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Cyclic peroxides as promising anticancer agents: in vitro cytotoxicity study of synthetic ozonides and tetraoxanes on human prostate cancer cell lines

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Abstract

Synthetic ozonides and tetraoxanes were shown to have high cytotoxicity in vitro when tested on androgen-independent prostate cancer cell lines DU145 and PC3, which is in some cases was higher than that of doxorubicin, cisplatin, etoposide, artemisinin, and artesunate. Activity of ozonide stereoisomers differs from each other. This difference in activity and absence of correlation between activity of stereoisomers and their oxidative properties allow us to suggest existence of a quite specific mechanism of cytotoxicity of these endoperoxides different from a traditional mechanism based mainly on oxidative properties of peroxides.

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References

  • Alagbala AA, McRiner AJ, Borstnik K, Labonte T, Chang W, D’Angelo JG, Posner GH, Foster BA (2006) Biological mechanisms of action of novel C-10 non-acetal trioxane dimers in prostate cancer cell lines. J Med Chem 49:7836–7842

    Article  CAS  PubMed  Google Scholar 

  • Azarifar D, Khosravi K, Soleimanei F (2009) Stannous chloride dihydrate: a novel and efficient catalyst for the synthesis of gem-dihydroperoxides from ketones and aldehydes. Synthesis-Stuttgart 15:2553–2556

  • Balganesh T, Kundu TK, Chakraborty TK, Roy S (2014) Drug discovery research in India: current state and future prospects. Acs Med Chem Lett 5:724–726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boissier J, Portela J, Pradines V, Cosledan F, Robert A, Meunier B (2012) Activity of trioxaquine PA1259 in mice infected by Schistosoma mansoni. Cr Chim 15:75–78

    Article  CAS  Google Scholar 

  • Bunge A, Hamann HJ, Liebscher J (2009) A simple, efficient and versatile synthesis of primary gem-dihydroperoxides from aldehydes and hydrogen peroxide. Tetrahedron Lett 50:524–526

    Article  CAS  Google Scholar 

  • Chaturvedi D, Goswami A, Saikia PP, Barua NC, Rao PG (2010) Artemisinin and its derivatives: a novel class of anti-malarial and anti-cancer agents. Chem Soc Rev 39:435–454

    Article  CAS  PubMed  Google Scholar 

  • Chen HH, Zhou HJ, Fan X (2003) Inhibition of human cancer cell line growth and human umbilical vein endothelial cell angiogenesis by artemisinin derivatives in vitro. Pharmacol Res 48:231–236

    Article  CAS  PubMed  Google Scholar 

  • Chen HH, Zhou HJ, Wang WQ, Wu GD (2004) Antimalarial dihydroartemisinin also inhibits angiogenesis. Cancer Chemoth Pharm 53:423–432

    Article  CAS  Google Scholar 

  • Das B, Krishnaiah M, Veeranjaneyulu B, Ravikanth B (2007) A simple and efficient synthesis of gem-dihydroperoxides from ketones using aqueous hydrogen peroxide and catalytic ceric ammonium nitrate. Tetrahedron Lett 48:6286–6289

    Article  CAS  Google Scholar 

  • Dembitsky VM (2008) Bioactive peroxides as potential therapeutic agents. Eur J Med Chem 43:223–251

    Article  CAS  PubMed  Google Scholar 

  • Dembitsky VM, Gloriozova TA, Poroikov VV (2007) Natural peroxy anticancer agents. Mini Rev Med Chem 7:571–589

    Article  CAS  PubMed  Google Scholar 

  • Denisov ET, Denisova TG, Pokidova TS (2003) Handbook of free radical initiators

  • Differding E (2014) Drug discovery alliances in India-indications, targets, and new chemical entities. Chemmedchem 9:43–60

    Article  CAS  PubMed  Google Scholar 

  • Donkers RL, Workentin MS (1998) First determination of the standard potential for the dissociative reduction of the antimalarial agent artemisinin. J Phys Chem B 102:4061–4063

    Article  CAS  Google Scholar 

  • Dwivedi A, Mazumder A, du Plessis L, du Preez JL, Haynes RK, du Plessis J (2015) In vitro anti-cancer effects of artemisone nano-vesicular formulations on melanoma cells. Nanomed-Nanotechnol 11:2041–2050

    Article  CAS  Google Scholar 

  • Efferth T (2005) Mechanistic perspectives for 1,2,4-trioxanes in anti-cancer therapy. Drug Resist Update 8:85–97

    Article  CAS  Google Scholar 

  • Gahlot M (2012) First India-made malaria drug. Chem Ind-London 76:6–6

    Google Scholar 

  • Gahlot M (2012) Indian drug approvals come under fire. Chem Ind-London 76:6–6

    Google Scholar 

  • Ghorai P, Dussault PH, Hu CH (2008) Synthesis of spiro-bisperoxyketals. Org Lett 10:2401–2404

    Article  CAS  PubMed  Google Scholar 

  • Griesbeck AG, El-Idreesy TT, Hoinck LO, Lex J, Brun R (2005) Novel spiroanellated 1,2,4-trioxanes with high in vitro antimalarial activities. Bioorg Med Chem Lett 15:595–597

    Article  CAS  PubMed  Google Scholar 

  • Griesbeck AG, Schlundt V, Neudorfl JM (2013) Functionalized polar 1,2,4-trioxanes as building blocks by singlet oxygenation of 4-hydroxy tiglic acid using the solvent deuterium isotope trick. Rsc Adv 3:7265–7270

    Article  CAS  Google Scholar 

  • Hao HD, Wittlin S, Wu YK (2013) Potent antimalarial 1,2,4-trioxanes through perhydrolysis of epoxides. Chem-Eur J 19:7605–7619

    Article  CAS  PubMed  Google Scholar 

  • Ingram K, Yaremenko IA, Krylov IB, Hofer L, Terent’ev AO, Keiser J (2012) Identification of antischistosomal leads by evaluating bridged 1,2,4,5-tetraoxanes, alphaperoxides, and tricyclic monoperoxides. J Med Chem 55:8700–8711

    Article  CAS  PubMed  Google Scholar 

  • Jefford CW (2012) Synthetic peroxides as potent antimalarials. News and views. Curr Top Med Chem 12:373–399

    Article  CAS  PubMed  Google Scholar 

  • Keiser J, Ingram K, Vargas M, Chollet J, Wang XF, Dong YX, Vennerstrom JL (2012) In vivo activity of aryl ozonides against Schistosoma species. Antimicrob Agents Ch 56:1090–1092

    Article  CAS  Google Scholar 

  • Keiser J, Veneziano V, Rinaldi L, Mezzino L, Duthaler U, Cringoli G (2010) Anthelmintic activity of artesunate against Fasciola hepatica in naturally infected sheep. Res Vet Sci 88:107–110

    Article  CAS  PubMed  Google Scholar 

  • Kim J, Park E (2002) Cytotoxic anticancer candidates from natural resources. Curr Med Chem - Anti-Cancer Agents 2:485–537

    Article  CAS  PubMed  Google Scholar 

  • Kumar N, Sharma M, Rawat DS (2011) Medicinal chemistry perspectives of trioxanes and tetraoxanes. Curr Med Chem 18:3889–3928

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Hao HD, Zhang Q, Wu YK (2009) A broadly applicable mild method for the synthesis of gem-diperoxides from corresponding ketones or 1,3-dioxolanes. Org Lett 11:1615–1618

    Article  CAS  PubMed  Google Scholar 

  • Mankil J, Hanjo K, Kyunghoon L, Moonsoo P (2003) Naturally occurring peroxides with biological activities. Mini-Rev Med Chem 3:159–165

    Article  Google Scholar 

  • Moad G, Solomon DH (2006) The chemistry of radical polymerization second fully revised edition, Elsiever, Amsterdam.

  • Najjar F, Baltas M, Gorrichon L, Moreno Y, Tzedakis T, Vial H, André-Barrès C (2003) Synthesis and electrochemical studies of new antimalarial endoperoxides. Eur J Org Chem 2003:3335–3343

    Article  Google Scholar 

  • Najjar F, Fréville F, Desmoulin F, Gorrichon L, Baltas M, Gornitzka H, Tzedakis T, André-Barrès C (2004) Comparative electrochemical properties of fluorinated endoperoxides related to the G-factor series. Tetrahedron Lett 45:6919–6922

    Article  CAS  Google Scholar 

  • Nakase I, Lai H, Singh NP, Sasaki T (2008) Anticancer properties of artemisinin derivatives and their targeted delivery by transferrin conjugation. Int J Pharmaceut 354:28–33

    Article  CAS  Google Scholar 

  • Opsenica D, Angelovski G, Pocsfalvi G, Juranić Z, Žižak Ž, Kyle D, Milhous WK, Šolaja BA (2003a) Antimalarial and antiproliferative evaluation of Bis-Steroidal tetraoxanes. Bioorg Med Chem 11:2761–2768

    Article  CAS  PubMed  Google Scholar 

  • Opsenica D, Kyle DE, Milhous WK, Solaja BA (2003b) Antimalarial, antimycobacterial and antiproliferative activity of phenyl substituted mixed tetraoxanes. J Serb Chem Soc 68:291–302

    Article  CAS  Google Scholar 

  • Opsenica DM, Solaja BA (2009) Antimalarial peroxides. J Serb Chem Soc 74:1155–1193

    Article  CAS  Google Scholar 

  • Opsenica I, Terzić N, Opsenica D, Angelovski G, Lehnig M, Eilbracht P, Tinant B, Juranić Z, Smith KS, Yang YS, Diaz DS, Smith PL, Milhous WK, Doković D, Šolaja BA (2006) Tetraoxane antimalarials and their reaction with Fe(II). J Med Chem 49:3790–3799

    Article  CAS  PubMed  Google Scholar 

  • Parrish JD, Ischay MA, Lu Z, Guo S, Peters NR, Yoon TP (2012) Endoperoxide synthesis by Photocatalytic Aerobic [2+2+2] cycloadditions. Org Lett 14:1640–1643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Posner GH, D’Angelo J, O’Neill PM, Mercer A (2006) Anticancer activity of artemisinin-derived trioxanes. Expert Opin Ther Pat 16:1665–1672

    Article  CAS  Google Scholar 

  • Posner GH, McRiner AJ, Paik I-H, Sur S, Borstnik K, Xie S, Shapiro TA, Alagbala A, Foster B (2004) Anticancer and antimalarial efficacy and safety of artemisinin-derived trioxane dimers in rodents. J Med Chem 47:1299–1301

    Article  CAS  PubMed  Google Scholar 

  • Posner GH, Paik I-H, Sur S, McRiner AJ, Borstnik K, Xie S, Shapiro TA (2003) Orally active, antimalarial, anticancer, artemisinin-derived trioxane dimers with high stability and efficacy. J Med Chem 46:1060–1065

    Article  CAS  PubMed  Google Scholar 

  • Ravi M, Anand D, Maurya R, Chauhan P, Naikade NK, Shukla SK, Yadav PP (2013) Synthesis of 1,2,4-trioxepanes and 1,2,4-trioxanes via H2O2-mediated reaction of tertiary carbinols. Synlett 24:173–176

    CAS  Google Scholar 

  • Ray P (2002) Polymer cross-linkling, in encyclopedia of polymer science and technology, Wiley.

  • Reiter C, Fröhlich T, Zeino M, Marschall M, Bahsi H, Leidenberger M, Friedrich O, Kappes B, Hampel F, Efferth T, Tsogoeva SB (2015) New efficient artemisinin derived agents against human leukemia cells, human cytomegalovirus and Plasmodium falciparum: 2nd generation 1,2,4-trioxane-ferrocene hybrids. Eur J Med Chem 97:164–172

    Article  CAS  PubMed  Google Scholar 

  • Rosenthal AS, Chen XC, Liu JO, Weso DC, Hergenrother PJ, Shapiro TA, Posner GH (2009) Malaria-infected mice are cured by a single oral dose of new dimeric trioxane sulfones which are also selectively and powerfully cytotoxic to cancer cells. J Med Chem 52:1198–1203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rubush DM, Morges MA, Rose BJ, Thamm DH, Rovis T (2012) An asymmetric synthesis of 1,2,4-trioxane anticancer agents via desymmetrization of peroxyquinols through a bronsted acid catalysis cascade. J Am Chem Soc 134:13554–13557

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Slack RD, Jacobine AM, Posner GH (2012) Antimalarial peroxides: advances in drug discovery and design. Medchemcomm 3:281–297

    Article  CAS  Google Scholar 

  • Solaja BA, Terzic N, Pocsfalvi G, Gerena L, Tinant B, Opsenica D, Milhous WK (2002) Mixed steroidal 1,2,4,5-tetraoxanes: antimalarial and antimycobacterial activity. J Med Chem 45:3331–3336

    Article  CAS  PubMed  Google Scholar 

  • Terent’ev AO, Kutkin AV, Troizky NA, Ogibin YN, Nikishin GI (2005) Synthesis of geminal bisperoxides by acid-catalyzed reaction of acetals and enol ethers with tert-butyl hydroperoxide. Synthesis-Stuttgart 13:2215–2219

  • Terent’ev AO, Platonov MM, Kashin AS, Nikishin GI (2008a) Oxidation of cycloalkanones with hydrogen peroxide: an alternative route to the Baeyer–Villiger reaction. Synthesis of dicarboxylic acid esters. Tetrahedron 64:7944–7948

    Article  Google Scholar 

  • Terent’ev AO, Platonov MM, Krylov IB, Chernyshev VV, Nikishin GI (2008b) Synthesis of 1-hydroperoxy-1 ‘-alkoxyperoxides by the iodine-catalyzed reactions of geminal bishydroperoxides with acetals or enol ethers. Org Biomol Chem 6:4435–4441

    Article  PubMed  Google Scholar 

  • Terent’ev AO, Platonov MM, Kutkin AV (2006) A new oxidation process. Transformation of gem-bishydroperoxides into esters. Cent Eur J Chem 4:207–215

    Google Scholar 

  • Terent’ev AO, Platonov MM, Ogibin YN, Nikishin GI (2007) Convenient synthesis of geminal bishydroperoxides by the reaction of ketones with hydrogen peroxide. Synthetic Commun 37:1281–1287

    Article  Google Scholar 

  • Terent’ev AO, Yaremenko IA, Vil’ VA, Moiseev IK, Kon’kov SA, Dembitsky VM, Levitsky DO, Nikishin GI (2013) Phosphomolybdic and phosphotungstic acids as efficient catalysts for the synthesis of bridged 1,2,4,5-tetraoxanes from beta-diketones and hydrogen peroxide. Org Biomol Chem 11:2613–2623

    Article  PubMed  Google Scholar 

  • Terzić N, Opsenica D, Milić D, Tinant B, Smith KS, Milhous WK, Šolaja BA (2007) Deoxycholic acid-derived tetraoxane antimalarials and antiproliferatives. J Med Chem 50:5118–5127

    Article  PubMed  Google Scholar 

  • van Huijsduijnen RH, Guy RK, Chibale K, Haynes RK, Peitz I, Kelter G, Phillips MA, Vennerstrom JL, Yuthavong Y, Wells TNC (2013) Anticancer properties of distinct antimalarial drug classes. PloS ONE 8:e82962

  • Vennerstrom JL, Arbe-Barnes S, Brun R, Charman SA, Chiu FCK, Chollet J, Dong YX, Dorn A, Hunziker D, Matile H, McIntosh K, Padmanilayam M, Tomas JS, Scheurer C, Scorneaux B, Tang YQ, Urwyler H, Wittlin S, Charman WN (2004) Identification of an antimalarial synthetic trioxolane drug development candidate. Nature 430:900–904

    Article  CAS  PubMed  Google Scholar 

  • Vennerstrom JL, Fu HN, Ellis WY, Ager AL, Wood JK, Andersen SL, Gerena L, Milhous WK (1992) Dispiro-1,2,4,5-tetraoxanes - a new class of antimalarial peroxides. J Med Chem 35:3023–3027

    Article  CAS  PubMed  Google Scholar 

  • Wang XF, Dong YX, Wittlin S, Charman SA, Chiu FCK, Chollet J, Katneni K, Mannila J, Morizzi J, Ryan E, Scheurer C, Steuten J, Tomas JS, Snyder C, Vennerstrom JL (2013) Comparative antimalarial activities and ADME profiles of ozonides (1,2,4-trioxolanes) OZ277, OZ439, and their 1,2-Dioxolane, 1,2,4-Trioxane, and 1,2,4,5-Tetraoxane isosteres. J Med Chem 56:2547–2555

    Article  CAS  PubMed  Google Scholar 

  • WHO (2010) Guidelines for the treatment of malaria, WHO, Geneva

  • WHO (2013) Management of severe malaria, WHO, Geneva

  • Wongsrichanalai C, Sibley CH (2013) Fighting drug-resistant Plasmodium falciparum: the challenge of artemisinin resistance. Clin Microbiol Infec 19:908–916

    Article  CAS  Google Scholar 

  • Workentin MS, Maran F, Wayner DDM (1995) Reduction of Di-tert-Butyl Peroxide: evidence for nonadiabatic dissociative electron transfer. J Am Chem Soc 117:2120–2121

    Article  CAS  Google Scholar 

  • Wu W-M, Wu Y-L (2000) Chemical and electro-chemical reduction of qinghaosu (artemisinin). J Chem Soc, Perkin Trans 1:4279–4283

    Article  Google Scholar 

  • Xiao SH, Tanner M, N’Goran EK, Utzinger J, Chollet J, Bergquist R, Chen MG, Zheng J (2002) Recent investigations of artemether, a novel agent for the prevention of schistosomiasis japonica, mansoni and haematobia. Acta Trop 82:175–181

    Article  CAS  PubMed  Google Scholar 

  • Xie LJ, Zhai X, Ren LX, Meng HY, Liu C, Zhu WF, Zhao YF (2011) Design, synthesis and antitumor activity of novel artemisinin derivatives using hybrid approach. Chem Pharm Bull 59:984–990

    Article  CAS  PubMed  Google Scholar 

  • Yadav N, Sharma C, Awasthi SK (2014) Diversification in the synthesis of antimalarial trioxane and tetraoxane analogs. Rsc Adv 4:5469–5498

    Article  CAS  Google Scholar 

  • Yaremenko IA, Terent’ev AO, Vil’ VA, Novikov RA, Chernyshev VV, Tafeenko VA, Levitsky DO, Fleury F, Nikishin GI (2014) Approach for the preparation of various classes of peroxides based on the reaction of triketones with H2O2: first examples of ozonide rearrangements. Chem-Eur J 20:10160–10169

    Article  CAS  PubMed  Google Scholar 

  • Zhou HJ, Wang Z, Li A (2008) Dihydroartemisinin induces apoptosis in human leukemia cells HL60 via downregulation of transferrin receptor expression. Anti-Cancer Drug 19:247–255

    Article  Google Scholar 

  • Zizak Z, Juranic Z, Opsenica D, Solaja BA (2009) Mixed steroidal tetraoxanes induce apoptotic cell death in tumor cells. Invest New Drug 27:432–439

    Article  CAS  Google Scholar 

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Acknowledgments

The work on the synthesis and analysis of the organic peroxides was supported by the Russian Science Foundation (Grant № 14-23-00150) and biological experiments were funded by the Ligue Contre le Cancer (Comités 44 and 85).

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Authors and Affiliations

  1. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospect 47, Moscow, 119991, Russian Federation

    Ivan A. Yaremenko, Mikhail A. Syroeshkin & Alexander O. Terent’ev

  2. All-Russian Research Institute of Phytopathology, Bol’shie Vyazemy, Moscow region, 143050, Russian Federation

    Ivan A. Yaremenko, Dmitri O. Levitsky & Alexander O. Terent’ev

  3. Mechanism and regulation of DNA repair team Université de Nantes, UFIP CNRS UMR 6286, 2 rue de la Houssinière, Nantes, 44322, France

    Dmitri O. Levitsky & Fabrice Fleury

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  1. Ivan A. Yaremenko
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  2. Mikhail A. Syroeshkin
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Correspondence to Fabrice Fleury or Alexander O. Terent’ev.

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Yaremenko, I.A., Syroeshkin, M.A., Levitsky, D.O. et al. Cyclic peroxides as promising anticancer agents: in vitro cytotoxicity study of synthetic ozonides and tetraoxanes on human prostate cancer cell lines. Med Chem Res 26, 170–179 (2017). https://doi.org/10.1007/s00044-016-1736-2

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