Masking Strategies for the Bioorthogonal Release of Anticancer Glycosides

  • Belén Rubio-Ruiz
  • Thomas L. Bray
  • Ana M. López-Pérez
  • Asier Unciti-BrocetaEmail author


Significant progress in the bioorthogonal field has resulted in the advent of a new type of prodrug: bioorthogonal prodrugs, i.e. metabolically stable precursors of therapeutic agents that are specifically activated by non-native, non-biological, non-perturbing physical or chemical stimuli. The application of such unique drug precursors in conjunction with their corresponding activating source is under preclinical experimentation as a novel way to elicit site-specific activation of cytotoxic drugs, with particular emphasis on anticancer glycosides. In this chapter, the strategies developed for the masking and bioorthogonal release of cytotoxic nucleosides using benign electromagnetic radiations, biocompatible click chemistry and bioorthogonal organometallic (BOOM) catalysis will be discussed in detail.


Anthracyclines Cytotoxic nucleosides Photoactivation Bioorthogonal click chemistry BOOM chemistry 



BRR is grateful to the Alfonso Martín Escudero Foundation for a postdoctoral fellowship. T.L.B. is grateful to the University of Edinburgh for a Principal’s Career Development PhD Studentship and an Edinburgh Global Research Scholarship. A.P.L. and A.U.B. thank the MSD Scottish Life Sciences Fund for financial support.


  1. 1.
    Stipanuk MH, Caudill MA (2012) Biochemical, physiological, and molecular aspects of human nutrition, 3rd edn. Saunders/Elsevier, PhiladelphiaGoogle Scholar
  2. 2.
    McNaught AD (1996) Nomenclature of carbohydrates (IUPAC Recommendations 1996). Pure Appl Chem 68:1919–2008CrossRefGoogle Scholar
  3. 3.
    McNaught AD, Wilkinson A (eds) (1997) Compendium of chemical terminology the “gold book”, 2nd edn. International Union of Pure and Applied Chemistry. Blackwell Scientific Publications, OxfordGoogle Scholar
  4. 4.
    Kren V, Martínková L (2001) Glycosides in medicine: “The role of glycosidic residue in biological activity”. Curr Med Chem 8:1303–1328CrossRefGoogle Scholar
  5. 5.
    Weiss RB (1992) The anthracyclines: will we ever find a better doxorubicin? Semin Oncol 19:670–686Google Scholar
  6. 6.
    Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L (2004) Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 56:185–229CrossRefGoogle Scholar
  7. 7.
    Gewirtz DA (1999) A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol 57:727–741CrossRefGoogle Scholar
  8. 8.
    Hande KR (1998) Etoposide: four decades of development of a topoisomerase II inhibitor. Eur J Cancer 34:1514–1521CrossRefGoogle Scholar
  9. 9.
    van Maanen JM, Retèl J, de Vries J, Pinedo HM (1988) Mechanism of action of antitumor drug etoposide: a review. J Natl Cancer Inst 80:1526–1533CrossRefGoogle Scholar
  10. 10.
    Jordheim LP, Durantel D, Zoulim F, Dumontet C (2013) Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases. Nat Rev Drug Discov 12:447–464CrossRefGoogle Scholar
  11. 11.
    Shelton J, Lu X, Hollenbaugh JA, Cho JH, Amblard F, Schinazi RF (2016) Metabolism, biochemical actions, and chemical synthesis of anticancer nucleosides, nucleotides, and base analogs. Chem Rev 116:14379–14455Google Scholar
  12. 12.
    Wilson PM, Danenberg PV, Johnston PG, Lenz HJ, Ladner RD (2014) Standing the test of time: targeting thymidylate biosynthesis in cancer therapy. Nat Rev Clin Oncol 11:282–298CrossRefGoogle Scholar
  13. 13.
    Parker WB (2009) Enzymology of purine and pyrimidine antimetabolites used in the treatment of cancer. Chem Rev 109:2880–2893CrossRefGoogle Scholar
  14. 14.
    Chabner BA, Roberts TG Jr (2005) Chemotherapy and the war on cancer. Nat Rev Cancer 5:65–72CrossRefGoogle Scholar
  15. 15.
    DeVita VT Jr, Chu E (2008) A history of cancer chemotherapy. Cancer Res 68:8643–8653CrossRefGoogle Scholar
  16. 16.
    Rautio J, Kumpulainen H, Heimbach T, Oliyai R, Oh D, Järvinen T, Savolainen J (2008) Prodrugs: design and clinical applications. Nat Rev Drug Discov 7:255–270CrossRefGoogle Scholar
  17. 17.
    Huttunen KM, Raunio H, Rautio J (2008) Prodrugs-from serendipity to rational design. Pharmacol Rev 63:750–771CrossRefGoogle Scholar
  18. 18.
    Kratz F, Müller IA, Ryppa C, Warnecke A (2008) Prodrug strategies in anticancer chemotherapy. ChemMedChem 3:20–53CrossRefGoogle Scholar
  19. 19.
    Rooseboom M, Commandeur JN, Vermeulen NP (2004) Enzyme-catalyzed activation of anticancerprodrugs. Pharmacol Rev 56:53–102CrossRefGoogle Scholar
  20. 20.
    Yang Y, Aloysius H, Inoyama D, Chen Y, Hu L (2011) Enzyme-mediated hydrolytic activation of prodrugs. Acta Pharmaceutica Sinica B 11:143–159CrossRefGoogle Scholar
  21. 21.
    Tranoy-Opalinski I, Legigan T, Barat R, Clarhaut J, Thomas M, Renoux B, Papot S (2014) β-Glucuronidase-responsive prodrugs for selective cancer chemotherapy: an update. Eur J Med Chem 74:302–313CrossRefGoogle Scholar
  22. 22.
    Haisma HJ, Boven E, van Muijen M, de Jong J, van der Vijgh WJ, Pinedo HM (1992) A monoclonal antibody-beta-glucuronidase conjugate as activator of the prodrug epirubicin-glucuronide for specific treatment of cancer. Br J Cancer 66:474–478CrossRefGoogle Scholar
  23. 23.
    Mürdter TE, Sperker B, Kivistö KT, McClellan M, Fritz P, Friedel G, Linder A, Bosslet K, Toomes H, Dierkesmann R, Kroemer HK (1997) Enhanced uptake of Doxorubicin into bronchial carcinoma: β-glucuronidase mediates release of Doxorubicin from a glucuronide prodrug (HMR 1826) at the tumor site. Cancer Res 57:2440–2445Google Scholar
  24. 24.
    Houba PH, Boven E, van der Meulen-Muileman IH, Leenders RG, Scheeren JW, Pinedo HM, Haisma HJ (2001) A novel doxorubicin-glucuronide prodrug DOX-GA3 for tumour-selective chemotherapy: distribution and efficacy in experimental human ovarian cancer. Br J Cancer 84:550–557CrossRefGoogle Scholar
  25. 25.
    Houba PH, Leenders RG, Boven E, Scheeren JW, Pinedo HM, Haisma HJ (1996) Characterization of novel anthracycline prodrugs activated by human beta-glucuronidase for use in antibody-directed enzyme prodrug therapy. Biochem Pharmacol 52:455–463CrossRefGoogle Scholar
  26. 26.
    Houba PH, Boven E, Erkelens CA, Leenders RG, Scheeren JW, Pinedo HM, Haisma HJ (1998) The efficacy of the anthracycline prodrug daunorubicin-GA3 in human ovarian cancer xenografts. Br J Cancer 78:1600–1606CrossRefGoogle Scholar
  27. 27.
    Bagshawe KD (1987) Antibody directed enzymes revive anti-cancer prodrugs concept. Br J Cancer 56:531–532CrossRefGoogle Scholar
  28. 28.
    Brown JM, Wilson WR (2004) Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer 4:437–447CrossRefGoogle Scholar
  29. 29.
    McKeown SR, Cowen RL, Williams KJ (2007) Bioreductive drugs: from concept to clinic. Clin Oncol 19:427–442CrossRefGoogle Scholar
  30. 30.
    Chen Y, Hu L (2009) Design of anticancer prodrugs for reductive activation. Med Res Rev 29:29–64CrossRefGoogle Scholar
  31. 31.
    Hu L, Liu B, Hacking DR (2000) 5′-[2-(2-Nitrophenyl)-2-methylpropionyl]-2′-deoxy-5-fluorouridine as a potential bioreductively activated prodrug of FUDR: synthesis, stability and reductive activation. Bioorg Med Chem Lett 10:797–800CrossRefGoogle Scholar
  32. 32.
    Liu B, Hu L (2003) 5′-(2-Nitrophenylalkanoyl)-2′-deoxy-5-fluorouridines as potential prodrugs of FUDR for reductive activation. Bioorg Med Chem 11:3889–3899CrossRefGoogle Scholar
  33. 33.
    Saxon E, Bertozzi CR (2000) Cell surface engineering by a modified Staudinger reaction. Science 287:2007–2010CrossRefGoogle Scholar
  34. 34.
    Agard NJ, Prescher J, Bertozzi CR (2004) A strain-promoted [3 + 2] azide-alkyne cycloaddition for covalent modification of biomolecules in living systems. J Am Chem Soc 126:15046–15047CrossRefGoogle Scholar
  35. 35.
    Sletten EM, Bertozzi CR (2011) From mechanism to mouse: a tale of two bioorthogonal reactions. Acc Chem Res 44:666–676CrossRefGoogle Scholar
  36. 36.
    Bertozzi CR (2011) A decade of bioorthogonal chemistry. Acc Chem Res 44:651–653CrossRefGoogle Scholar
  37. 37.
    Weiss JT, Carragher NO, Unciti-Broceta A (2015) Palladium-mediated dealkylation of N-propargyl-floxuridine as a bioorthogonal oxygen-independent prodrug strategy. Sci Rep 5:9329CrossRefGoogle Scholar
  38. 38.
    Weiss JT, Fraser C, Rubio-Ruiz B, Myers SH, Crispin R, Dawson JC, Brunton VG, Patton EE, Carragher NO, Unciti-Broceta A (2015) N-alkynyl derivatives of 5-fluorouracil: susceptibility to palladium-mediated dealkylation and toxigenicity in cancer cell culture. Front Chem 2:56Google Scholar
  39. 39.
    Von Tappeiner H, Jesionek A (1903) Therapeutische Versuche mit fluoreszierenden Stoffen. Münchner Med Wochenschr 47:2042–2044Google Scholar
  40. 40.
    Diamond I, Granelli SG, McDonagh AF, Nielsen S, Wilson CB, Jaenicke R (1972) Photodynamic therapy of malignant tumours. Lancet 2:1175–1177CrossRefGoogle Scholar
  41. 41.
    Doiron DR, Gomer CJ (1984) Porphyrin localization and treatment of tumors. AR Liss Inc, New YorkGoogle Scholar
  42. 42.
    Ward BG, Forbes IJ, Cowled PA, McEvoy MM, Cox LW (1982) The treatment of vaginal recurrences of gynecological malignancy with phototherapy following hematoporphyrin derivative pre-treatment. Am J Obstet Gynecol 142:356–357CrossRefGoogle Scholar
  43. 43.
    Gomer CJ, Doiron DR, Jester JV, Szirth BC, Murphree AL (1983) Hematoporphyrin derivative photoradiation therapy for the treatment of intraocular tumors: examination of acute normal ocular toxicity. Cancer Res 43:721–727Google Scholar
  44. 44.
    Hill JS, Kaye AH, Sawyer WH, Morstyn G, Megison PD, Stylli SS (1990) Selective uptake of hematoporphyrin derivative into human cerebral glioma. Neurosurgery 26:248–254CrossRefGoogle Scholar
  45. 45.
    Wenig BL, Kurtzman DM, Grossweiner LI, Mafee MF, Harris DM, Lobraico RV, Prycz RA, Appelbaum EL (1990) Photodynamic therapy in the treatment of squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg 116:1267–1270CrossRefGoogle Scholar
  46. 46.
    Barr H, Krasner N, Boulos PB, Chatlani P, Bown SG (1990) Photodynamic therapy for colorectal cancer: a quantitative pilot study. Br J Surg 77:93–96CrossRefGoogle Scholar
  47. 47.
    Dougherty TJ, Gomer CJ, Henderson BW, Jori G, Kessel D, Korbelik M, Moan J, Peng Q (1998) Photodynamic therapy. J Natl Cancer Inst 90:889–905CrossRefGoogle Scholar
  48. 48.
    Hendersonand B, Dougherty T (1992) How does photodynamic therapy work? Photochem Photobiol 55:145–157CrossRefGoogle Scholar
  49. 49.
    Tietze LF, Müller M, Duefert SC, Schmuck K, Schuberth I (2013) Photoactivatable prodrugs of highly potent duocarmycin analogues for a selective cancer therapy. Chem Eur J 19:1726–1731CrossRefGoogle Scholar
  50. 50.
    Horbert R, Pinchuk B, Davies P, Alessi D, Peifer C (2015) Photoactivatable prodrugs of anti-melanoma agent vemurafenib. ACS Chem Biol 10:2099–2107CrossRefGoogle Scholar
  51. 51.
    Hossion AML, Bio M, Nkepang G, Awuah SG, You Y (2013) Visible light controlled release of anticancer drug through double activation of prodrug. ACS Med Chem Lett 4:124–127CrossRefGoogle Scholar
  52. 52.
    Forrest RA, Swift LP, Rephaeli A, Nudelman A, Kimura K, Phillips DR, Cutts SM (2012) Activation of DNA damage response pathways as a consequence of anthracycline-DNA adduct formation. Biochem Pharmacol 83:1602–1612CrossRefGoogle Scholar
  53. 53.
    Agudelo D, Bourassa P, Bérubé G (2014) Intercalation of antitumor drug doxorubicin and its analogue by DNA duplex: structural features and biological implications. Int J Biol Macromol 66:144–150CrossRefGoogle Scholar
  54. 54.
    Pawar SK, Badhwar AJ, Kharas F, Khandare JJ, Vavia PR (2012) Design, synthesis and evaluation of N-acetyl glucosamine (NAG)-PEG-doxorubicin targeted conjugates for anticancer delivery. Int J Pharm 436:183–193CrossRefGoogle Scholar
  55. 55.
    Mita MM, Natale RB, Wolin EM, Laabs B, Dinh H, Wieland S, Levitt DJ, Mita AC (2015) Pharmacokinetic study of aldoxorubicin in patients with solid tumors. Invest New Drugs 33:341–348CrossRefGoogle Scholar
  56. 56.
    Ibsen S, Zahavy E, Wrasdilo W, Berns M, Chan M, Esener S (2010) A novel doxorubicin prodrug with controllable photolysis activation for cancer chemotherapy. Pharm Res 27:1848–1860CrossRefGoogle Scholar
  57. 57.
    Ibsen S, Zahavy E, Wrasidlo W, Hayashi T, Norton J, Su Y, Adams S, Esener S (2013) Localized in vivo activation of a photoactivatable doxorubicin prodrug in deep tumor tissue. Photochem Photobiol 89:698–708CrossRefGoogle Scholar
  58. 58.
    Olejnik J, Sonar S, Krzymanska-Olejnik E, Rothschild KJ (1995) Photocleavable biotin derivatives: a versatile approach for the isolation of biomolecules. Proc Natl Acad Sci USA 92:7590–7594CrossRefGoogle Scholar
  59. 59.
    Power DG, Kemeny NE (2009) The role of floxuridine in metastatic liver disease. Mol Cancer Therapeutics 8:1015–1025CrossRefGoogle Scholar
  60. 60.
    Galmarini CM, Mackey JR, Dumontet C (2002) Nucleoside analogues and nucleobases in cancer treatment. Lancet Oncol 3:415–424CrossRefGoogle Scholar
  61. 61.
    Tobias SC, Borch RF (2001) Synthesis and biological studies of novel nucleoside phosphoramidate prodrugs. J Med Chem 44:4475–4480CrossRefGoogle Scholar
  62. 62.
    Wei Y, Yan Y, Pei D, Gong B (1998) A photoactivated prodrug. Bioorganic Med Chem Lett 8:2419–2422CrossRefGoogle Scholar
  63. 63.
    Longley DB, Harkin DP, Johnston PG (2003) 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 3:330–338CrossRefGoogle Scholar
  64. 64.
    Schwartz EL, Baptiste N, Wadler S, Makower D (1995) Thymidine phosphorylase mediates the sensitivity of human colon-carcinoma cells to 5-fluorouracil. J Biol Chem 270:19073–19077CrossRefGoogle Scholar
  65. 65.
    Dobritzsch D, Ricagno S, Schneider G, Schnackerz KD, Lindqvist Y (2002) Crystal structure of the productive ternary complex of dihydropyrimidine dehydrogenase with NADPH and 5-iodouracil. Implications for mechanism of inhibition and electron transfer. J Biol Chem 277:13155–13166CrossRefGoogle Scholar
  66. 66.
    Nishimoto S, Hatta H, Ueshima H, Kagiya T (1992) 1-(5′-Fluoro-6′-hydroxy-5′,6′-dihydrouracil-5′-yl)-5-fluorouracil, a novel N(1)-C(5′)-linked dimer that releases 5-fluorouracil by radiation activation under hypoxic conditions. J Med Chem 35:2711–2712CrossRefGoogle Scholar
  67. 67.
    Ito T, Tanabe K, Yamada H, Hatta H, Nishimoto S (2008) Radiation- and photo-induced activation of 5-fluorouracil prodrugs as a strategy for the selective treatment of solid tumors. Molecules 13:2370–2384CrossRefGoogle Scholar
  68. 68.
    Zhang Z, Hatta H, Ito T, Nishimoto S (2005) Synthesis and photochemical properties of photoactivated antitumor prodrugs releasing 5-fluorouracil. Org Biomol Chem 3:592–596CrossRefGoogle Scholar
  69. 69.
    Pasqualini R, Koivunen E, Kain R, Lahdenranta J, Sakamoto M, Stryhn A, Ashmun RA, Shapiro LH, Arap W, Ruoslahti E (2000) Aminopeptidase N is a receptor for tumor-homing peptides and a target for inhibiting angiogenesis. Cancer Res 60:722–727Google Scholar
  70. 70.
    Lin W, Peng D, Wang B, Long L, Guo C, Yuan J (2008) A model for light-triggered porphyrin anticancer prodrugs based on an o-nitrobenzyl photolabile group. Eur J Org Chem 793–796Google Scholar
  71. 71.
    Takiuchi H, Ajani JA (1998) Uracil-tegafur in gastric carcinoma: a comprehensive review. J Clin Oncol 16:2877–2885CrossRefGoogle Scholar
  72. 72.
    Sinkel C, Greiner A, Agarwal S (2008) Synthesis, characterization, and properties evaluation of methylcoumarin end-functionalized poly(methyl methacrylate) for photoinduced drug release. Macromolecules 41:3460–3467CrossRefGoogle Scholar
  73. 73.
    Kolb HC, Finn MG, Sharpless KB (2001) Click chemistry: diverse chemical function from a few good reactions. Angew Chem Int Ed Engl 40:2004–2021CrossRefGoogle Scholar
  74. 74.
    Meldal M, Tornøe CW (2008) Cu-catalyzed azide-alkyne cycloaddition. Chem Rev 108:2952–3015CrossRefGoogle Scholar
  75. 75.
    Agard N, Baskin J, Prescher J, Lo A, Bertozzi C (2006) A comparative study of bioorthogonal reactions with azides. ACS Chem Biol 1:644–648CrossRefGoogle Scholar
  76. 76.
    Binder WH (2008) “Click”—chemistry in polymer and material science: the update. Macromol Rapid Commun 29:951CrossRefGoogle Scholar
  77. 77.
    Hou J, Liu X, Shen J, Zhao G, Wang PG (2012) The impact of click chemistry in medicinal chemistry. Expert Opin Drug Discov 7:489–501CrossRefGoogle Scholar
  78. 78.
    Kolb HC, Sharpless KB (2003) The growing impact of click chemistry on drug discovery. Drug Discov Today 8:1128–1137CrossRefGoogle Scholar
  79. 79.
    Lahann J (2009) Click chemistry for biotechnology and materials science. In: Click chemistry for biotechnology and materials science. Wiley, ChichesterGoogle Scholar
  80. 80.
    Neibert K, Gosein V, Sharma A, Khan M, Whitehead MA, Maysinger D, Kakkar A (2013) “Click” dendrimers as anti-inflammatory agents: with insights into their binding from molecular modeling studies. Mol Pharm 10:2502–2508CrossRefGoogle Scholar
  81. 81.
    Sevenson S, Tomalia DA (2012) Dendrimers in biomedical applications-reflections on the field. Adv Drug Delivery Rev 64:102–115CrossRefGoogle Scholar
  82. 82.
    Sletten EM, Bertozzi CR (2009) Bioorthogonal chemistry: fishing for selectivity in a sea of functionality. Angew Chem Int Ed 48:6974–6998CrossRefGoogle Scholar
  83. 83.
    van Berkel SS, Dirks AT, Debets MF, van Delft FL, Cornelissen JJ, Nolte RJ, Rutjes FP (2007) Metal-free triazole formation as a tool for bioconjugation. ChemBioChem 8:1504–1508CrossRefGoogle Scholar
  84. 84.
    McKay CS, Moran J, Pezacki JP (2010) Nitrones as dipoles for rapid strain-promoted 1,3-dipolar cycloadditions with cyclooctynes. Chem Commun 46:931–933CrossRefGoogle Scholar
  85. 85.
    Blackman ML, Royzen M, Fox JM (2008) Tetrazine ligation: fast bioconjugation based on inverse-electron-demand Diels-Alder reactivity. J Am Chem Soc 130:13518–13519CrossRefGoogle Scholar
  86. 86.
    Devaraj NK, Weissleder R (2011) Biomedical applications of tetrazine cycloadditions. Acc Chem Res 44:816–827CrossRefGoogle Scholar
  87. 87.
    Koo H, Lee S, Na JH, Kim SH, Hahn SK, Choi K, Kwon IC, Jeong SY, Kim K (2012) Bioorthogonal copper-free Click Chemistry in vivo for tumor-targeted delivery of nanoparticles. Angew Chem Int Ed 51:11836–11840CrossRefGoogle Scholar
  88. 88.
    Hapuarachchige S, Zhu W, Kato Y, Artemov D (2014) Bioorthogonal, two-component delivery systems based on antibody and drug-loaded nanocarriers for enhanced internalization of nanotherapeutics. Biomaterials 7:2346–2354CrossRefGoogle Scholar
  89. 89.
    Brudno Y, Desai RM, Kwee BJ, Neel SJ, Aizenberg M, Mooney DJ (2015) In vivo targeting through Click Chemistry. ChemMedChem 10:617–620CrossRefGoogle Scholar
  90. 90.
    Azoulay M, Tuffin G, Sallem W, Floret JC (2006) A new drug-release method using the Staudinger ligation. Bioorg Med Chem Lett 16:3147–3149CrossRefGoogle Scholar
  91. 91.
    Carl PL, Chakravarty PK, Katzenellenbogen JA (1981) A novel connector linkage applicable in prodrug design. J Med Chem 24:479–480CrossRefGoogle Scholar
  92. 92.
    van Brakel R, Vulders RC, Bokdam RJ, Grull H, Robillard MS (2008) A doxorubicin prodrug activated by the Staudinger reaction. Bioconjugate Chem 19:714–718CrossRefGoogle Scholar
  93. 93.
    Gorska K, Manicardi A, Barluenga S, Winssinger N (2011) DNA-templated release of functional molecules with an azide-reduction-triggered immolative linker. Chem Commun 47:4364–4366CrossRefGoogle Scholar
  94. 94.
    Versteegen RM, Rossin R, ten Hoeve W, Janssen HM, Robillard MS (2013) Click to release: instantaneous doxorubicin elimination upon tetrazine ligation. Angew Chem Int Ed 52:14112–14116CrossRefGoogle Scholar
  95. 95.
    Bielski R, Witczak Z (2013) Strategies for coupling molecular units if subsequent decoupling is required. Chem Rev 113:2205–2243CrossRefGoogle Scholar
  96. 96.
    Matikonda SS, Orsi DL, Staudacher V, Jenkins IA, Fiedler F, Chen J, Gamble AB (2015) Bioorthogonal prodrug activation driven by a strain-promoted 1,3-dipolar cycloaddition. Chem Sci 6:1212–1218CrossRefGoogle Scholar
  97. 97.
    Crabtree RH (2014) The organometallic chemistry of the transition metals, 6th edn. Wiley, HobokenCrossRefGoogle Scholar
  98. 98.
    Beller M, Bolm C (2008) Transition metals for organic synthesis: building blocks and fine chemicals, 2nd edn. Wiley-VCH Verlag GmbH, WeinheimGoogle Scholar
  99. 99.
    Waldron KJ, Rutherford JC, Ford D, Robinson NJ (2009) Metalloproteins and metal sensing. Nature 460:823–830CrossRefGoogle Scholar
  100. 100.
    Unciti-Broceta A, Johansson EM, Yusop RM, Sánchez-Martín RM, Bradley M (2012) Synthesis of polystyrene microspheres and functionalization with Pd(0) nanoparticles to perform bioorthogonal organometallic chemistry in living cells. Nat Protocols 7:1207–1218CrossRefGoogle Scholar
  101. 101.
    Völker T, Meggers E (2015) Transition-metal-mediated uncaging in living human cells—an emerging alternative to photolabile protecting groups. Curr Opin Chem Biol 25:48–54CrossRefGoogle Scholar
  102. 102.
    Li J, Chen PR (2016) Development and application of bond cleavage reactions in bioorthogonal chemistry. Nat Chem Biol 12:129–137CrossRefGoogle Scholar
  103. 103.
    Streu C, Meggers E (2006) Ruthenium-induced allylcarbamate cleavage in living cells. Angew Chem Int Ed 45:5645–5648CrossRefGoogle Scholar
  104. 104.
    Sasmal PK, Carregal-Romero S, Parak WJ, Meggers E (2012) Light-triggered ruthenium-catalyzed allylcarbamate cleavage in biological environments. Organometallics 31:5968–5970CrossRefGoogle Scholar
  105. 105.
    Yusop RM, Unciti-Broceta A, Johansson EM, Sánchez-Martín RM, Bradley M (2011) Palladium-mediated intracellular chemistry. Nat Chem 3:239–243CrossRefGoogle Scholar
  106. 106.
    Unciti-Broceta A, Yusop RM, Richardson PR, Walton JGA, Bradley M (2009) A fluorescein-derived anthocyanidin-inspired pH sensor. Tetrahedron Lett 50:3713–3715CrossRefGoogle Scholar
  107. 107.
    Weiss JT, Dawson JC, Macleod KG, Rybski W, Fraser C, Torres-Sánchez C, Patton EE, Bradley M, Carragher NO, Unciti-Broceta A (2014) Extracellular palladium-catalysed dealkylation of 5-fluoro-1-propargyl-uracil as a bioorthogonally activated prodrug approach. Nat Commun 5:3277CrossRefGoogle Scholar
  108. 108.
    Weiss JT, Dawson JC, Fraser C, Rybski W, Torres-Sánchez C, Bradley M, Patton EE, Carragher NO, Unciti-Broceta A (2014) Development and bioorthogonal activation of palladium-labile prodrugs of gemcitabine. J Med Chem 57:5395–5404CrossRefGoogle Scholar
  109. 109.
    Li J, Yu J, Zhao J, Wang J, Zheng S, Lin S, Chen L, Yang M, Jia S, Zhang X, Chen PR (2014) Palladium-triggered deprotection chemistry for protein activation in living cells. Nat Chem 6:352–361CrossRefGoogle Scholar
  110. 110.
    Tonga GY, Jeong Y, Duncan B, Mizuhara T, Mout R, Das R, Kim ST, Yeh YC, Yan B, Hou S, Rotello VM (2015) Supramolecular regulation of bioorthogonal catalysis in cells using nanoparticle-embedded transition metal catalysts. Nat Chem 7:597–603CrossRefGoogle Scholar
  111. 111.
    Unciti-Broceta A (2015) Bioorthogonal catalysis: rise of the nanobots. Nat Chem 7:538–539CrossRefGoogle Scholar
  112. 112.
    Völker T, Dempwolff F, Graumann PL, Meggers E (2014) Progress towards bioorthogonal catalysis with organometallic compounds. Angew Chem Int Ed Engl 53:10536–10540CrossRefGoogle Scholar
  113. 113.
    Pérez-López AM, Rubio-Ruiz B, Sebastián V, Hamilton L, Adam C, Bray TL, Irusta S, Brennan PM, Lloyd-Jones GC, Sieger D, Santamaría J, Unciti-Broceta A (2017) Gold-triggered uncaging chemistry in living systems. Angew Chem Int Ed Engl 56.  10.1002/anie.201705609

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© Springer International Publishing AG 2018

Authors and Affiliations

  • Belén Rubio-Ruiz
    • 1
  • Thomas L. Bray
    • 1
  • Ana M. López-Pérez
    • 1
  • Asier Unciti-Broceta
    • 1
    Email author
  1. 1.Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular MedicineUniversity of EdinburghEdinburghUK

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