140-ps trajectory for d(CGCGAATTCGCG) based on the GROMOS force field. J. Am. Chem. Soc. 113, 5027-5040.
- 21. VanGunsteren, W.F., Berendsen, H.J.C., Geursten, R.G. & Zwinderman, H.R.J. (1986) A molecular computer dynamics simulation of an eight-base-pair DNA fragment in aqueous solution: Comparison with experimental 2D NMR data. Ann. N. Y. Acad. Sci. 482, 287-303.
- 22. Müller, W., Crother, D.M. & Waring, M.J. (1973) A non-intercalating proflavine derivative. Eur. J. Biochem. 39, 223-234.
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