Skip to main content

Crystal structure, DNA binding studies, nucleolytic property and topoisomerase I inhibition of zinc complex with 1,10-phenanthroline and 3-methyl-picolinic acid

Abstract

Crystal structure analysis of the zinc complex establishes it as a distorted octahedral complex, bis(3-methylpicolinato-κ2 N,O)2(1,10-phenanthroline-κ2 N,N)-zinc(II) pentahydrate, [Zn(3-Me-pic)2(phen)]·5H2O. The trans-configuration of carbonyl oxygen atoms of the carboxylate moieties and orientation of the two planar picolinate ligands above and before the phen ligand plane seems to confer DNA sequence recognition to the complex. It cannot cleave DNA under hydrolytic condition but can slightly be activated by hydrogen peroxide or sodium ascorbate. Circular Dichroism and Fluorescence spectroscopic analysis of its interaction with various duplex polynucleotides reveals its binding mode as mainly intercalation. It shows distinct DNA sequence binding selectivity and the order of decreasing selectivity is ATAT > AATT > CGCG. Docking studies lead to the same conclusion on this sequence selectivity. It binds strongly with G-quadruplex with human tolemeric sequence 5′-AG3(T2AG3)3-3′, can inhibit topoisomerase I efficiently and is cytotoxic against MCF-7 cell line.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

References

  • Addess KJ, Sinsheimer JS, Feigon J (1993) Solution structure of a complex between [N-MeCys3, N-MeCys7]TANDEM and [d(GATATC)]2. Biochemistry 32:2498–2508

    Article  CAS  PubMed  Google Scholar 

  • Baker ES, Bernstein SL, Gabelica V, De Pauw E, Bowers MT (2006) G-quadruplexes in telomeric repeats are conserved in a solvent-free environment. Int J Mass Spectrom 253:225–237

    Article  CAS  Google Scholar 

  • Bazzicalupi C, Bencini A, Bonaccini C, Giorgi C, Gratteri P, Moro S, Palumbo A, Simionato A, Sgrignani J, Sissi C, Valtancoli B (2008) Tuning the activity of Zn(II) complexes in DNA cleavage: clues for design of new efficient metallo-hydrolases. Inorg Chem 47:5473–5484

    Article  CAS  PubMed  Google Scholar 

  • Beretta GL, Perego P, Zunino F (2008) Targeting topoisomerase I: molecular mechanisms and cellular determinants of response to topoisomerase I inhibitors. Expert Opin Ther Targets 12:1243–1256

    Article  CAS  PubMed  Google Scholar 

  • Boger DL, Fink BE, Brunette SR, Tse WC, Hedrick MP (2001) A simple, high-resolution method for establishing DNA binding affinity and sequence selectivity. J Am Chem Soc 123:5878–5891

    Article  CAS  PubMed  Google Scholar 

  • Boseggia E, Gatos M, Lucatello L, Mancin F, Moro S, Palumbo M, Sissi C, Tecilla P, Tonellato U, Zagotto G (2004) Toward efficient Zn(II)-based artificial nucleases. J Am Chem Soc 126:4543–4549

    Article  CAS  PubMed  Google Scholar 

  • Bruker (2007) APEX2 and SAINT. Bruker AXS Inc, Madison

    Google Scholar 

  • Carey JF, Schultz SJ, Sisson L, Fazzio TG, Champoux JJ (2003) DNA relaxation by human topoisomerase I occurs in the closed clamp conformation of the protein. Proc Nat Acad Sci 100:5640–5645

    Article  CAS  PubMed  Google Scholar 

  • Chuang N–N, Lin C-L, Chen H–K (1996) Modification of DNA topoisomerase I enzymatic activity with phosphotyrosyl protein phosphatase and alkaline phosphatase from the hepatopancreas of the shrimp Penaeus japonicus (Crustacea: Decapoda). Comp Biochem Physiol l14B:145–151

    Google Scholar 

  • Desai AN, Shankar V (2003) Single-strand-specific nucleases. FEMS Microbiol Rev 26:457–491

    Article  CAS  PubMed  Google Scholar 

  • Diana P, Martorana A, Barraja P, Montalbano A, Dattolo G, Cirrincione G, Dall’ Acqua F, Salvador A, Vedaldi D, Basso Giuseppe, Viola G (2008) Isoindolo[2,1-a]quinoxaline derivatives, novel potent antitumour agents with dual inhibition of tubulin polymerization and topoisomerase I. J Med Chem 51:2387–2399

  • Di Marco VB, Tapparo A, Dolmella A, Bombi GG (2004) Complexation of 2-hydroxynicotinic and 3-hydroxypicolinic acids with zinc(II). Solution state study and crystal structure of trans-diaaqua-bis-(3-hdyroxypicolinato)zinc(II). Inorg Chim Acta 357:135–142

    Article  CAS  Google Scholar 

  • Douvas A, Lambie PB, Turman MA, Nitahara KS, Hammond L (1991) Negative regulation of Sc1-70/topoisomerase I by zinc and an endogenous macromolecule. Biochem Biophy Res Commun 178:414–421

    Article  CAS  Google Scholar 

  • DS VISUALIZER™—Accelrys Software Inc. Discovery Studio Visualizer 2.0

  • Galezowska E, Masternak A, Rubis B, Czyrski A, Rybxzyńska, Hermann TW, Juskowia B (2007) Spectroscopic study and G-quadruplex DNA bindinging affinity of two bioactive papaverine-derived ligands. Int J Biol Macro 41:558–563

  • He J, Sun J, Mao Z-W, Ji L-N, Sun H (2009) Phosphodieste hydrolysis and specific DNA binding and cleavage promoted by guanidinium-functionalized zinc complexes. J Inorg Biochem 103:851–858

    Article  CAS  PubMed  Google Scholar 

  • Ivanow VI, Minchenkova LE, Schyolkina AK, Poletayer AI (1973) Different conformations of double-stranded nucleic acid in solution as revealed by circular dichroism. Biopolymers 12:89–110

    Article  Google Scholar 

  • Jiang A-L, Cheng Y, Li J, Zhang W (2008) A zinc-dependent endonuclease is responsible for DNA laddering during nuclear salt-induced programmed cell death in root tip cells of rice. J Plant Physiol 165:1134–1141

    Article  CAS  PubMed  Google Scholar 

  • Jones G, Willet P, Glen RC (1995) Molecular recognition of receptor sites using a genetic algorithm with a description of desolvation. J Mol Biol 245:43–53

    Google Scholar 

  • Jones G, Willet P, Glen RC, Leach AR, Taylor R (1997) Development and validation of a genetic algorithm for flexible docking. J Mol Biol 267:727–748

    Google Scholar 

  • Kikuta E, Koike T, Kimura E (2000) Controlling gene expression by zinc(II)–macrocyclic tetraamine complexes. J Inorg Biochem 79:253–259

    Article  CAS  PubMed  Google Scholar 

  • Kumar Singh S, Joshi S, Ranjan Singh A, Saxena JK, Pandey DS (2007) DNA binding and topoisomerase II inhibitory activity of water-soluble ruthenium(II) and rhodium(III) complexes. Inorg Chem 46:10869–10876

    Article  Google Scholar 

  • Kypr J, Kejnovská I, Renčiuk D, Vorličková M (2009) Circular dichroism and conformational polymorphism of DNA. Nucleic Acids Res 37:1713–1725

    Article  CAS  PubMed  Google Scholar 

  • Li Q-L, Huang J, Wang Q, Jiang N, Xia C-Q, Lin H–H, Wu J, Yu X-Q (2006) Monometallic complexes of 1, 4, 7, 10-tetraazacyclododecane containing an imidazolium side: synthesis, characterization, and their interaction with plasmid DNA. Bioorg Med Chem 14:4151–4157

    Article  CAS  PubMed  Google Scholar 

  • Li J-H, Wang J-T, Zhang L-Y, Chen Z-N, Mao Z-W (2009) Structure, speciation, DNA binding and nuclease activity of two bipyridyl-zinc complexes bearing trimethylaminomethyl groups. Inorg Chim Acta 362:1918–1924

    Article  CAS  Google Scholar 

  • Lin L, Ozaki T, Takada Y, Kageyama H, Nakamura Y, Hata A, Zhang J-H, Simonds WF, Nakagawara A, Koseki H (2005) Topors, a p53 and topoisomerase I-binding RING finger protein, is a coactivator of p53 in growth suppression induced by DNA damage. Oncogene 24:3385–3396

    Article  CAS  PubMed  Google Scholar 

  • Liu C-L, Wang M, Zhang T-L, Sun H-Z (2004) DNA hydrolysis promoted by di- and multi-nuclear metal complexes. Coord Chem Rev 248:147–168

    Article  CAS  Google Scholar 

  • Lu Y-J, Ou T-M, Tan J-H, Hou J-Q, Shao W-Y, Peng D, Sun N, Wang X-D, Wu W-B, Bu X-Z, Huang Z-S, Ma D-L, Wong K-Y, Gu L-Q (2008) 5-N-methyalated quinoline derivatives as telomeric G-quadruplex stabilising ligands: effects of 5-N positive charge on quadruplex binding affinity and cell proliferation. J Med Chem 51:6381–6392

    Google Scholar 

  • Malinina L, Soler-López M, Aymamí J, Subirana JA (2002) Intercalation of an acridine-peptide drug in an AA/TT base step in the crystal structure of [d(CGCGAATTCGCG)](2) with six duplexes and seven Mg(2+) ions in the asymmetric unit. Biochemistry 41:9341–9348

    Article  CAS  PubMed  Google Scholar 

  • Mancin F, Tecilla P (2007) Zinc(II) complexes as hydrolytic catalysts of phosphate diester cleavage: from model substrates to nucleic acids. New J Chem 31:800–817

    Article  CAS  Google Scholar 

  • Nagaoka M, Sugiura Y (2000) Artificial zinc finger peptides: creation, DNA recognition, and gene regulation. J Inorg Biochem 82:57–63

    Article  CAS  PubMed  Google Scholar 

  • Nagesh N, Krishnaiah A (2003) A comparative study on the interaction of acridine and synthetic bis-acridine with G-quadruplex structure. J Biochem Biophys Methods 57:65–74

    Article  CAS  PubMed  Google Scholar 

  • Ng CH, Kong KC, Von ST, Balraj P, Jensen P, Thirthagiri E, Hamad H, Chikira M (2008) Synthesis, characterization, DNA-binding study and anticancer property of ternary metal(II) complexes of EDDA and an intercalating ligand. Dalton Trans (4):447–454

  • Nordell P, Westerlund F, Wilhelmsson M, Nordén B, Lincoln P (2007) Kinetic recognition of AT-rich DNA by ruthenium complexes. Angew Chem Int Ed 46:2203–2206. Also references quoted therein

    Google Scholar 

  • Okabe N, Oya N (2000) Copper(II) and zinc(II) complexes of pyridine-2, 6-dicarboxylic acid. Acta Crystallogr C 56:305–307

    Article  PubMed  Google Scholar 

  • Papworth M, Kolasinska P, Minczuk M (2006) Designer zinc-finger proteins and their applications. Gene 366:27–38

    Article  CAS  PubMed  Google Scholar 

  • Patra AK, Bhowmick T, Ramakumar S, Chakravarty AR (2007) Metal-based netropsin mimics showing AT-selective DNA binding and DNA cleavage activity at red light. Inorg Chem 46:9030–9032

    Article  CAS  PubMed  Google Scholar 

  • Pedretti A, Villa L, Vistoli G (2002) Vega: a versatile program to convert, handle and visualize molecular structure on windows-based PCs. J Mol Graph 21:47–49

    Article  CAS  Google Scholar 

  • Pedretti A, Villa L, Vistoli G (2003) Atom-type description language: a universal language to recognize atom types implemented in the vega program. Theor Chem Acta 109:229–232

    CAS  Google Scholar 

  • Pedretti A, Villa L, Vistoli G (2004) Vega—an open platform to develop chemo-bio-informatics applications, using plug-in architecture and script programming. J Comput Aided Mol Des 18:167–173

    Article  CAS  PubMed  Google Scholar 

  • Pommier Y (2008) Topoisomerase I inhibitors: camptothecins and beyond. Nat Rev Cancer 6:789–802

    Article  Google Scholar 

  • Proudfoot EM, Mackay JP, Vagg RS, Vickery KA, Williams PA, Karuso P (1997) D-cis-α-[Ru(RR-picchxnMe2)(phen)]2+ shows minor groove AT selectivity with oligonucleotides. Chem Comm (17):1623–1624

  • Qian J, Gu W, Liu H, Gao F, Feng L, Yan S, Liao D, Cheng P (2007) The first dinuclear copper(II) and zinc(II) complexes containing novel bis-TACN: syntheses, structures, and DNA cleavage activities. Dalton Trans (10):1060–1066

  • Rajendiran V, Murali M, Suresh E, Palaniandavar M, Periasamy VS, Akbarsha MA (2008) Non-covalent DNA binding and cytotoxicity of certain mixed-ligand ruthenium(II) complexes of 2,2′-dipyridylamine and diimines. Dalton Trans (16):2157–2170

  • Rajendran A, Nair BU (2006) Unprecedented binding behaviour of acridine group of dye: a combined experimental and theoretical investigation for the development of anticancer chemotherapeutic agents. Biochim Biophys Acta (1760):1794–1801

  • Ramakrishnan S, Palaniandavar M (2008) Interaction of rac-[Cu(diimine)3]2+ and rac-[Zn(diimine)3]2+ complexes with CT DNA: effect of fluxional Cu(II) geometry on DNA binding, ligand–promoted exciton coupling and prominent DNA cleavage. Dalton Trans (29):3866–3878

  • Rothenberg ML (1997) Topoisomerase I inhibitors: review and update. Ann Oncol 8:837–855

    Article  CAS  PubMed  Google Scholar 

  • Seng HL, Alan Ong HK, Raja Noor ZRAR, Bohari MY, Tiekink ERT, Tan KW, Mohd Jamil M, Caracelli I, Ng CH (2008) Factors affecting nucleolytic efficiency of some ternary metal complexes with DNA binding and recognition domains. Crystal and molecular structure of Zn(phen)(edda). J Inorg Biochem 102:1997–2011

    Article  CAS  PubMed  Google Scholar 

  • Seng HL, Tan KW, Mohd Jamil M, Tan WT, Hamada H, Chikira M, Ng CH (2009) Copper(II) complexes of methylated glycine derivatives: effect of methyl substituent on their DNA binding and nucleolytic property. Polyhedron 28:2219–2227

    Article  CAS  Google Scholar 

  • Sheldrick GM (1996) SADABS. University of Göttingen, Germany

    Google Scholar 

  • Sheldrick GM (2008) A short history of SHELX. Acta Crystallogr A 64:112–122

    Google Scholar 

  • Stehbens WE (2003) Oxidative stress, toxic hepatitis, and antioxidants with particular emphasis on zinc. Exp Mol Pathol 75:265–276

    Article  CAS  PubMed  Google Scholar 

  • Sunami S, Nishimura T, Nishimura I, Ito S, Arakawa H, Ohkubo M (2009) Synthesis and biological activities of topoisomerase I inhibitors, 6-arylmethylamino analogues of edotecarin. J Med Chem 52:3225–3237

    Article  CAS  PubMed  Google Scholar 

  • Talib J, Green C, Davis KJ, Urathamakul T, Beck JL, Aldrich-Wright JR, Ralph SF (2008) A comparison of the binding of metal complexes to duplex and quadruplex DNA. Dalton Trans 1018–1026

  • Teicher BA (2008) Next generation topoisomerase I inhibitors: rationale and biomarker strategies. Biochem Pharmacol 75:1262–1271

    Article  CAS  PubMed  Google Scholar 

  • Wang X, Wang L-K, Kingsbury WD, Johnson RK, Hecht SM (1998) Differential effects of camptothecin derivatives on topoisomerase I-mediated DNA structure modifications. Biochemistry 37:9399–9408

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Schnetz-Boutaud NC, Kroth H, Yagi H, Sayer JM, Kumar S, Jerina DM, Stone MP (2008) 3′-Intercalation of a N2-dG 1R-trans-anti-benzo[c]phenanthrene DNA adduct in an iterated (CG)3 repeat. Chem Res Toxicol 21:1348–1358

    Article  CAS  PubMed  Google Scholar 

  • Waterborg JH, Kuyper CMA (1982) Substrate specificity and mode of action of the zinc-metallo nuclease from Physarum polycephalum. J Biochem 92:1655–1661

    CAS  PubMed  Google Scholar 

  • Webb MR, Ebeler SE (2008) Comparative analysis of topoisomerase IB inhibition and DNA intercalation by flavonoids and similar compounds: structural determinates of activity. J Food Biochem 32:576–596

    Article  CAS  PubMed  Google Scholar 

  • Wei C, Tang Q, Li C (2008) Structural transition from the random coil to quadruplex of AG3(T2AG3)3 induced by Zn2+. Biophys Chem 132:110–113

    Article  CAS  PubMed  Google Scholar 

  • Xu Y, Noguchi Y, Sugiyama H (2006) The new models of the human telomere d[AGGG(TTAGGG)3] in K+ solution. Bioorg Med Chem 14:5584–5591

    Article  CAS  PubMed  Google Scholar 

  • Zeglis BM, Pierre VC, Barton JK (2007) Metallo-intercalators and metallo-insertors. Chem Commun (45):4565–4579

  • Zhang N, Lin C, Huang X, Kolbanovskiy A, Hingerty BE, Amin S, Broyde S, Geacintov NE, Patel DJ (2005) Methylation of cytosine at C5 in a CpG sequence context causes a conformational switch of a benzo[a]pyrene diol epoxide-N2-guanine adduct in DNA from a minor groove alignment to intercalation with base displacement. J Mol Biol 346:951–965

    Article  CAS  PubMed  Google Scholar 

  • Zhang W-J, Ou T-M, Lu Y-J, Huang Y-Y, Wu W-B, Huang Z-S, Zhou J-L, Wong K-Y, Gu L-Q (2007) 9-Substituted derivatives as G-quadruplex stabilising ligands in telomeric DNA. Bioorg Med Chem 15:5493–5501

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors like to thank MOSTI of Malaysia for an Science grant (02-02-11-SF0033). IC thanks CNPq (Proc. 472237/2008-0) and Fundunesp (Proc. 00525/08-DFP).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Chew-Hee Ng.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Seng, HL., Von, ST., Tan, KW. et al. Crystal structure, DNA binding studies, nucleolytic property and topoisomerase I inhibition of zinc complex with 1,10-phenanthroline and 3-methyl-picolinic acid. Biometals 23, 99 (2010). https://doi.org/10.1007/s10534-009-9271-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s10534-009-9271-y

Keywords

  • Zinc(II) ternary complex
  • Duplex and quadruplex DNA binding
  • Nucleolytic
  • Topo I inhibition
  • Molecular modeling
  • Docking