Acetylation of 1,2,5,8-tetrahydroxy-9,10-anthraquinone Improves Binding to DNA and Shows Enhanced Superoxide Formation that Explains Better Cytotoxicity on JURKAT T Lymphocyte Cells

• Sayantani Mukherjee

  Department of Chemistry, Jadavpur University, Kolkata – 700 032, India

• Priya Kalyan Gopal

  Laboratory of Experimental Immunology, Department of Botany, Gurudas College, Kolkata 700 054, India

• Santanu Paul

  Laboratory of Experimental Immunology, Department of Botany, Gurudas College, Kolkata 700 054, India

• Saurabh Das

  Department of Chemistry, Jadavpur University, Kolkata – 700 032, India

 Background: Hydroxy-9,10-anthraquinones form the core unit of anthracycline anticancer drugs and are close structural analogues to these drugs. Although they show close resemblance to anthracyclines in physicochemical characteristics and electrochemical behavior their biophysical interactions are somewhat weaker than anthracyclines which is a disadvantage. One reason is the formation of anionic species by hydroxy-9,10-anthraquinones. Hence if formation of anionic species is prevented there could be a possibility hydroxy-9,10-anthraquinones would bind DNA better.

Procedure: For this 1, 2, 5, 8-tetrahydroxy-9,10-anthraquinone (THAQ) was acetylated to obtain a tetra-acetylated derivative (THAQ-ace) whose interaction with calf thymus DNA was studied using UV-Vis spectroscopy at different pH.

Results: Binding constant values for THAQ-ace (~10⁵) were higher than THAQ at different pH. Increase in binding constant was attributed to anionic species not formed for THAQ-ace at physiological pH. Hence, unlike THAQ, binding constant values for THAQ-ace interacting with calf thymus DNA did not show variation with pH. In fact, it remained more or less constant. Increase in size of the acetylated form (THAQ-ace) compared to THAQ had a negative influence on binding. THAQ-ace showed enhanced superoxide formation. Both DNA binding and superoxide formation were responsible for a significant improvement in anticancer activity for THAQ-ace compared to THAQ on Jurkat T lymphocyte cells.

Conclusion: Binding constant values for THAQ-ace binding to DNA were close to that reported for some standard anthracyclines. Hence, suitable modification of the less costly hydroxy-9,10-anthraquinones could provide alternatives to anthracyclines in cancer chemotherapy.

Mukherjee S, Das P, Das S. Exploration of small hydroxy-9,10-anthraquinones as anthracycline analogues. J Phys Org Chem 2012; 25: 385-93.

http://dx.doi.org/10.1002/poc.1928

Frezard F, Garnier-Suillerot A. Comparison of the binding of anthracycline derivatives to purified DNA and to cell nuclei. Biochim Biophys Acta 1990; 1036: 121-7.

http://dx.doi.org/10.1016/0304-4165(90)90023-P

Das S, Saha A, Mandal PC. Studies on the formation of Cu(II) and Ni(II) complexes of 1,2-dihydroxy-9,10-anthraquinone and lack of stimulated superoxide formation by the complexes. Talanta 1996; 43: 95-102.

http://dx.doi.org/10.1016/0039-9140(95)01720-8

Guin PS, Das S, Mandal PC. Studies on the formation of a complex of Cu(II) with sodium 1,4-dihydroxy-9,10-anthraquinone-2-sulphonate – An analogue of the core unit of anthracycline anticancer drugs and its interaction with calf thymus DNA. J Inorg Biochem 2009; 103: 1702-10.

http://dx.doi.org/10.1016/j.jinorgbio.2009.09.020

Guin PS, Das S, Mandal PC. Sodium 1, 4-dihydroxy-9, 10-anthraquinone-2-sulphonate interacts with calf thymus DNA in a way that mimics anthracycline antibiotics:an electrochemical and spectroscopic study. J Phys Org Chem 2010; 23: 477-82.

http://dx.doi.org/10.1002/poc.1624

Das P, Guin PS, Mandal PC, Paul M, Paul S, Das S. Cyclic voltammetric studies of 1,2,4-trihydroxy-9,10-anthraquinone, its interaction with calf thymus DNA and anti-leukemic activity on MOLT-4 cell lines: a comparison with anthracycline anticancer drugs. J Phys Org Chem 2011; 24: 774-85.

Guin PS, Mandal PC, Das S. A comparative study on the interaction with calf thymus DNA of a Ni(II) complex of the anticancer drug adriamycin and a Ni(II) complex of sodium 1,4–dihydroxy–9,10–anthraquinone–2–sulphonate. J Coord Chem 2012; 65: 705-21.

http://dx.doi.org/10.1080/00958972.2012.659730

Guin PS, Mandal PC, Das S. The Binding of a Hydroxy-9,10-Anthraquinone Cu(II) Complex to Calf Thymus DNA: Electrochemistry and UV/Vis Spectroscopy. ChemPlusChem 2012; 77: 361-9.

http://dx.doi.org/10.1002/cplu.201100046

Sinha BK, Motten AG, Hanck KW. The electrochemical reduction of 1,4-bis-(2-[(2-hydroxyethyl)-amino] ethylamino)-anthracenedione and daunomycin: biochemical significance in superoxide formation. Chem Biol Interact 1983; 43: 371-7.

http://dx.doi.org/10.1016/0009-2797(83)90120-5

Kappus H. Overview of enzyme systems involved in bio-reduction of drugs and in redox cycling. Biochem Pharmacol 1986; 35: 1-6.

http://dx.doi.org/10.1016/0006-2952(86)90544-7

Kolodziejczyk P, Reszka K, Lown JW. Enzymatic oxidative activation and transformation of the antitumor agent mitoxantrone. Free Radical Biol Med 1988; 5: 13-25.

http://dx.doi.org/10.1016/0891-5849(88)90058-5

DuVernay VH, Pachter JA, Crooke ST. Molecular pharmacological differences between carminomycin and its analog, carminomycin-1 1-methyl ether, and adriamycin. Cancer Research 1980; 40: 387-94.

Connors NC, Bartel PL, Strohl WR. Biosynthesis of anthracyclines: carminomycin-4-O-methyltransferase, the terminal enzymatic step in the formation of daunomycin. J Gen Microbiol 1990; 136: 1895-8.

http://dx.doi.org/10.1099/00221287-136-9-1895

Banerjee T, Mukhopadhyay R. Structural effects of nogalamycin, an antibiotic antitumour agent, on DNA. Biochem Biophys Res Comm 2008; 374: 264-8.

http://dx.doi.org/10.1016/j.bbrc.2008.07.053

Furniss BS, Hannaford AJ, Smith PWG, Tatchel AR. Vogel’s Textbook of Practical Organic Chemistry. Fifth Edn. ELBS-Longman, Singapore 1996.

Priebe W. Targeting DNA with anthracyclines: The importance of the sugar moiety. Molecules 2000; 5: 299-301.

http://dx.doi.org/10.3390/50300299

Scatchard G. The attractions of proteins for small molecules and ions. Ann NY Acad Sci 1949; 51: 660-5.

http://dx.doi.org/10.1111/j.1749-6632.1949.tb27297.x

Mahler HR. In: Colowick SP, Kaplan NO (eds) Methods in Enzymology 11, Academic Press, New York 1955; pp. 688-705.

Butler J, Jayson GG, Swallow AJ. The reaction between the superoxide anion radical and cytochrome c. Biochim Biophys Acta 1975; 408: 215-22.

http://dx.doi.org/10.1016/0005-2728(75)90124-3

Fiallo MML, Garnier-Suillerot A. Physicochemical studies of the Fe(III)-carminomycin complex and evidence of the lack of stimulated superoxide production by NADH dehydrogenase. Biochim Biophys Acta 1985; 840: 91-8.

http://dx.doi.org/10.1016/0304-4165(85)90165-5

Koppenol WH, van Buuren KJ, Butler J, Braams R. The kinetics of the reduction of cytochrome c by the superoxide anion radical. Biochim Biophys Acta 1976; 449:157-68.

http://dx.doi.org/10.1016/0005-2728(76)90130-4

Pal S, Ghosh S, Bandyopadhyay S, Mandal CN, Bandyopadhyay S, Bhattacharya DK, Mandal C. Differential expression of 9-O-acetylated sialoglycoconjugates on leukemic blasts: a potential tool for long-term monitoring of children with acute lymphoblastic leukaemia. Int J Cancer 2004; 11: 270-7.

http://dx.doi.org/10.1002/ijc.20246

Lipshultz SE, Alvarez JA, Scully RE. Anthracycline associated cardiotoxicity in survivors of childhood cancer. Heart 2008; 94: 525-33.

http://dx.doi.org/10.1136/hrt.2007.136093

Li LH, Kuentzel SL, Murch LL, Pschigoda LM, Krueger WC. Comparative biological and biochemical effects of nogalamycin and its analogs on L1210 leukemia. Cancer Research 1979; 39: 4816-22.

Di Marco A, Zunino F, Silverstrini R, Gambarucci C, Gambetta RA. Interaction of some daunomycin derivatives with deoxyribonucleic acid and their biological activity. Biochem Pharmacol 1971; 20: 1323-8.

http://dx.doi.org/10.1016/0006-2952(71)90365-0

Das S, Mandal PC. Anthracyclines as radiosensitizers: A Cu(II) complex of a simpler analogue modifies DNA in Chinese Hamster V79 cells under low dose ?-radiation. J Radioanal Nucl Chem 2014; 299: 1665-70.

http://dx.doi.org/10.1007/s10967-013-2826-y

Das S, Dasgupta D. Binding of (MTR)2Zn2+ complex to chromatin: A comparison with (MTR)2Mg2+ complex. J Inorg Biochem 2005; 99: 707-15.

http://dx.doi.org/10.1016/j.jinorgbio.2004.11.027

Chakrabarti S, Bhattacharyya B, Dasgupta D. Interaction of Mithramycin and Chromomycin A3 with d(TAGCTAGCTA)2:? Role of Sugars in Antibiotic?DNA Recognition. J Phys Chem B 2002; 106: 6947-53.

http://dx.doi.org/10.1021/jp014710i

Huang CH, Mong S, Crooke ST. Interactions of a new antitumor antibiotic BBM-928A with deoxyribonucleic acid. Bifunctional intercalative binding studied by fluorometry and viscometry. Biochemistry 1980; 19: 5537-42.

http://dx.doi.org/10.1021/bi00565a012

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