Structure-activity relationship and apoptosis induction in A549 cells by the potential anticancer compound cis-bis(3-aminoflavone)dichloroplatinum(II)

Abstract

cis-DDP (cis-diamminedichloroplatinu-m(II), CAS 15663-27-1) is widely used in chemotherapy of many types of cancer. However, besides effectiveness, it gives many side effects which limit its clinical application. Therefore, nowadays studies are focused on searching for novel analogs of cis-DDP, at least equally effective in chemotherapy but less toxic. One of them might be cis-BAFDP (cis-bis(3-aminoflavone)dichloroplatinum(II)) with one of the hydrogen atoms of the amino group of cis-DDP replaced by a flavone ring. 3Aminoflavone (AF) which posseses the desired NH₂ group has been used as non-leaving ligand. The complex has been obtained in the reaction of AF and K₂PtCl₄. There are no data concerning evaluation of structural studies of cis-BAFDP, the beneficial anticancer properties of which were proved in vitro and in vivo. Therefore it was worthwhile to undertake a confirmation of the chemical structure of this compound by applying various spectroscopic techniques especially because of its potential pharmacological application. With this aim in mind this compound was characterized by: IR, ¹H NMR, ¹⁹⁵Pt NMR, UV absorption and fluorescence spectroscopy. Moreover, stronger apoptosis induction by cis-BAFDP than cis-DDP in the human non-small cancer cell line A549 was observed using Hoechst 33258/propidium iodide double staining.

Key words

Anticancer drugs - Apoptosis - cis-bis(3-aminoflavone)di-chloroplatinum(II), structure - CAS 15663-27-1 - cis-diamminedichloro-platinum(II)

• References

• 1 Wong E, Giandomenico CM. Current status of platinum-based antitumor drugs. Chem Rev. 1999; 99: 2451-66
• 2 Ferguson LR, Pearson AE. The clinical use of mutagenic anticancer drugs. Mutat Res. 1996; 355: 1-12
• 3 Reedijk J. Improved understanding in platinum antitumour chemistry. Chem Commun. 1996; 801: 6
• 4 Nijveldt RJ, Nood E, Hoorn DEC, Boelens PG, Norren K, Leeuwen PAM. Flavonoids: a review of probable mechanisms of action and potential applications. Am J Clin Nutr. 2001; 74: 418-25
• 5 Aitken RA, Bibby MC, Cooper PA, Double JA, Laws AL, Ritchie RB et al. Synthesis and antitumour activity of new derivatives of flavone-8-acetic acid (FAA). Part 4: Variation of the basic structure. Arch Pharm (Weinheim). 2000; 333: 181-8
• 6 Akama T, Shida Y, Sugaya T, Ishida H, Gomi K, Kasai M. Novel 5-aminoflavone derivatives as specific antitumor agents in breast cancer. J Med Chem. 1996; 39: 3461-9
• 7 Akama T, Ishida H, Shida Y, Kimura U, Gomi K, Saito K et al. Design and synthesis of potent antitumor 5,4′-diami-noflavone derivatives based on metabolic considerations. J Med Chem. 1997; 40: 1894-1900
• 8 Dauzonne D, Folléas B, Martinez L, Chabot GG. Synthesis and in vitro cytotoxicity of a series of 3-aminoflavones. Eur J Med Chem. 1997; 32: 71-82
• 9 Krol W, Dworniczak S, Pietsz G, Czuba ZP, Kunicka M, Kopacz M et al. Synthesis and tumoricidal activity evaluation of new morin and quercetin sulfonic derivatives. Acta Polon Pharm Drug Res. 2002; 59: 77-9
• 10 McLean L, Soto U, Agama K, Francis J, Jimenez R, Pommier Y et al. Aminoflavone induces oxidative DNA damage and reactive oxidative species-mediated apoptosis in breast cancer cells. Int J Cancer. 2008; 122: 1665-74
• 11 Meng LH, Kohn KW, Pommier Y. Dose-response transition from cell cycle arrest to apoptosis with selective degradation of Mdm2 and p21WAFl/CIPl in response to the novel anticancer agent, aminoflavone (NSC 686,288). Oncogene. 2007; 26: 4806-16
• 12 Valenti P, Fabbri G, Rampa A, Bisi A, Gobbi S, Da Re P et al. Synthesis and antitumor activity of some analogues of flavone acetic acid. Anticancer Drug Design. 1996; 11: 243-52
• 13 Ochocki J, Zyner E. The new platinum (II) compounds with 3-aminoflavone and the method of the synthesis of the new platinum (II) compounds with 3-aminoflavone. Pol. Pat. P.185585. 2003 October 6
• 14 Jansen BA, Pérez JM, Pizarro A, Alonso C, Reedijk J, Navarro-Ranninger C. Sterically hindered cisplatin derivatives with multiple carboxylate auxiliary arms: synthesis and reactions with guanosine-5’-monophosphate and plasmid DNA. J Inorg Biochem. 2001; 85: 229-35
• 15 Kostka K, Zyner E. Structure and protolytic equilibra of 3-hydroksyiminoflavanone. Chem Anal. 1987; 32: 253-61
• 16 Kosmider B, Zyner E, Osiecka R, Ochocki J. Induction of apoptosis and necrosis in A549 cells by the cis-Pt(II) complex of 3-aminoflavone in comparison with cis-DDP. Mutat Res. 2004; 563: 61-70
• 17 Elstein KH, Zucker RM. Comparison of cellular and nuclear flow cytometric techniques for discriminating apoptotic subpopulations. Exp Cell Res. 1994; 211: 322-31
• 18 Gasiorowski K, Brokos B, Kulma A, Ogorzalek A, Skorkowska K. A comparison of the methods applied to detect apoptosis in genotoxically-damaged lymphocytes cultured in the presence of four antimutagens. Cell Mol Biol Lett. 2001; 6: 141-59
• 19 Jakupec MA, Galanski M, Keppler BK. Tumour-inhibiting platinum complexes: state of the art and future perspectives. Rev Physiol Biochem Pharmacol. 2003; 146: 154
• 20 Magnani L, Gaydou EM, Hubaud JC. Spectrophotometric measurement of antioxidant properties of flavones and flavonols against superoxide anion. Anal Chim Acta. 2000; 411: 209-16
• 21 Rice-Evans CA, Nicholas J, Miller J, Paganga G. Antioxidant properties of plant-derived compounds. Trends Plant Sci. 1997; 2: 152-9
• 22 Kosmider B, Osiecka R. Flavonoid compounds: a review of anticancer properties and interactions with cis-diammine-dichloroplatinum(II). Drug Dev Res. 2004; 63: 200-11
• 23 Kosmider B, Wyszynska K, Janik-Spiechowicz E, Osiecka R, Zyner E, Ochocki J et al. Evaluation of the genotoxicity of cis-bis(3-aminoflavone)dichloroplatinum(II) in comparison with cis-DDP. Mutat Res. 2004; 558: 93-110
• 24 Kosmider B, Osiecka R, Ciesielska E, Szmigiero L, Zyner E, Ochocki J. Induction of apoptosis and necrosis in lymphocytes by the cis-Pt(II) complex of 3-aminoflavone in comparison with cis-DDP. Mutat Res. 2004; 558: 169-79
• 25 Kosmider B, Wojcik I, Osiecka R, Bartkowiak J, Zyner E, Ochocki J et al. Enhanced P53 and BAX gene expression and apoptosis in A549 cells by cis-Pt(II) complex of 3-aminoflavone in comparison with cis-DDP. Invest New Drugs. 2005; 23: 287-97
• 26 Ciesielska E, Studzian K, Zyner E, Ochocki J, Szmigiero L. DNA damage and apoptosis induction in L1210 cells by cis-diamminedichloroplatinum(II) and its new aminoflavone analogue. Cell Mol Biol Lett. 2000; 5: 441-50
• 27 Kosmider B, Osiecka R, Zyner E, Ochocki J. Comparison between the genotoxicity of cisPt(11) complex of 3-aminoflavone and cis-DDP in lymphocytes evaluated by the comet assay. Drug Chem Toxicol. 2005; 28: 231-44
• 28 Kosmider B, Zyner E, Osiecka R, Ochocki J. Genotoxicity of cis-PtII complex of 3-aminoflavone in comparison with cis-DDP in A549 cells evaluated by comet assay. Can J Physiol Pharmacol. 2004; 82: 353-8
• 29 Pietras T, Kakowski R, Zyner E, Stolarek R, Ochocki J, Musial A et al. Deoxiribose degradation by cis-platinum and its derivatives choline, hydroaspartate and aminoflavone. J Cosmetol. 1998; 4: 177-80
• 30 Zyner E, Graczyk J, Ochocki J. Pt(II) and Pd(II) complexes of 3-aminoflavone: In vitro and in vivo evaluation. Pharmazie. 1999; 54: 945-6
• 31 Liu W, Wang Y, Tang J, Shen G, Yu R. An optic-fiber sensor for metronidazole based on the fluorescence quenching of a copolymer bound flavone derivative. Anal Sci. 1998; 14: 547-51
• 32 Roshal AD, Grigorovich AV, Doroshenko AO. Flavonols and crown-flavonols as metal cation chelators: the different nature of Ba²⁺ and Mg²⁺ complexes. J Phys Chem. 1998; 102: 5907-14
• 33 Kushev D, Gorneva G, Taxirov S, Spassovska N, Grancharov K. Synthesis, cytotoxicity and antitumor activity of platinum(II) complexes of cyclopentanecarboxylic acid hydrazide. Biol Chem. 1999; 380: 1287-94
• 34 Criado JJ, Herrera MC, Palomero MF, Medarde M, Rodriguez E, Marin JJG. Synthesis and characterization of a new bile acid and platinum(II) complex with cytostatic activity. J Lipid Res. 1997; 38: 1022-32
• 35 Criado JJ, Garcia-Moreno MC, Macias RR, Marin JIG, Medarde M, Rodriguez-Fernandez E. Synthesis and characterization of sodium cis-dichloro-chenodeoxycholylglycinato (O,N) platinum(II)-cytostatic activity. Bio Metals. 1999; 12: 281-8
• 36 Joseph-Nathan P, Mares J, Hernández C, Shoolery JN. Proton and carbon-13 nuclear magnetic resonance studies of flavone and deuterated analogs. J Magn Res. 1974; 16: 447-53
• 37 Chen Y, Guo Z, Sadler PJ. 195Pt- and 15N-NMR spectroscopic studies of cisplatin reaction with biomolecules. In: Lippert B. editor Cisplatin. Chemistry and biochemistry of a leading anticancer drug. Zurich: Verlag Helvetica Chimica Acta; Weinheim: Wiley-VCH, Weinheim; 1999: 293-318
• 38 Bancroft DP, Lepre CA, Lippard SJ. ¹⁹⁵Pt NMR kinetic and mechanistic studies of cis- and trans-diamminedichloro-platinum(II) binding to DNA. Am J Chem Soc. 1990; 112: 6860-71
• 39 Sundquist WI, Ahmed KJ, Hollis LS, Lippard SJ. Solvolysis reactions of cis- and trans-diamminechloroplatinum(II) in dimethyl sulfoxide. Structural characterization and DNA binding of trans-[Pt(NH₃)₂(Me₂SO)Cl]⁺ . Inorg Chem. 1987; 26: 1524-28
• 40 Mira L, Fernandez MT, Santos M, Rocha R, Florêncio MH, Jennings KR. Interactions of flavonoids with iron and copper ions: a mechanism for their antioxidant activity. Free Radic Res. 2002; 36: 1199-208
• 41 Molenaar C, Teuben JM, Heetebrij RJ, Tanke HJ, Reedijk J. New insights in the cellular processing of platinum antitumor compounds, using fluorophore-labeled platinum complexes and digital fluorescence microscopy. J Biol Inorg Chem. 2000; 5: 655-65
• 42 Naik AD, Revankar VK. Design, synthesis and physico-chemical investigation of adinuclear zinc(II) complex with a novel “end-off”compartmental ligand. Proc Indian Acad Sci (Chem Sci). 2001; 113: 285-90