Chemistry and catalysis advances in organometallic chemistry and catalysis
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Figure 44.15 Live cell uptake of complex 24 in PC3 cells, visualized by time-lapse confocal microscopy imaging [93]. CONCLUDING REMARKS 601 O HO HO O S O O HO HO O S O O O HO HO OH (NH 2 ·TFA)x HN O N NH N N M CO CO OC O O HO HO O S HN NH O S OH HO HO OH y z M = Re (25), M = 99m Tc (25a) x = 9, y = 8, z = 13 Figure 44.16 Schematic representation of mannosylated dextran derivatives functionalized with pyrazolyldiamine 99m Tc(I)/Re(I) tricarbonyl complexes. SLN
Injection site Figure 44.17 SPECT/CT image in mice after subcutaneous injection of the 99m Tc-labeled dextran derivative 25a (see Fig. 44.16) [96]. specificity (Fig. 44.16) [94–96]. The chemical and physical characterization of the 99m
Tc nanostructures was based on the rhenium congeners. The hydrodynamic diameter of the nanopolymers increases with the polymer backbone functionalization (dextran 4.3 nm and final polymeric compounds 6.5–7 nm) and the overall charge was positive for the pyrazolyldiamine- dextran and negative for the cysteine-dextran derivatives. SPECT/CT studies in mice confirmed that the corresponding 99m Tc-labeled dextran nanopolymers accumulate in the popliteal lymph node, allowing their clear visualization (Fig. 44.17). Therefore, these nanocompounds hold promising as radiopharmaceuticals for SLND and deserve further clinical evaluation. 44.7 CONCLUDING REMARKS The introduction of the precursors fac-[M(CO) 3 (H
O) 3 ] + (M = Re, Tc) opened new avenues in radiopharmaceutical chemistry. On the basis of these starting materials, we and other groups have introduced a variety of organometallic building blocks stable in water and with biological features favorable to design perfusion or target-specific tools for molecular imaging applications and TRT. For kidney and myocardium imaging, some complexes have shown biological properties superior to those of radiopharmaceuticals in clinical use, deserving further evaluation in larger animals or in humans. The labeling of peptidic biomolecules for imaging of receptors has also given encouraging results. Despite the hydrophobicity of the
3 ] + (M = Tc, Re) core, it has been shown that it is possible to modulate the pharmacokinetics of peptide-based 602 ORGANOMETALLIC CHEMISTRY OF RHENIUM AND TECHNETIUM FUELED BY BIOMEDICAL APPLICATIONS complexes using BFCAs with substituents of different polarity. By an appropriate choice of such substituents, the abdominal and hepatobiliar accumulation can be improved without compromising the tumor uptake. However, the labeling of small biomolecules with this core still remains very challenging and the corresponding bioconjugates with clinical potential are scarce. This reflects the difficulties encountered by several authors to avoid the interference of the organometallic fragments with the biological performance of small biomolecules, such as, for example, amino acids or sugar derivatives [97–112]. To overcome these drawbacks and fully profit from the unique features of Re(I)/Tc(I) tricarbonyl complexes, it is necessary to pursue with the innovative design of chelators that can mimic structural motifs of small biomolecules to minimize the probability of inducing changes on their biological behavior. REFERENCES 1. Top, S.; Dauer, B.; Vaissermann, J.; Jaouen, G. J. Organomet. Chem. 1997, 541 , 355. 2. Strohfeldt, K.; Tacke, M. Chem. Soc. Rev. 2008, 37 , 1174. 3. Alberto, R.; Schibli, R.; Egli, A.; Schubiger, P. A.; Herrmann, W. A.; Artus, G.; Abram, U.; Kaden, T. A. J. Organomet. Chem. 1995, 493 , 119. 4. Alberto, R.; Schibli, R.; Egli, A.; Schubiger, A. P.; Abram, U.; Kaden, T. A. J. Am. Chem. Soc. 1998, 120 , 7987. 5. Schibli, R.; Schwarzbach, R.; Alberto, R.; Ortner, K.; Schmalle, H.; Dumas, C.; Egli, A.; Schubiger, P. A. Bioconjug. Chem. 2002,
6. Liu, S.; Edwards, D. S. Bioconjug. Chem. 2001, 12 , 7. 7. Shokeen, M.; Anderson, C. J. Acc. Chem. Res. 2009, 42 , 832. 8. Mewis, R. E.; Archibald, S. J. Coord. Chem. Rev. 2010, 254 , 1686. 9. Wadas, T. J.; Wong, E. H.; Weisman, G. R.; Anderson, C. J. Chem. Rev. 2010, 110 , 2858. 10. Liu, S. Chem. Soc. Rev. 2004, 33 , 445. 11. Abram, U.; Alberto, R. J. Braz. Chem. Soc. 2006, 17 , 1486. 12. Correia, J. D. G.; Paulo, A.; Raposinho, P. D.; Santos, I. Dalton Trans. 2011, 40 , 6144. 13. Alberto, R.; Ortner, K.; Wheatley, N.; Schibli, R.; Schubiger, A. P. J. Am. Chem. Soc. 2001, 123 , 3135. 14. Moura, C.; Fernandes, C.; Gano, L.; Paulo, A.; Santos, I. C.; Santos, I.; Calhorda, M. J. J. Organomet. Chem. 2009, 694 , 950. 15. Alves, S.; Paulo, A.; Correia, J. D. G.; Domingos, A.; Santos, I. J. Chem. Soc. Dalton Trans. 2002, 4714. 16. Fernandes, C.; Santos, I. C.; Santos, I.; Pietzsch, H. J.; Kunstler, J. U.; Kraus, W.; Rey, A.; Margaritis, N.; Bourkoula, A.; Chiotellis, A.; Paravatou-Pestsotas, M.; Pirmettis, I. Dalton Trans. 2008, 3215. 17. Banerjee, S. R.; Levadala, M. K.; Lazarova, N.; Wei, L. H.; Valliant, J. F.; Stephenson, K. A.; Babich, J. W.; Maresca, K. P.; Zubieta, J. Inorg. Chem. 2002, 41 , 6417. 18. Liu, Y.; Pak, J. K.; Schmutz, P.; Bauwens, M.; Mertens, J.; Knight, H.; Alberto, R. J. Am. Chem. Soc. 2006, 128 , 15996. 19. Schibli, R.; La Bella, R.; Alberto, R.; Garcia-Garayoa, E.; Ortner, K.; Abram, U.; Schubiger, P. A. Bioconjug. Chem. 2000, 11 , 345. 20. Alberto, R.; Pak, J. K.; van Staveren, D.; Mundwiler, S.; Benny, P. Biopolymers 2004, 76 , 324. 21. Hafliger, P.; Mundwiler, S.; Ortner, K.; Spingler, B.; Alberto, R.; Andocs, G.; Balogh, L.; Bodo, K. Synth. React. Inorg. Met.-Org.
22. van Staveren, D. R.; Benny, P. D.; Waibel, R.; Kurz, P.; Pak, J. K.; Alberto, R. Helvet. Chim. Acta 2005, 88 , 447. 23. Liu, Y.; Oliveira, B. L.; Correia, J. D. G.; Santos, I. C.; Santos, I.; Spingler, B.; Alberto, R. Org. Biomol. Chem. 2010, 8 , 2829. 24. Mindt, T. L.; Struthers, H.; Spingler, B.; Brans, L.; Tourwe, D.; Garcia-Garayoa, E.; Schibli, R. ChemMedChem 2010, 5 , 2026. 25. Mindt, T. L.; Schweinsberg, C.; Brans, L.; Hagenbach, A.; Abram, U.; Tourwe, D.; Garcia-Garayoa, E.; Schibli, R. ChemMedChem
26. Pak, J. K.; Benny, P.; Spingler, B.; Ortner, K.; Alberto, R. Chem. Eur. J. 2003, 9 , 2053. 27. Bernard, J.; Ortner, K.; Spingler, B.; Pietzsch, H. J.; Alberto, R. Inorg. Chem. 2003, 42 , 1014. 28. Valliant, J. F.; Morel, P.; Schaffer, P.; Kaldis, J. H. Inorg. Chem. 2002, 41 , 628. 29. Maria, L.; Paulo, A.; Santos, I. C.; Santos, I.; Kurz, P.; Spingler, B.; Alberto, R. J. Am. Chem. Soc. 2006, 128 , 14590. 30. Wald, J.; Alberto, R.; Ortner, K.; Candreia, L. Angew. Chem. Int. Ed. 2001, 40 , 3062. 31. Liu, Y.; Spingler, B.; Schmultz, P.; Alberto, R. J. Am. Chem. Soc. 2008, 130 , 1554. 32. Sogbein, O. O.; Merdy, P.; Morel, P.; Valliant, J. F. Inorg. Chem. 2004, 43 , 3032. 33. Sogbein, O. O.; Green, A. E. C.; Valliant, J. F. Inorg. Chem. 2005, 44 , 9585. 34. Green, A. E. C.; Causey, P. W.; Louie, A. S.; Armstrong, A. F.; Harrington, L. E.; Valliant, J. F. Inorg. Chem. 2006, 45 , 5727. REFERENCES 603 35. Garcia, R.; Paulo, A.; Domingos, A.; Santos, I.; Ortner, K.; Alberto, R. J. Am. Chem. Soc. 2000, 122 , 11240. 36. Garcia, R.; Paulo, A.; Domingos, K.; Santos, I. J. Organomet. Chem. 2001, 632 , 41. 37. Garcia, R.; Gano, L.; Maria, L.; Paulo, A.; Santos, I.; Spies, H. J. Biol. Inorg. Chem. 2006, 11 , 769. 38. Garcia, R.; Domingos, A.; Paulo, A.; Santos, I.; Alberto, R. Inorg. Chem. 2002, 41 , 2422. 39. Garcia, R.; Paulo, A.; Domingos, A.; Santos, I.; Pietzsch, H. J. Synth. React. Inorg. Met.-Org. Nano-Met. Chem. 2005, 35 , 35. 40. Videira, M.; Maria, L.; Paulo, A.; Santos, I. C.; Santos, I.; Vaz, P. D.; Calhorda, M. J. Organometallics 2008, 27 , 1334. 41. Videira, M.; Moura, C.; Datta, A.; Paulo, A.; Santos, I. C.; Santos, I. Inorg. Chem. 2009, 48 , 4251. 42. Moura, C.; Gano, L.; Santos, C. I.; Paulo, A.; Santos, I. Curr. Radiopharm. 2012, 5 , 150. 43. He, H. Y.; Lipowska, M.; Christoforou, A. M.; Marzilli, L. G.; Taylor, A. T. Nucl. Med. Biol. 2007, 34 , 709. 44. He, H. Y.; Lipowska, M.; Xu, X. L.; Taylor, A. T.; Marzilli, L. G. Inorg. Chem. 2007, 46 , 3385. 45. Lipowska, M.; He, H. Y.; Malveaux, E.; Xu, X. L.; Marzilli, L. G.; Taylor, A. J. Nucl. Med. 2006, 47 , 1032. 46. Lipowska, M.; Marzilli, L. G.; Taylor, A. T. J. Nucl. Med. 2009, 50 , 454. 47. Liu, S. Dalton Trans. 2007, 1183. 48. Liu, Z. L.; Chen, L. Y.; Liu, S. A.; Barber, C.; Stevenson, G. D.; Furenlid, L. R.; Barrett, H. H.; Woolfenden, J. M. J. Nucl. Cardiol.
49. Maria, L.; Fernandes, C.; Garcia, R.; Gano, L.; Paulo, A.; Santos, I. C.; Santos, I. Dalton Trans. 2009, 603. 50. Goethals, L. R.; Santos, I.; Caveliers, V.; Paulo, A.; De Geeter, F.; Lurdes, P. G.; Fernandes, C.; Lahoutte, T. Contrast Media Mol.
51. Maria, L.; Cunha, S.; Videira, M.; Gano, L.; Paulo, A.; Santos, I. C.; Santos, I. Dalton Trans. 2007, 3010. 52. Mendes, F.; Gano, L.; Fernandes, C.; Paulo, A.; Santos, I. Nucl. Med. Biol. 2012, 39 , 207. 53. Bartholoma, M.; Valliant, J.; Maresca, K. P.; Babich, J.; Zubieta, J. Chem. Commun. 2009, 493. 54. Alberto, R. Eur. J. Inorg. Chem. 2009, 2013 , 21. 55. Alberto, R. Top. Organomet. Chem. 2010, 32 , 219. 56. Alberto, R. J. Organomet. Chem. 2007, 692 , 1179. 57. Santos, I.; Paulo, A.; Correia, J. D. G. Top. Curr. Chem. 2005, 252 , 45. 58. Garcia, R.; Paulo, A.; Santos, I. Inorg. Chim. Acta 2009, 362 , 4315. 59. Correia, J. D. G.; Paulo, A.; Santos, I. Curr. Radiopharm. 2009, 2 , 277. 60. Mendes, F.; Paulo, A.; Santos, I. Dalton Trans. 2011, 40 , 5377. 61. Alves, S.; Paulo, A.; Correia, J. D. G.; Gano, L.; Smith, C. J.; Hoffman, T. J.; Santos, I. Bioconjug. Chem. 2005, 16 , 438. 62. Alves, S.; Correia, J. D.; Santos, I.; Veerendra, B.; Sieckman, G. L.; Hoffman, T. J.; Rold, T. L.; Figueroa, S. D.; Retzloff, L.; McCrate, J.; Prasanphanich, A.; Smith, C. J. Nucl. Med. Biol. 2006, 33 , 625. 63. Retzloff, L. B.; Heinzke, L.; Figueroa, S. D.; Sublett, S. V.; Ma, L.; Sieckman, G. L.; Rold, T. L.; Santos, I.; Hoffman, T. J.; Smith, C. J. Anticancer Res. 2010, 30 , 19. 64. Decristoforo, C.; Santos, I.; Pietzsch, H. J.; Kuenstler, J. U.; Duatti, A.; Smith, C. J.; Rey, A.; Alberto, R.; Von Guggenberg, E.; Haubner, R. Q. J. Nucl. Med. Mol Imaging 2007, 51 , 33. 65. Alves, S.; Correia, J. D.; Gano, L.; Rold, T. L.; Prasanphanich, A.; Haubner, R.; Rupprich, M.; Alberto, R.; Decristoforo, C.; Santos, I.; Smith, C. J. Bioconjug. Chem. 2007, 18 , 530. 66. Raposinho, P. D.; Correia, J. D. G.; Alves, S.; Botelho, M. F.; Santos, A. C.; Santos, I. Nucl. Med. Biol. 2008, 35 , 91. 67. Raposinho, P. D.; Xavier, C.; Correia, J. D. G.; Falcao, S.; Gomes, P.; Santos, I. J. Biol. Inorg. Chem. 2008, 13 , 449. 68. Valldosera, M.; Monso, M.; Xavier, C.; Raposinho, P.; Correia, J. D. G.; Santos, I.; Gomes, P. Int. J. Pept. Res. Ther. 2008, 14 , 273. 69. Morais, M. M.; Raposinho, P. D.; Correia, J. D. G.; Santos, I. J. Pept. Sci. 2010, 16 , 186. 70. Correia, J. D. G.; Morais, M.; Raposinho, P. D.; Oliveira, M. C.; Santos, I. Biopolymers 2011, 96 , 504. 71. Morais, M.; Raposinho, P. D.; Oliveira, M. C.; Correia, J. D. G.; Santos, I. J. Biol. Inorg. Chem. 2012, 17 , 491. 72. Morais, M.; Raposinho, P. D.; Correia, J. D. G.; Santos, I. J. Med. Chem. 2013, 56 (5), 1961. 73. Louie, A. S.; Vasdev, N.; Valliant, J. F. J. Med. Chem. 2011, 54 , 3360. 74. Garcia, R.; Xing, Y. H.; Paulo, A.; Domingos, A.; Santos, I. J. Chem. Soc. Dalton Trans. 2002, 4236. 75. Can, D.; Spingler, B.; Schmutz, P.; Mendes, F.; Raposinho, P. D.; Fernandes, C.; Carta, F.; Innocenti, A.; Santos, I.; Supuran, C.; Alberto, R. Angew. Chem. Int. Ed. Engl. 2012, 51 , 3354–3357. 76. Can, D.; Schmutz, P.; Raposinho, P. D.; Santos, I.; Alberto, R, Chem. Biodivers. 2012, 9 (9), 1849. 77. Schibli, R.; Netter, M.; Scapozza, L.; Birringer, M.; Schelling, P.; Dumas, C.; Schoch, J.; Schubiger, P. A. J. Organomet. Chem.
604 ORGANOMETALLIC CHEMISTRY OF RHENIUM AND TECHNETIUM FUELED BY BIOMEDICAL APPLICATIONS 78. Desbouis, D.; Schubiger, P. A.; Schibli, R. J. Organomet. Chem. 2007, 692 , 1340. 79. Stichelberger, M.; Desbouis, D.; Spiwok, V.; Scapozza, L.; Schubiger, P. A.; Schibli, R. J. Organomet. Chem. 2007, 692 , 1255. 80. Desbouis, D.; Struthers, H.; Spiwok, V.; Kuster, T.; Schibli, R. J. Med. Chem. 2008, 51 , 6689. 81. Struthers, H.; Viertl, D.; Kosinski, M.; Spingler, B.; Buchegger, F.; Schibli, R. Bioconjug. Chem. 2010, 21 , 622. 82. Oliveira, B. L.; Correia, J. D. G.; Raposinho, P. D.; Santos, I.; Ferreira, A.; Cordeiro, C.; Freire, A. P. Dalton Trans. 2009, 152. 83. Oliveira, B. L.; Raposinho, P. D.; Mendes, F.; Figueira, F.; Santos, I.; Ferreira, A.; Cordeiro, C.; Freire, A. P.; Correia, J. D. G. Bioconjug. Chem. 2010, 21 , 2168. 84. Oliveira, B. L.; Raposinho, P. D.; Mendes, F.; Santos, I. C.; Santos, I.; Ferreira, A.; Cordeiro, C.; Freire, A. P.; Correia, J. D. G. J. Organomet. Chem. 2011, 696 , 1057. 85. Palma, E.; Oliveira, B. L.; Correia, J. D. G.; Gano, L.; Maria, L.; Santos, I. C.; Santos, I. J. Biol. Inorg. Chem. 2007, 12 , 667. 86. Palma, E.; Correia, J. D. G.; Oliveira, B. L.; Gano, L.; Santos, I. C.; Santos, I. Dalton Trans. 2011, 40 , 2787. 87. de Rosales, R. T. M.; Finucane, C.; Foster, J.; Mather, S. J.; Blower, P. J. Bioconjug. Chem. 2010, 21 , 811. 88. Haefliger, P.; Agorastos, N.; Renard, A.; Giambonini-Brugnoli, G.; Marty, C.; Alberto, R. Bioconjug. Chem. 2005, 16 , 582. 89. Agorastos, N.; Borsig, L.; Renard, A.; Antoni, P.; Viola, G.; Spingler, B.; Kurz, P.; Alberto, R. Chem. Eur. J. 2007, 13 , 3842. 90. Vitor, R. F.; Correia, I.; Videira, M.; Marques, F.; Paulo, A.; Pessoa, J. C.; Viola, G.; Martins, G. G.; Santos, I. ChemBioChem 2008,
91. Vitor, R. F.; Esteves, T.; Marques, F.; Raposinho, P.; Paulo, A.; Rodrigues, S.; Rueff, J.; Casimiro, S.; Costa, L.; Santos, I. Cancer Biother. Radiopharm. 2009, 24 , 551. 92. Esteves, T.; Xavier, C.; Gama, S.; Mendes, F.; Raposinho, P. D.; Marques, F.; Paulo, A.; Pessoa, J. C.; Rino, J.; Viola, G.; Santos, I. Org. Biomol. Chem. 2010, 8 , 4104. 93. Esteves, T.; Marques, F.; Paulo, A.; Rino, J.; Nanda, P.; Smith, C. J.; Santos, I. J. Biol. Inorg. Chem. 2011, 16 , 1141. 94. Morais, M.; Subramanian, S.; Pandey, U.; Samuel, G.; Venkatesh, M.; Martins, M.; Pereira, S.; Correia, J. D. G.; Santos, I. Mol.
95. Pirmettis, I.; Arano, Y.; Tsotakos, K.; Okada, K.; Yamaguchi, A.; Uehara, T.; Morais, M.; Correia, H. D. G.; Santos, I.; Martins, M.; Pereira, S.; Triantis, C.; Kyprianidou, P.; Pelecanou, M.; Papadopoulos, M. Mol. Pharm. 2012, 9 , 1681. 96. Arano, Y.; Yamaguchi, A.; Uehara, T.; Morais, M.; Correia, J. D. G.; Santos, I. Unpublished results. 97. Bowen, M. L.; Orvig, C. Chem. Commun. 2008, 5077. 98. Petrig, J.; Schibli, R.; Dumas, C.; Alberto, R.; Schubiger, P. A. Chem. Eur. J. 2001, 7 , 1868. 99. Dumas, C.; Petrig, J.; Frei, L.; Spingler, B.; Schibli, R. Bioconjug. Chem. 2005, 16 , 421. 100. Bayly, S. R.; Fisher, C. L.; Storr, T.; Adam, M. J.; Orvig, C. Bioconjug. Chem. 2004, 15 , 923. 101. Storr, T.; Fisher, C. L.; Mikata, Y.; Yano, S.; Adam, M. J.; Orvig, C. Dalton Trans. 2005, 654. 102. Storr, T.; Sugai, Y.; Barta, C. A.; Mikata, Y.; Adam, M. J.; Yano, S.; Orvig, C. Inorg. Chem. 2005, 44 , 2698. 103. Storr, T.; Obata, M.; Fisher, C. L.; Bayly, S. R.; Green, D. E.; Brudzinska, I.; Mikata, Y.; Patrick, B. O.; Adam, M. J.; Yano, S.; Orvig, C. Chem. Eur. J. 2005, 11 , 195. 104. Ferreira, C. L.; Bayly, S. R.; Green, D. E.; Storr, T.; Barta, C. A.; Steele, J.; Adam, M. J.; Orvig, C. Bioconjug. Chem. 2006, 17 , 1321.
105. Ferreira, C. L.; Ewart, C. B.; Bayly, S. R.; Patrick, B. O.; Steele, J.; Adam, M. J.; Orvig, C. Inorg. Chem. 2006, 45 , 6979. 106. Bowen, M. L.; Chen, Z. F.; Roos, A. M.; Misri, R.; Hafeli, U.; Adam, M. J.; Orvig, C. Dalton Trans. 2009, 9228. 107. Bowen, M. L.; Lim, N. C.; Ewart, C. B.; Misri, R.; Ferreira, C. L.; Hafeli, U.; Adam, M. J.; Orvig, C. Dalton Trans. 2009, 9216. 108. Ferreira, C. L.; Marques, F. L. N.; Okamoto, M. R. Y.; Otake, A. H.; Sugai, Y.; Mikata, Y.; Storr, T.; Bowen, M.; Yano, S.; Adam, M. J.; Chammas, R.; Orvig, C. Appl. Radiat. Isot. 2010, 68 , 1087. 109. Gottschaldt, M.; Koth, D.; Muller, D.; Klette, I.; Rau, S.; Gorls, H.; Schafer, B.; Baum, R. P.; Yano, S. Chem. Eur. J. 2007, 13 , 10273. 110. Banerjee, S. R.; Babich, J. W.; Zubieta, J. Inorg. Chim. Acta 2006, 359 , 1603. 111. Dapueto, R.; Castelli, R.; Fernandez, M.; Chabalgoity, J. A.; Moreno, M.; Gambini, J. P.; Cabral, P.; Porcal, W. Bioorg. Med. Chem. Lett. 2011, 21 , 7102. 112. Schibli, R.; Dumas, C.; Petrig, J.; Spadola, L.; Scapozza, L.; Garcia-Garayoa, E.; Schubiger, P. A. Bioconjug. Chem. 2005, 16 , 105. 45 METAL-BASED INDOLOBENZAZEPINES AND INDOLOQUINOLINES: FROM MODERATE cdk INHIBITORS TO POTENTIAL ANTITUMOR DRUGS Michael F. Primik, Lukas K. Filak, and Vladimir B. Arion *
The first metal complexes synthesized for medical purposes can be dated back to the dawn of the last century, when Paul Ehrlich (1854–1915, 1908 Nobel Prize winner in physiology or medicine) and coworkers synthesized and systematically screened more than 600 compounds in order to assess their biological activity. This ultimately led to the discovery of the organoarsenic arsphenamine, also referred to as Salvarsan, the first medicine providing efficient treatment for syphilis [1]. Although Salvarsan is no longer in clinical use, as it was replaced by “modern” antibiotics, such as penicillin derivatives, Ehrlich’s approach is still widely used in biochemical research. The second very important concept introduced by Ehrlich has been termed magic bullet and describes the goal of targeted chemotherapy. In Ehrlich’s words, chemotherapeutics should be substances “that fly in search of the enemy after the manner of the bewitched bullets” [2]. More than a century later, the hunt for those “magic bullets” is still a hot topic of medicinal research. Scientists attempt to develop substances that would enable physicians to provide chemotherapy without any side effects. Although the meaning of the words changed over the years, the principle has remained the same: gaining selectivity for cancerous cells over normal tissue. The next tremendous impact on medicine made by metal-based drugs was the introduction of square-planar platinum(II) complexes in clinical cancer therapy. Approved in the late 1970s, cisplatin (cis-diamminedichloridoplatinum(II)) and its second- and third-generation derivatives carboplatin and oxaliplatin, are administered in 80% of all chemotherapies. The results speak for themselves, as before the clinical use of cisplatin, testicular cancer manifested a mortality rate of 90%, which was literally inverted by a platinum drug-based combination therapy regimen. This leaves 10% of the diseases incurable, mainly owing to late diagnosis accompanied by already strong metastasis [3]. The well-recognized target of anticancer platinum drugs is DNA. As tumor cells tend to divide more frequently than healthy ones, it is possible to obtain certain selectivity for cancer over normal tissue [4]. However, as nearly all benign cells also replicate themselves from time to time, the general toxicity of the drug is high and side effects, such as nausea, hair loss, nephrotoxicity, and neuropathy, are frequent. Furthermore, certain types of cancer are intrinsically resistant or acquire resistance against platinum-containing drugs throughout consecutive chemotherapy cycles [5]. All these findings prompted researchers to gain insight into the interactions between the platinum drugs and biomolecules such as nucleic acids, proteins, and carbohydrates, ultimately leading to a better understanding of the mode of action of these drugs and building the foundation for rational metal-based drug design.
First Edition. Edited by Armando J. L. Pombeiro. © 2014 John Wiley & Sons, Inc. Published 2014 by John Wiley & Sons, Inc.
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