Metal-Based Anticancer Agents: In vitro DNA Binding, Cleavage and Cytotoxicity

Two new metal-based anticancer chemotherapeutic
agents, [(Ph2Sn)2(HGuO)2(phen)Cl2] 1 and [(Ph3Sn)(HGuO)(phen)]-
Cl.CH3OH.H2O 2, were designed, prepared and characterized by
analytical and spectral (IR, ESI-Mass, 1H, 13C and 119Sn NMR)
techniques. The proposed geometry of Sn(IV) in 1 and 2 is distorted
octahedral and distorted trigonal-bipyramidal, respectively. Both 1
and 2 exhibit potential cytotoxicity in vitro against MCF-7, HepG-2
and DU-145 cell lines. The intrinsic binding constant (Kb) values of 1
(2.33 × 105 M-1) and 2 (2.46 × 105 M-1) evaluated from UV-Visible
absorption studies suggest non-classical electrostatic mode of
interaction via phosphate backbone of DNA double helix. The Stern-
Volmer quenching constant (Ksv) of 1 (9.74 × 105 M-1) and 2 (2.9 ×
106 M-1) determined by fluorescence studies suggests the groove
binding and intercalation mode for 1 and 2, respectively. Effective
cleavage of pBR322 DNA is induced by 1.Their interaction with
DNA of cancer cells may account for potency.

• Mala Nath
• Nagamani Kompelli
• Partha Roy
• Snehasish Das

• Anticancer agents
• DNA binding studies
• NMR spectroscopy
• organotin.

[1] S. G. Ward, R. C. Taylor, "Anti-tumor activity of the main-group
elements: aluminum, gallium, indium, thallium, germanium, lead,
antimony and bismuth,” in Metal-Based Anti-Tumor Drugs, M. F.
Gielen, Ed. London: Freund Publishing House, 1988, pp. 1.
[2] P. K¨opf-Maier, H. K¨opf, " Non-platinum-group metal antitumor
agents: history, current status, and perspectives,” Chem. Rev., vol. 87,
1987, pp. 1137–1152.
[3] B. K. Keppler, C. Friesen, H. G. Moritz, H. Vongerichten, E. Vogel,
"Tumor inhibiting bis(β-diketonato) metal complexes. Budotitane, cisdiethoxybis(
1-phenylbutane-1,3- dionato)titanium-(IV); The first
transition metal complex after platinum to qualify for clinical trials,”
Struct. Bond., vol. 78, 1991, pp. 97–127.
[4] S. Fruhauf, W. J. Zeller, "In vitro evaluation of platinum, titanium and
ruthenium metal complexes in cisplatin-sensitive and -resistant rat
ovarian tumors,” Cancer Chemoth. Pharm., vol. 27, 1991, pp. 301–307.
[5] G. Sava, S. Zorzet, T. Giraldi, "Antineoplastic activity and toxicity of an
organometallic complex of ruthenium(II) in comparison with cis-PDD in
mice bearing solid malignant neoplasms,” Eur. J. Cancer Clin. Oncol.,
vol. 20, 1984, pp. 841–847.
[6] C. Pettinari, F. Marchetti, "Chemical and biotechnological developments
in organotin cancer chemotherapy,” in Tin Chemistry, Fundamentals,
Frontiers, and Applications, A. G. Davies, M. Gielen, K. H. Pannell, and
E. R. T. Tiekink, Ed. New York: JohnWiley & Sons, 2008, pp. 454–468.
[7] A. K. Saxena, F. Huber, "Organotin compounds and cancer
chemotherapy,” Coord. Chem. Rev., vol. 95, 1989, pp. 109–123.
[8] M. Gielen, P. Lelieveld, D. de Vos, R. Willem, "In vitro antitumor
activity of organotin compounds,” in Metal-Based Antitumor Drugs, M.
Gielen Ed. London: Freund Publishing House, 1992.
[9] M. J. Clarke, F. Zhu, D. R. Frasca, "Non-platinum chemotherapeutic
metallopharmaceuticals,” Chem. Rev., vol. 99, 1999, pp. 2511–2533.
[10] M. Nath, S. Pokharia, R. Yadav, "Organotin(IV) complexes of amino
acids and peptides,” Coord. Chem. Rev., vol. 215, 2001, pp. 99–149.
[11] Q. Li, P. Yang, H. Wang, G. Maolin, "Diorganotin(IV) antitumor agent.
(C2H5)2SnCl2 (phen)/nucleotides aqueous and solid-state coordination
chemistry and its DNA binding studies,” J. Inorg. Biochem., vol. 64,
1996, pp. 181–195.
[12] R. Huang, A. Wallqvist, D. G. Covell, "Anticancer metal compounds in
NCI’s tumor-screening database: putative mode of action,” Biochem.
Pharmacol., vol. 69, 2005, pp. 1009–1039.
[13] F. Arjmand, G. C. Sharma, F. Sayeed, M. Muddassir, S. Tabassum, "De
novo design of chiral organotin cancer drug candidates: validation of
enantiopreferential binding to molecular target DNA and 5’-GMP by
UV–visible, fluorescence, 1H and 31P NMR,” J. Photochem. Photobiol.,
vol. 105, 2011, pp. 167–174.
[14] C. F. J. Barnard, M. J. Cleare, P. C. Hydes, "Second generation
anticancer platinum compounds,” Chem. in Brit., vol. 22, 1986, pp.
1001–1004.
[15] B. Desoize, "Cancer and metals and metal compounds: part II—cancer
treatment,” Crit. Rev. Oncol. Hematol., vol. 42, 2002, pp. 213–215.
[16] B. Desoize, C. Madoulet, "Particular aspects of platinum compounds
used at present in cancer treatment,” Crit. Rev. Oncol. Hematol., vol. 42,
2002, pp. 317–325.
[17] P. Yang, M. Guo, "Interactions of organometallic anticancer agents with
nucleotides and DNA,” Coord. Chem. Rev., vol. 185–186, 1999, pp.
189–211.
[18] L. Pellerito, L. Nagy, "Organotin(IV)n+ complexes formed with
biologically active ligands: equilibrium and structural studies, and some
biological aspects,” Coord. Chem. Rev., vol. 224, 2002, pp. 111–150.
[19] S. Tabassum, C. Pettinari, "Chemical and biotechnological
developments in organotin cancer chemotherapy,” J. Organomet. Chem.,
vol. 691, 2006, pp. 1761–1766.
[20] Zolt´an Szab´o, "Multinuclear NMR studies of the interaction of metal
ions with adenine-nucleotides,” Coord. Chem. Rev., vol. 252, 2008, pp.
2362–2380.
[21] A. Alama, B. Tasso, F. Novelli, F. Sparatore, "Organometallic
compounds in oncology: implications of novel organotins as antitumor
agents,” Drug Discov. Today, vol. 14, 2009, pp.9-10.
[22] A. M. Florea, D. Büsselberg, "Anti-cancer drugs interfere with
intracellular calcium signaling,” NeuroToxicol., vol. 1006, 2009, pp. 1–
8.
[23] S. K. Hadjikakou, N. Hadjiliadis, "Antiproliferative and anti-tumor
activity of organotin compounds,” Coord. Chem. Rev., vol. 253, 2009,
pp. 235–249.
[24] A. Y. Louie, T. J. Meade, "Metal complexes as enzyme inhibitors,”
Chem. Rev., vol. 99, 1999, pp. 2711–2734.
[25] P. J. Barnard, S. J. Berners-Price, "Target in the mitochondrial cell death
pathway with gold compounds,” Coord. Chem. Rev., vol. 251, 2007, pp.
1889–1902.
[26] J. D. Robertson, S. Orrenius, "Role of mitochondria in toxic cell death,”
Toxicology, vol. 181–182, 2002, pp. 491–496.
[27] A. J. Crowe, "The chemotherapeutic properties of tin compounds”,
Drugs Future, vol. 12, 1987, pp. 255–275.
[28] M. Gielen, Tin-Based Antitumor Drugs, Springer Verlag, Berlin, 1990.
[29] M. Gielen, E. R. T. Tiekink, Tin compounds and their therapeutic
potential, Metallotherapeutic Drugs and Metal-Based Diagnostic
Agents. The Use of Metals in Medicine, JohnWiley & Sons, New York,
2005.
[30] R. C. Poller, The chemistry of organotin compounds, Logos Press
Limited, London, 1970.
[31] A. G. Davies, Organotin chemistry, VCH, Weinheim, Germany, 2004.
[32] M. Gielen, "An overview of forty years organotin chemistry developed
at the Free Universities of Brussels ULB and VUB,” J. Braz. Chem.
Soc., vol. 14, 2003, pp. 1.
[33] M. Nath, S. Pokharia, G. Eng, X. Song, M. Gielen, M. Kemmer, M.
Biesemans, R. Willem, D. de Vos, "New organotin(IV) derivatives of
dipeptides as models for metal-protein interactions: In vitro antitumor
activity,” Appl. Organmet. Chem., vol. 17, 2003, pp. 305–314.
[34] M. Nath, M. Vats, P. Roy, "Di- and triorganotin(IV) complexes of
biologically important orotic acid: synthesis, spectroscopic studies, in
vitro anti-cancer, DNA fragmentation, enzymes assays, and in vivo antiinflammatory
activities,” Eur. J. Med. Chem., vol. 59, 2013, pp.310–
321.
[35] S. R. Collinson, D. E. Fenton, "Metal complexes of bibracchial Schiff
base macrocycles,” Coord. Chem. Rev., vol. 148, 1996, pp. 19.
[36] M. Nath, S. Pokharia, G. Eng, X. Song, A. Kumar, "Comparative study
of structure-activity relationship of di- and triorganotin( IV) derivatives
of amino acid and peptides,” J. Organomet. Chem., vol. 669, 2003, pp.
109–123.
[37] M. Nath, S. Pokharia, G. Eng, X. Song, A. Kumar, "Diorganotin(IV)
derivatives of dipeptides containing at least one essential amino acid
residue: synthesis, characteristic spectral data, cardiovascular, and antiinflammatory
activities,” Synth. React. Inorg. Metal-Org. Chem., vol.
34, 2004, pp. 1689–1708.
[38] M. Nath, R. Jairath, G. Eng, X. Song, A. Kumar, "Interaction of
triorganotin(IV) cations with pyrimidine bases/nucleoside: synthesis,
spectral characterization and biological studies of a novel
triphenyltin(IV) derivative of thymidine,” Inorg. Chem. Commun., vol.
7, 2004, pp. 1161–1163.
[39] M. Nath, S. Pokharia, G. Eng, X. Song, A. Kumar, M.Gielen, R.
Willem, M. Biesemans, "New trimethyltin(IV) derivatives of dipeptides:
synthesis, characteristic spectral studies and biological activity,” Appl.
Organomet. Chem., vol. 18, 2004, pp. 460–470.
[40] M. Nath, S. Pokharia, G. Eng, X. Song, A. Kumar, "New
triorganotin(IV) derivatives of dipeptides as anti-inflammatoryantimicrobial
agents,” Eur. J. Med. Chem., vol. 40, 2005, pp. 289–298.
[41] M. Nath, S. Pokharia, G. Eng, X. Song, A. Kumar, "New triorganotin
(IV) derivatives of dipeptides as models for metal-protein interactions:
synthesis, structural characterization and biological studies,”
Spectrochim. Acta—Part A, vol. 63, 2006, pp. 66–75.
[42] M. Nath, H. Singh, P. Kumar, A. Kumar, X. Song, G. Eng,
"Organotin(IV) tryptophanylglycinates: potential nonsteroidal anti
inflammatory agents; crystal structure of dibutyltin(IV)
tryptophanylglycinate,” Appl. Organomet. Chem., vol. 23, 2009, pp.
347–358.
[43] M.Nath, H. Singh, G. Eng, X. Song, A. Kumar, "Syntheses,
characterization and biological activity of diorganotin(IV) derivatives of
2-amino-6-hydroxypurine (guanine),” Inorg. Chem. Commun., vol. 12,
2009, pp. 1049–1052.
[44] M. Nath, H. Singh, G. Eng, X. Song, "Interaction of organotin(IV)
moieties with nucleic acid constituent: synthesis, structural
characterization and anti-inflammatory activity of tri-n-propyltin(IV)
and diorganotin(IV) derivatives of guanosine,” Inorg. Chem. Commun.,
vol. 14, 2011, pp. 1381–1385.
[45] M. Nath, H. Singh, G. Eng, X. Song, "Interaction of 5’-guanosine
monophosphate with organotin(IV) moieties: synthesis, structural
characterization, and anti-inflammatory activity,” ISRN Org. Chem.,
2012, pp. 1–9.
[46] M. I. Khan, M. K. Baloch, M. Ashfaq, G. Stoter, "In vivo toxicological
effects and spectral studies of new triorganotin(IV)–N–
maleoyltranexanates,” J. Organomet. Chem., vol. 691, 2006, pp. 2554.
[47] A. Atkinson, M. D. Rodriguez, T. E. Shewmaker, J. A. Walmsley,
"Synthesis and characterization of compounds of di- and tributyltin
chloride with adenine and guanine mononucleotides,” Inorg. Chim.
Acta, vol. 285, 1999, pp. 60–69.
[48] H. Jankovics, L. Nagy, N. Buz´as, L. Pellerito, R. Barbieri,
"Coordination properties of adenosine-5’-monophosphate and related
ligands towards Me2Sn(IV)2+ in aqueous solution,” J. Inorg. Biochem.,
vol. 92, 2002, pp. 55.
[49] F. Gharib, E. Farzad, M. M. Amini, "Interaction of dimethyltin(IV)
dichloride with 5’-AMP and 5’-GMP,” Can. J. Chem., vol. 84, 2006, pp.
1534.
[50] S. Roy, K. D. Hagen, P. U. Maheswari, M. Lutz, A. L. Spek, J.
Reedijk, G. P. van Wezel, "Phenanthroline derivatives with improved
selectivity as DNA-targeting anticancer or antimicrobial drugs,” Chem.
Med. Chem., vol. 3, 2008, pp. 1427–1434.
[51] W. D. Honnick, M. C. Hughes, C. D. Schaeffer, Jr., J. J. Zuckerman,
"Tin– 119m mössbauer, infrared, nuclear magnetic resonance,
equilibrium, and thermodynamic measurements on complexes of
dimethyltin dichloride with substituted 1,l0-phenanthrolines and 2,2'-
bipyridines,” Inorg. Chem., vol. 15, 1976, pp. 1391–1396.
[52] M. E. Reicmann, S. A. Rice, C. A. Thomas, P. Doty, "A further
examination of the molecular weight and size of desoxypentose nucleic
acid,” J. Am. Chem. Soc., vol. 76, 1954, pp. 3047–3053.
[53] L. F. Tan, H. Chao, K. C. Zhen, J. J. Fei, F. Wang, Y. F. Zhou, N. J.
Liang, "Co(III) complexes of Me-salpn and Me-salbn and the ring size
effect on the coordination modes and electrochemical properties: the
crystal structures of trans-[CoIII(Me-salpn)(py)2]PF6 and cis-α-[CoIII(Me-salbn)(4-Mepy)2]BPh4 4-Mepy,” Polyhedron, vol. 26, 2007,
pp. 5448–5457.
[54] L. J. Childs, J. Malina, B. E. Rolfsnes, M. Pascu, M. J. Prieto, M. J.
Broome, P. M. Rodger, E. Sletten, V. Moreno, A. Rodger, M. J. Hannon,
"A DNA-binding copper(I) metallosupramolecular cylinder that acts as
an artificial nuclease,” Chem..Eur. J., vol. 12, 2006, pp. 4919–4927.
[55] S. Yellappa, J. Seetharamappa, L. M. Rogers, R. Chitta, R. P. Singhal, F.
D’Souza, "Binding, electrochemical activation, and cleavage of DNA by
Cobalt(II) Tetrakis-N-methylpyridyl Porphyrin and its β-Pyrrole
brominated derivative,” Bioconjugate Chem., vol. 17, 2006, pp. 1418–
1425.
[56] S. Satyanarayana, J. C. Dabrowiak, J. B. Chaires, "Neither DELTA- nor
LAMBDA -tris(phenanthroline)ruthenium(II) binds to DNA by classical
intercalation,” Biochemistry, vol. 31, 1992, pp. 9319–9324.
[57] D. -L. Ma, C. -M. Che, "A bifunctional platinum(II) complex capable of
intercalation and hydrogen-bonding interactions with DNA: Binding
studies and cytotoxicity,” Chem. Eur. J., vol. 9, 2003, pp. 6133–6144.
[58] D. -L. Ma, C. -M. Che, F. -M. Siu, M. Yang, K. -Y. Wong, "DNA
binding and cytotoxicity of ruthenium(II) and rhenium(I) complexes of
2-Amino-4-phenylamino-6-(2-pyridyl)-1,3,5-triazine,” Inorg. Chem.,
vol. 46, 2007, pp. 740–749.
[59] S. Wang, R. Cosstick, J. F. Gardner, R. I. Gumport, "The specific
binding of Escherichia coli integration host factor involves both major
and minor grooves of DNA,” Biochemistry, vol. 34, 1995, pp.13082–
13090.
[60] S. Tabassum, R. A. Khan, F. Arjmand, M. Aziz, A. S. Juvekar, S. M.
Zingde, "Carbohydrate-conjugate heterobimetallic complexes: synthesis,
DNAbinding studies, artificial nuclease activity and in vitro
cytotoxicity,” Carbohydr. Res., vol. 346, 2011, pp. 2886–2895.
[61] K. Aoki, "The Anti-tumor activity of tin compounds,” in Metal-Based
Anti-Tumor Drugs, M. F. Gielen, Ed. London: Freund Publishing House,
1988, pp. 127.