Bioinorganic Chemistry and Applications

Bioinorganic Chemistry and Applications / 2007 / Article

Research Article | Open Access

Volume 2007 |Article ID 98732 | 15 pages | https://doi.org/10.1155/2007/98732

Complexes of Pd(II) and Pt(II) with 9-Aminoacridine: Reactions with DNA and Study of Their Antiproliferative Activity

Academic Editor: Giovanni Natile
Received16 Mar 2007
Accepted10 May 2007
Published19 Aug 2007

Abstract

Four new metal complexes {M = Pd(II) or Pt(II)} containing the ligand 9-aminoacridine (9AA) were prepared. The compounds were characterized by FT-IR and H, C, and Pt NMR spectroscopies. Crystal structure of the palladium complex of formulae [Pd(9AA)(μ-Cl)]2·2DMF was determined by X-ray diffraction. Two 9-acridine molecules in the imine form bind symmetrically to the metal ions in a bidentate fashion through the imine nitrogen atom and the C(1) atom of the aminoacridine closing a new five-membered ring. By reaction with phosphine or pyridine, the Cl bridges broke and compounds with general formulae [Pd(9AA)Cl(L)] (where L=PPh3 or py) were formed. A mononuclear complex of platinum of formulae [Pt(9AA)Cl(DMSO)] was also obtained by direct reaction of 9-aminoacridine and the complex [PtCl2(DMSO)2]. The capacity of the compounds to modify the secondary and tertiary structures of DNA was evaluated by means of circular dichroism and electrophoretic mobility. Both palladium and platinum compounds proved active in the modification of both the secondary and tertiary DNA structures. AFM images showed noticeable modifications of the morphology of the plasmid pBR322 DNA by the compounds probably due to the intercalation of the complexes between base pairs of the DNA molecule. Finally, the palladium complex was tested for antiproliferative activity against three different human tumor cell lines. The results suggest that the palladium complex of formula [Pd(9AA)(μ-Cl)]2 has significant antiproliferative activity, although it is less active than cisplatin.

References

  1. N. Farrell, Transition Metal Complexes as Drugs and Chemotherapeutic Agents, Kluwer Academic Publishers, Dordrecht, The Netherlands, 1989.
  2. L. S. Lerman, “Structural considerations in the interaction of DNA and acridines,” Journal of Molecular Biology, vol. 3, pp. 18–30, 1961. View at: Google Scholar
  3. L. S. Lerman, “Acridine mutagens and DNA structure,” Journal of Cellular and Comparative Physiology, vol. 64, no. S1, pp. 1–18, 1964. View at: Publisher Site | Google Scholar
  4. W. A. Denny, B. C. Baguley, B. F. Cain, and M. J. Waring, “Antitumor acridines,” in Molecular Aspects of Anti-Cancer Drug Action, M. J. Waring and S. Neidle, Eds., vol. 3 of Topics in Molecular & Structural Biology, pp. 1–4, Verlag Chemie, Weinheim, Germany, 1983. View at: Google Scholar
  5. C. Radzikowski, A. Ledóchowski, M. Hrabowska et al., “A search for antitumor compounds. V. Biologic studies. Antitumor properties of 41 new acridine derivatives,” Archivum Immunologiae et Therapiae Experimentalis, vol. 17, no. 1, pp. 86–98, 1969. View at: Google Scholar
  6. C. Korth, B. C. H. May, F. E. Cohen, and S. B. Prusiner, “Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 17, pp. 9836–9841, 2001. View at: Publisher Site | Google Scholar
  7. W. A. Denny and B. C. Baguley, “Acridine-based anticancer drugs,” in Molecular Aspects of Drug-DNA Interactions, M. J. Waring and S. Neidle, Eds., vol. 2, MacMillan, London, UK, 1994. View at: Google Scholar
  8. M. Wirth, O. Buchardt, T. Koch, P. E. Nielsen, and B. Nordén, “Interactions between DNA and mono-, bis-, tris-, tetrakis-, and hexakis(aminoacridines). A linear and circular dichroism, electric orientation relaxation, viscometry, and equilibrium study,” Journal of the American Chemical Society, vol. 110, no. 3, pp. 932–939, 1988. View at: Publisher Site | Google Scholar
  9. E. S. Canellakis, Y. H. Shaw, W. E. Hanners, and R. A. Schwartz, “Diacridines: bifunctional intercalators—I: chemistry, physical chemistry and growth inhibitory properties,” Biochimica et Biophysica Acta, vol. 418, no. 3, pp. 277–289, 1976. View at: Google Scholar
  10. A. Lorente, M. Fernández-Saiz, J.-M. Lehn, and J.-P. Vigneron, “Cyclo-bis- and cyclo-tris-intercalands based on acridine subunits,” Tetrahedron Letters, vol. 36, no. 45, pp. 8279–8282, 1995. View at: Publisher Site | Google Scholar
  11. B. E. Bowler, L. S. Hollis, and S. J. Lippard, “Synthesis and DNA binding and photonicking properties of acridine orange linked by a polymethylene tether to (1,2-diaminoethane)dichloroplatinum(II),” Journal of the American Chemical Society, vol. 106, no. 20, pp. 6102–6104, 1984. View at: Publisher Site | Google Scholar
  12. B. E. Bowler, K. J. Ahmed, W. I. Sundquist, L. S. Hollis, E. E. Whang, and S. J. Lippard, “Synthesis, characterization, and DNA-binding properties of (1,2-diaminoethane)platinum(II) complexes linked to the DNA intercalator acridine orange by trimethylene and hexamethylene chains,” Journal of the American Chemical Society, vol. 111, no. 4, pp. 1299–1306, 1989. View at: Publisher Site | Google Scholar
  13. J. Rak, J. Błaźejowski, and R. J. Zauhar, “Theoretical studies on the prototropic tautomerism, structure, and features of acridine and 9-acridinamine free bases and their protonated forms,” Journal of Organic Chemistry, vol. 57, no. 13, pp. 3720–3725, 1992. View at: Publisher Site | Google Scholar
  14. J. Rak and J. Błaźejowski, “Experimental and INDO CI calculations of the electronic absorption spectra of acridine and 9-acridinamine free bases and their protonated forms with regard to tautomeric phenomena,” Journal of Photochemistry and Photobiology A, vol. 67, no. 3, pp. 287–299, 1992. View at: Publisher Site | Google Scholar
  15. J. Rak, P. Skurski, M. Gutowski, L. Jóźwiak, and J. Błaźejowski, “Hartree-fock and density functional methods and IR and NMR spectroscopies in the examination of tautomerism and features of neutral 9-acridinamine in gaseous and condensed media,” Journal of Physical Chemistry A, vol. 101, no. 3, pp. 283–292, 1997. View at: Publisher Site | Google Scholar
  16. T. D. Sakore, B. S. Reddy, and H. M. Sobell, “Visualization of drug-nucleic acid interactions at atomic resolution—IV: structure of an aminoacridine-dinucleoside monophosphate crystalline complex, 9-aminoacridine-5-iodocytidylyl 35 guanosine,” Journal of Molecular Biology, vol. 135, no. 4, pp. 763–785, 1979. View at: Publisher Site | Google Scholar
  17. S. A. Woodson and D. M. Crothers, “Binding of 9-aminoacridine to bulged-base DNA oligomers from a frame-shift hot spot,” Biochemistry, vol. 27, no. 25, pp. 8904–8914, 1988. View at: Publisher Site | Google Scholar
  18. F. E. Hahn, “Berberine,” in Antibiotics, Mechanism of Action of Antimicrobial and Antitumor Agents, J. W. Corcovan and F. E. Hahn, Eds., vol. 3, pp. 577–584, Springer, New York, NY, USA, 1975. View at: Google Scholar
  19. G. E. Bass, D. R. Hudson, J. E. Parker, and W. P. Purcell, “Mechanism of antimalarial activity of chloroquine analogs from quantitative structure-activity studies. Free energy related model,” Journal of Medicinal Chemistry, vol. 14, no. 4, pp. 275–283, 1971. View at: Publisher Site | Google Scholar
  20. Y. Mikata, M. Yokoyama, K. Mogami et al., “Intercalator-linked cisplatin: synthesis and antitumor activity of cis-dichloroplatinum(II) complexes connected to acridine and phenylquinolines by one methylene chain,” Inorganica Chimica Acta, vol. 279, no. 1, pp. 51–57, 1998. View at: Publisher Site | Google Scholar
  21. W. I. Sundquist, D. P. Bancroft, and S. J. Lippard, “Synthesis, characterization, and biological activity of cis-diammineplatinum(II) complexes of the DNA intercalators 9-aminoacridine and chloroquine,” Journal of the American Chemical Society, vol. 112, no. 4, pp. 1590–1596, 1990. View at: Publisher Site | Google Scholar
  22. E. Ceci, R. Cini, J. Konopa, L. Maresca, and G. Natile, “Coordination and peri-carbon metalation of 1-nitro-9-[(2-aminoethyl)amino]acridines toward platinum(II). evidences for hydrogen bonding between endocyclic N(10)H and chloride ion,” Inorganic Chemistry, vol. 35, no. 4, pp. 876–882, 1996. View at: Publisher Site | Google Scholar
  23. L. Maresca, C. Pacifico, M. C. Pappadopoli, and G. Natile, “Endocyclic versus exocyclic N-coordination to platinum(II) of some nitro-9-[(2-dialkylaminoethyl)amino]acridines,” Inorganica Chimica Acta, vol. 304, no. 2, pp. 274–282, 2000. View at: Publisher Site | Google Scholar
  24. M. Carlone, N. G. Di Masi, L. Maresca, N. Margiotta, and G. Natile, “Role of metal ions and hydrogen bond acceptors in the tautomeric equilibrium of nitro-9[(alkylamino)amino]-acridine drugs,” Bioinorganic Chemistry and Applications, vol. 2, no. 1-2, pp. 93–104, 2004. View at: Publisher Site | Google Scholar
  25. M. D. Temple, W. D. McFadyen, R. J. Holmes, W. A. Denny, and V. Murray, “Interaction of cisplatin and DNA-targeted 9-aminoacridine platinum complexes with DNA,” Biochemistry, vol. 39, no. 18, pp. 5593–5599, 2000. View at: Publisher Site | Google Scholar
  26. R. J. Holmes, M. J. McKeage, V. Murray, W. A. Denny, and W. D. McFadyen, “cis-dichloroplatinum(II) complexes tethered to 9-aminoacridine-4-carboxamides: synthesis and action in resistant cell lines in vitro,” Journal of Inorganic Biochemistry, vol. 85, no. 2-3, pp. 209–217, 2001. View at: Publisher Site | Google Scholar
  27. M. D. Temple, P. Recabarren, W. D. McFadyen, R. Holmes, W. Denny, and V. Murray, “The interaction of DNA-targeted 9-aminoacridine-4-carboxamide platinum complexes with DNA in intact human cells,” Biochimica et Biophysica Acta, vol. 1574, no. 3, pp. 223–230, 2002. View at: Publisher Site | Google Scholar
  28. E. T. Martins, H. Baruah, J. Kramarczyk et al., “Design, synthesis, and biological activity of a novel non-cisplatin-type platinum-acridine pharmacophore,” Journal of Medicinal Chemistry, vol. 44, no. 25, pp. 4492–4496, 2001. View at: Publisher Site | Google Scholar
  29. J. M. Brow, C. R. Pleatman, and U. Bierbach, “Cytotoxic acridinylthiourea and its platinum conjugate produce enzyme-mediated DNA strand breaks,” Bioorganic and Medicinal Chemistry Letters, vol. 12, no. 20, pp. 2953–2955, 2002. View at: Publisher Site | Google Scholar
  30. T. M. Augustus, J. Anderson, S. M. Hess, and U. Bierbach, “Bis(acridinylthiourea)platinum(II) complexes: synthesis, DNA affinity, and biological activity in glioblastoma cells,” Bioorganic and Medicinal Chemistry Letters, vol. 13, no. 5, pp. 855–858, 2003. View at: Publisher Site | Google Scholar
  31. H. Baruah, C. S. Day, M. W. Wright, and U. Bierbach, “Metal-intercalator-mediated self-association and one-dimensional aggregation in the structure of the excised major DNA adduct of a platinum-acridine agent,” Journal of the American Chemical Society, vol. 126, no. 14, pp. 4492–4493, 2004. View at: Publisher Site | Google Scholar
  32. H. Baruah and U. Bierbach, “Biophysical characterization and molecular modeling of the coordinative-intercalative DNA monoadduct of a platinum-acridinylthiourea agent in a site-specifically modified dodecamer,” Journal of Biological Inorganic Chemistry, vol. 9, no. 3, pp. 335–344, 2004. View at: Publisher Site | Google Scholar
  33. M. C. Ackley, C. G. Barry, A. M. Mounce et al., “Structure-activity relationships in platinum-acridinylthiourea conjugates: effect of the thiourea nonleaving group on drug stability, nucleobase affinity, and in vitro cytotoxicity,” Journal of Biological Inorganic Chemistry, vol. 9, no. 4, pp. 453–461, 2004. View at: Publisher Site | Google Scholar
  34. J. R. Choudhury and U. Bierbach, “Characterization of the bisintercalative DNA binding mode of a bifunctional platinum-acridine agent,” Nucleic Acids Research, vol. 33, no. 17, pp. 5622–5632, 2005. View at: Publisher Site | Google Scholar
  35. C. G. Barry, C. S. Day, and U. Bierbach, “Duplex-promoted platination of adenine-N3 in the minor groove of DNA: challenging a longstanding bioinorganic paradigm,” Journal of the American Chemical Society, vol. 127, no. 4, pp. 1160–1169, 2005. View at: Publisher Site | Google Scholar
  36. R. Guddneppanavar, G. Saluta, G. L. Kucera, and U. Bierbach, “Synthesis, biological activity, and DNA-damage profile of platinum-threading intercalator conjugates designed to target adenine,” Journal of Medicinal Chemistry, vol. 49, no. 11, pp. 3204–3214, 2006. View at: Publisher Site | Google Scholar
  37. S. Ghirmai, E. Mume, H. Lundqvist, V. Tolmachev, and S. Sjöberg, “Synthesis and radioiodination of some 9-aminoacridine derivatives for potential use in radionuclide therapy,” Journal of Labelled Compounds and Radiopharmaceuticals, vol. 48, no. 12, pp. 855–871, 2005. View at: Publisher Site | Google Scholar
  38. J. Reedijk, “Improved understanding in platinum antitumour chemistry,” Chemical Communications, no. 7, pp. 801–806, 1996. View at: Publisher Site | Google Scholar
  39. M. S. Khapasch, R. C. Seyler, and F. R. Mayo, “Coordination Compounds of Palladous Chloride,” Journal of the American Chemical Society, vol. 60, pp. 882–884, 1938. View at: Google Scholar
  40. G. M. Sheldrick, “Phase annealing in SHELX-90: direct methods for larger structures,” Acta Crystallographica Section A, vol. 46, no. 6, pp. 467–473, 1990. View at: Publisher Site | Google Scholar
  41. G. M. Sheldrick, A Computer Program for Determination of Crystal Structure, University of Göttingen, Göttingen, Germany, 1994.
  42. J. A. Ibers and W. C. Hamilton, International Tables for X-ray Crystallography, vol. 4, The Kynoch Press, Birmingham, UK, 1974.
  43. J. Albert, J. Granell, J. Sales, M. Font-Bardía, and X. Solans, “Optically active exocyclic cyclopalladated derivatives of benzylidene-(R)-(1-phenylethyl)amines: syntheses and X-ray molecular structures of [Pd(2-{(E)-(R)-CHMeN=CH-2,6-Cl2C6H3}C6H4)Cl(PPh3)] and [Pd(2-{(Z)-(R)-CHMeN=CH-2,6-F2C6H3}C6H4)I(PPh3)],” Organometallics, vol. 14, no. 3, pp. 1393–1404, 1995. View at: Publisher Site | Google Scholar
  44. G. B. Deacon and J. H. S. Green, “Vibrational spectra of ligands and complexes—II Infra-red spectra (3650–375 cm1 of triphenyl-phosphine, triphenylphosphine oxide, and their complexes,” Spectrochimica Acta Part A, vol. 24, no. 7, pp. 845–852, 1968. View at: Publisher Site | Google Scholar
  45. E. Boschmann and G. Wollaston, “Spectroscopy illustrated—a lecture experiment,” Journal of Chemical Education, vol. 59, no. 1, pp. 57–58, 1982. View at: Google Scholar
  46. P. S. Belton, I. P. Parkin, D. J. Williams, and J. D. Woollins, “The reactions of sulphur-nitrogen species in liquid ammonia,” Journal of the Chemical Society, Chemical Communications, no. 22, pp. 1479–1480, 1988. View at: Publisher Site | Google Scholar
  47. Y. Fuchita, H. Tsuchiya, and A. Miyafuji, “Cyclopalladation of secondary and primary benzylamines,” Inorganica Chimica Acta, vol. 233, no. 1-2, pp. 91–96, 1995. View at: Publisher Site | Google Scholar
  48. J. Albert, M. Gómez, J. Granell, J. Sales, and X. Solans, “Five- and six-membered exo-cyclopalladated compounds of N-benzylideneamines. Synthesis and X-ray crystal structure of [cyclic] [PdBr{p-MeOC6H3(CH2)2N:CH(2,6-Cl2C6H3)}(PPh3)] and [PdBr{C6H4CH2N:CH(2,6-Cl2C6H3)}(PEt3)2],” Organometallics, vol. 9, no. 5, pp. 1405–1413, 1990. View at: Publisher Site | Google Scholar
  49. R. Bosque, C. López, X. Solans, and M. Font-Bardia, “heterodi- and heterotrimetallic compounds containing five-membered rings and σ(Pd-Csp2, ferrocene) bonds. X-ray crystal structure of the meso-form of [Pd2{Fe[(η5C5H3)C(CH3)=NC6H5]}2Cl2(PPh3)2],” Organometallics, vol. 18, no. 7, pp. 1267–1274, 1999. View at: Publisher Site | Google Scholar
  50. P. Ramani, R. Ranatunge-Bandarage, B. H. Robinson, and J. Simpson, “Ferrocenylamine complexes of platinum(II) including cycloplatinated derivatives,” Organometallics, vol. 13, no. 2, pp. 500–510, 1994. View at: Publisher Site | Google Scholar
  51. J. Albert, R. M. Ceder, M. Gómez, J. Granell, and J. Sales, “Cyclopalladation of N-mesitylbenzylideneamines. Aromatic versus aliphatic C-H activation,” Organometallics, vol. 11, no. 4, pp. 1536–1541, 1992. View at: Publisher Site | Google Scholar
  52. P. S. Pregosin, Transition Metal Nuclear Magnetic Resonance, Elsevier, Zürich, Switzerland, 1991.
  53. P. R. R. Ranatunge-Bandarage, N. W. Duffy, S. M. Johnston, B. H. Robinson, and J. Simpson, “Synthesis and stereochemistry of bis(platinum) complexes of ferrocenylamines,” Organometallics, vol. 13, no. 2, pp. 511–521, 1994. View at: Publisher Site | Google Scholar
  54. C. Navarro-Ranninger, F. Zamora, I. López-Solera, A. Monge, and J. R. Masaguer, “Cyclometallated complexes of Pd(II) and Pt(II) with 2-phenylimidazoline,” Journal of Organometallic Chemistry, vol. 506, no. 1-2, pp. 149–154, 1996. View at: Publisher Site | Google Scholar
  55. J. E. Baldwin, R. H. Jones, C. Najera, and M. Yus, “Functionalisation of unactivated methyl groups through cyclopalladation reactions,” Tetrahedron, vol. 41, no. 4, pp. 699–711, 1985. View at: Publisher Site | Google Scholar
  56. C. A. O'Mahoney, I. P. Parkin, D. J. Williams, and J. D. Woollins, “New metal-sulphur-nitrogen compounds from reactions in liquid ammonia. The X-ray structures of trans-bis(acetophenone dimethylhydrazone-Nα)dichloropalladium(II) and [di(azathien)-1-yl-S1N4][2-(hydrazonoethyl)phenyl]palladium(II),” Journal of the Chemical Society, Dalton Transactions, no. 6, pp. 1179–1185, 1989. View at: Publisher Site | Google Scholar
  57. C. Navarro-Ranninger, I. López-Solera, A. Alvarez-Valdés et al., “Cyclometalated complexes of palladium(II) and platinum(II) with N-benzyl- and N-(phenylethyl)-a-benzoylbenzylideneamine. Delocalization in the cyclometalated ring as a driving force for the orthometalation,” Organometallics, vol. 12, no. 10, pp. 4104–4111, 1993. View at: Publisher Site | Google Scholar
  58. D. G. Allen, G. M. Mclaughlin, G. B. Robertson, W. L. Steffen, G. Salem, and S. B. Wild, “Resolutions involving metal complexation. Preparation and resolution of (R,S)-methylphenyl(8-quinolyl)phosphine and its arsenic analogue. Crystal and molecular structure of (+)589-[(R)-dimethyl(1-ethyl-α-naphthyl)aminato-C2,N]-[(S)-methylphenyl(8-quinolyl)phosphine]palladium(II) hexafluorophosphate,” Inorganic Chemistry, vol. 21, no. 3, pp. 1007–1014, 1982. View at: Publisher Site | Google Scholar
  59. H. Jendralla, C. H. Li, and E. Paulus, “Efficient synthesis of (R)- and (S)-(6,6-difluorobiphenyl-2,2-diyl) bis(diphenylphosphine); electron-poor biphenyl-type ligands for transition metal catalysts,” Tetrahedron Asymmetry, vol. 5, no. 7, pp. 1297–1320, 1994. View at: Publisher Site | Google Scholar
  60. J. W. L. Martin, F. S. Stephens, K. D. V. Weerasuria, and S. B. Wild, “Optically active arsenic macrocycles. Highly stereoselective syntheses of diastereomers and enantiomers of 14-membered macrocyclic dimers of (±)-2,3-dihydro- and (±)-2,3,4,5-tetrahydro-1-methyl-1,4-benzazarsepine,” Journal of the Chemical Society, vol. 110, no. 13, pp. 4346–4356, 1988. View at: Publisher Site | Google Scholar
  61. H. Adams, N. A. Bailey, T. N. Briggs, J. A. McCleverty, and H. M. Colquhoun, “Reactions of arylpalladium complexes with ammonia and chelating amines. Crystal and molecular structure of [Pd(oC6H4CH=NCH2CH2NH2)(NH2CH2CH2NH2)][PF6], a product of transamination and ligand substitution,” Journal of the Chemical Society, Dalton Transactions, no. 8, pp. 1521–1526, 1982. View at: Publisher Site | Google Scholar
  62. M. V. Keck and S. J. Lippard, “Unwinding of supercoiled DNA by platinum-ethidium and related complexes,” Journal of the American Chemical Society, vol. 114, no. 9, pp. 3386–3390, 1992. View at: Publisher Site | Google Scholar
  63. J. Ruiz, J. Lorenzo, L. Sanglas et al., “Palladium(II) and platinum(II) organometallic complexes with the model nucleobase anions of thymine, uracil, and cytosine: antitumor activity and interactions with DNA of the platinum compounds,” Inorganic Chemistry, vol. 45, no. 16, pp. 6347–6360, 2006. View at: Publisher Site | Google Scholar
  64. L. H. Pope, M. C. Davies, C. A. Laughton, C. J. Roberts, S. J. B. Tendler, and P. M. Williams, “Atomic force microscopy studies of intercalation-induced changes in plasmid DNA tertiary structure,” Journal of Microscopy, vol. 199, no. 1, pp. 68–78, 2000. View at: Publisher Site | Google Scholar
  65. X. Qu, C. Wan, H.-C. Becker, D. Zhong, and A. H. Zewail, “The anticancer drug-DNA complex: femtosecond primary dynamics for anthracycline antibiotics function,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 25, pp. 14212–14217, 2001. View at: Publisher Site | Google Scholar

Copyright © 2007 X. Riera et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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