Synthesis, Structural Characterization, and Cytotoxic Activity of Novel Paramagnetic Platinum Hematoporphyrin IX Complexes: Potent Antitumor Agents

Gencheva, G.; Tsekova, D.; Gochev, G.; Momekov, G.; Tyuliev, G.; Skumryev, V.; Karaivanova, M.; Bontchev, P. R.

doi:https://doi.org/10.1155/2007/67376

Metal-Based Drugs

On this page

Abstract References Copyright Related Articles

Research Article | Open Access

Volume 2007 | Article ID 067376 | https://doi.org/10.1155/2007/67376

Synthesis, Structural Characterization, and Cytotoxic Activity of Novel Paramagnetic Platinum Hematoporphyrin IX Complexes: Potent Antitumor Agents

G. Gencheva,¹D. Tsekova,¹G. Gochev,¹G. Momekov,²G. Tyuliev,³V. Skumryev,⁴M. Karaivanova,²and P. R. Bontchev¹

Academic Editor: Irena Kostova

Received09 Feb 2007

Accepted09 May 2007

Published07 Aug 2007

Abstract

Three novel stable Pt(III) complexes with distorted octahedral structure and (dz2)1 ground state have been obtained in the course of Pt(II)-hematoporphyrin IX ((7,12-bis(1-hydroxyethyl)-3,8,13,17-tetramethyl-21H-23H-porphyn-2,18-dipropionic acid), Hp) interaction in alkaline aqueous medium and aerobic conditions. A redox interaction also takes place together with the complexation process leading to the formation of Pt(III) species and organic radicals. The processes in the reaction system and the structure of the complexes formed cis-[Pt(III)(NH3)2(Hp−3H)(H2O)2]⋅H2O1, [Pt(III)(Hp−3H)(H2O)2]⋅H2O2, and [Pt((O,O)Hp−2H)Cl(H2O)3] 3, were studied by UV-Vis, IR, EPR and XPS spectra, thermal (TGS, DSC), potentiometric and magnetic methods. The newly synthesized complexes show promising cytotoxic activity comparable with that of cis-platin in in vitro tests against a panel of human leukemia cell lines. The observed cytotoxicity of the complex 2 against SKW-3 cells (KE-37 derivative) is due to induction of cell death through apoptosis.

References

B. Rosenberg, “Platinum complexes for the treatment of cancer: why the search goes on?,” in Cisplatin. Chemistry and Biochemistry of a Leading Anticancer Drug, B. Lippert, Ed., pp. 3–27, Wiley-VCH, Zürich, Switzerland, 1999.
View at: Google Scholar
J. Reedijk, “Improved understanding in platinum antitumour chemistry,” Chemical Communications, no. 7, pp. 801–806, 1996.
View at: Publisher Site | Google Scholar
E. R. Jamieson and S. J. Lippard, “Structure, recognition, and processing of cisplatin-DNA adducts,” Chemical Reviews, vol. 99, no. 9, pp. 2467–2498, 1999.
View at: Publisher Site | Google Scholar
V. Barbec and J. Kasparkova, “DNA interactions of platinum anticancer drugs. Recent advances and mechanisms of action,” in Metal Compounds in Cancer Chemotherapy, J. M. Pérez, M. A. Fuertes, and C. Alonso, Eds., pp. 187–218, Research Signpost, Kerala, India, 2005.
View at: Google Scholar
E. Wong and Ch. M. Giandomenico, “Current status of platinum-based antitumor drugs,” Chemical Reviews, vol. 99, no. 9, pp. 2451–2466, 1999.
View at: Publisher Site | Google Scholar
V. Brabec and J. Kasparkova, “Platinum-based drugs,” in Metallotherapeutic Drugs & Metal-Based Diagnostic Agents, M. Gielen and Ed. Tiekink, Eds., pp. 489–506, John Wiley & Sons, London, UK, 2005.
View at: Google Scholar
J. Reedijk, “Why does cisplatin reach Guanine-N7 with competing S-donor ligands available in the cell?,” Chemical Reviews, vol. 99, no. 9, pp. 2499–2510, 1999.
View at: Publisher Site | Google Scholar
B. P. Espósito and R. Najjar, “Interactions of antitumoral platinum-group metallodrugs with albumin,” Coordination Chemistry Reviews, vol. 232, no. 1-2, pp. 137–149, 2002.
View at: Publisher Site | Google Scholar
V. M. Gonzalez, M. A. Fuertes, C. Alonso, and J. M. Pérez, “Is cisplatin-induced cell death always produced by apoptosis?,” Molecular Pharmacology, vol. 59, no. 4, pp. 657–663, 2001.
View at: Google Scholar
M. A. Fuertes, J. Castilla, C. Alonso, and J. M. Pérez, “Cisplatin biochemical mechanism of action: from cytotoxicity to induction of cell death through interconnections between apoptotic and necrotic pathways,” Current Medicinal Chemistry, vol. 10, no. 3, pp. 257–266, 2003.
View at: Google Scholar
C. J. Ziegler, A. P. Silverman, and S. J. Lippard, “High-throughput synthesis and screening of platinum drug candidates,” Journal of Biological Inorganic Chemistry, vol. 5, no. 6, pp. 774–783, 2000.
View at: Publisher Site | Google Scholar
V. Brabec and J. Kasparkova, “Modifications of DNA by platinum complexes. Relation to resistance of tumors to platinum antitumor drugs,” Drug Resistance Updates, vol. 8, no. 3, pp. 131–146, 2005.
View at: Publisher Site | Google Scholar
D. Lebwohl and R. Canetta, “Clinical development of platinum complexes in cancer therapy: an historical perspective and an update,” European Journal of Cancer, vol. 34, no. 10, pp. 1522–1534, 1998.
View at: Publisher Site | Google Scholar
Ch.-H. Choi, Y.-J. Cha, and Ch.-S. An et al., “Molecular mechanisms of heptaplatin effective against cisplatin-resistant cancer cell lines: less involvement of metallothionein,” Cancer Cell International, vol. 4, p. 6, 2004.
View at: Publisher Site | Google Scholar
M. J. Cleare and J. D. Hoeschele, “Studies on the antitumor activity of group VIII transition metal complexes—part I. Platinum (II) complexes,” Bioinorganic Chemistry, vol. 2, no. 3, pp. 187–210, 1973.
View at: Publisher Site | Google Scholar
J. Reedijk, “Medicinal applications of heavy-metal compound,” Current Opinion in Chemical Biology, vol. 3, no. 2, pp. 236–240, 1999.
View at: Publisher Site | Google Scholar
Ch. X. Zhang and S. J. Lippard, “New metal complexes as potential therapeutics,” Current Opinion in Chemical Biology, vol. 7, no. 4, pp. 481–489, 2003.
View at: Publisher Site | Google Scholar
M. D. Hall and T. W. Hambley, “Platinum(IV) antitumour compounds: their bioinorganic chemistry,” Coordination Chemistry Reviews, vol. 232, no. 1-2, pp. 49–67, 2002.
View at: Publisher Site | Google Scholar
R. W. Boyle and D. Dolphin, “Structure and biodistribution relationships of photodynamic sensitizers,” Photochemistry and Photobiology, vol. 64, no. 3, pp. 469–485, 1996.
View at: Google Scholar
R. Pottier and J. C. Kennedy, “The possible role of ionic species in selective biodistribution of photochemotherapeutic agents toward neoplastic tissue,” Journal of Photochemistry and Photobiology B: Biology, vol. 8, no. 1, pp. 1–16, 1990.
View at: Publisher Site | Google Scholar
H. Brunner, M. R. Arndt, and B. Treittinger, “Porphyrin platinum conjugates—new aims,” Inorganica Chimica Acta, vol. 357, no. 6, pp. 1649–1669, 2004.
View at: Publisher Site | Google Scholar
H. Ali and J. E. van Lier, “Metal complexes as photo- and radiosensitizers,” Chemical Reviews, vol. 99, no. 9, pp. 2379–2450, 1999.
View at: Publisher Site | Google Scholar
A. Zajac, Zd. Jankiewicz, M. Skórczakowski, W. Zendzian, and G. A. Skripko, “Laser radiation sources applied to HpD diagnosis and therapy,” in Laser Technology V: Applications in Medicine and Ecology, vol. 3188 of Proceedings of SPIE, pp. 16–33, Szczecin-Swinoujscie, Poland, September 1996.
View at: Publisher Site | Google Scholar
J. P. Macquet, M. M. Millard, and T. Theophanides, “X-ray photoelectron spectroscopy of porphyrins,” Journal of the American Chemical Society, vol. 100, no. 15, pp. 4741–4746, 1978.
View at: Publisher Site | Google Scholar
H. Kunkely and A. Vogler, “Photoreactivity of hematoporphyrin IX-dichloroplatinum(II). Light-induced release and activation of free base hematoporphyrin,” Inorganica Chimica Acta, vol. 254, no. 2, pp. 417–419, 1997.
View at: Publisher Site | Google Scholar
H. Brunner, K.-M. Schellerer, and B. Treittinger, “Synthesis and in vitro testing of hematoporphyrin type ligands in platinum(II) complexes as potent cytostatic and phototoxic antitumor agents,” Inorganica Chimica Acta, vol. 264, no. 1-2, pp. 67–79, 1997.
View at: Publisher Site | Google Scholar
Ch. Lottner, K.-Ch. Bart, G. Bernhardt, and H. Brunner, “Hematoporphyrin-derived soluble porphyrin-platinum conjugates with combined cytotoxic and phototoxic antitumor activity,” Journal of Medicinal Chemistry, vol. 45, no. 10, pp. 2064–2078, 2002.
View at: Publisher Site | Google Scholar
Ch. Lottner, R. Knuechel, G. Bernhardt, and H. Brunner, “Distribution and subcellular localization of a water-soluble hematoporphyrin-platinum(II) complex in human bladder cancer cells,” Cancer Letters, vol. 215, no. 2, pp. 167–177, 2004.
View at: Publisher Site | Google Scholar
P. R. Bontchev, M. Mitewa, and G. Gencheva, “New platinum(lI) and platinum(lll) complexes of creatinine,” Pure & Applied Chemistry, vol. 61, no. 5, pp. 897–902, 1989.
View at: Google Scholar
G. Gencheva, M. Mitewa, and P. R. Bontchev, “Dimeric and oligomeric platinum(II, II), (II, III) and palladium(II, II) complexes with creatinine,” Polyhedron, vol. 11, no. 18, pp. 2357–2361, 1992.
View at: Publisher Site | Google Scholar
M. Mitewa and G. Gencheva, “Platinum(III) formation and stabilization as “Platinum blues” with different types of ligands in the course of their interaction with ${PtCl}_{4}^{2 -}$ – and cis-Pt ${({NH}_{3})}_{2} {Cl}_{2}$ ,” Research on Chemical Intermediates, vol. 18, no. 2-3, pp. 115–129, 1992.
View at: Google Scholar
M. Mitewa, G. Gencheva, and M. Mechkova, ““Platinum blue” complex with a new type of bridging ligand,” Journal of Inorganic Biochemistry, vol. 53, no. 2, pp. 151–156, 1994.
View at: Publisher Site | Google Scholar
G. Gencheva, M. Mitewa, G. Gochev, I. Wawer, and V. Enchev, “Synthesis and structure of a new dimeric Pt(II)-Pt(III) complex with o-phthalic acid,” Synthesis and Reactivity in Inorganic and Metal-Organic Chemistry, vol. 28, no. 4, pp. 515–527, 1998.
View at: Google Scholar
M. Mitewa, G. Gencheva, Sv. Bobev, G. Gochev, D. Mehandjiev, and I. Wawer, “Formation and stabilization of monomeric PT(III) species through complexation with linear tetrapyrrole ligand bilirubin,” Research on Chemical Intermediates, vol. 25, no. 5, pp. 431–439, 1999.
View at: Google Scholar
J. P. Davidson, P. J. Faber, and R. G. Fischer Jr. et al., ““Platinum pyrimidine blues” and related complexes: a new class of potent antitumor agents,” Cancer Chemotherapy Report, vol. 59, no. 2, part 1, pp. 287–300, 1975.
View at: Google Scholar
T. Mosmann, “Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays,” Journal of Immunological Methods, vol. 65, no. 1-2, pp. 55–63, 1983.
View at: Publisher Site | Google Scholar
S. M. Konstantinov, H. Eibl, and M. R. Berger, “BCR-ABL influences the antileukaemic efficacy of alkylphosphocholines,” British Journal of Haematology, vol. 107, no. 2, pp. 365–374, 1999.
View at: Publisher Site | Google Scholar
M. Inamo, N. Kamiya, Y. Inada, M. Nomura, and Sh. Funahashi, “Structural characterization and formation kinetics of sitting-atop (SAT) complexes of some porphyrins with copper(II) ion in aqueous acetonitrile relevant to porphyrin metalation mechanism. Structures of aquacopper(II) and Cu(II)-SAT complexes as determined by XAFS spectroscopy,” Inorganic Chemistry, vol. 40, no. 22, pp. 5636–5644, 2001.
View at: Publisher Site | Google Scholar
G. Gencheva, D. Tsekova, G. Gochev, D. Mehandjiev, and P. R. Bontchev, “Monomeric Au(II) complex with hematoporphyrin IX,” Inorganic Chemistry Communications, vol. 6, no. 3, pp. 325–328, 2003.
View at: Publisher Site | Google Scholar
K. Nakamoto, Infrared and Raman Spectra of Inorganic and Coordination Compounds—Part B, John Wiley & Sons, New York, NY, USA, 5th edition, 1997.
View at: Google Scholar
C. C. Uphoff, S. Habig, S. Fombonne, Y. Matsuo, and H. G. Drexler, “ABL-BCR expression in BCR-ABL-positive human leukemia cell lines,” Leukemia Research, vol. 23, no. 11, pp. 1055–1060, 1999.
View at: Publisher Site | Google Scholar
B. Desoize and C. Madoulet, “Particular aspects of platinum compounds used at present in cancer treatment,” Critical Reviews in Oncology/Hematology, vol. 42, no. 3, pp. 317–325, 2002.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2007 G. Gencheva 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.

PDF Download Citation Order printed copies

Views

227

Downloads

77

Citations