Purine-based NHC complexes
Scheme 3.23 Synthesis of the bis(PTA) complexes 25-28
2. As for the A2780 line (cisPt sensitive) only one complex (17a) shows activity comparable to that of cisplatin, while for A2780-R line, the number of compounds able to equal its
performance is higher (15b, 15d, 16a, 17a, 19d, 20a and 26); two of the synthesized complexes (24a and 25) are definitely better than cisplatin. The results of compound 25 appear particularly interesting for the water-solubility of the complex, an important feature for a potential biomedical agent.
3. With regard to the A2780 line, the change of the cordinated olefin in complexes with the same spectator ligands does not influence the activity of the complex. Likewise, maintaining the same type of olefin (tmetc) and changing the type of carbene ligand, there are no substantial differences in terms of activity.
4. With regard to the A2780-R line, for the same spectator ligands, the most efficient complexs are those coordinating fumaronitrile and maleic anhydride. On the other hand, complexes with tmetc are poorly active, with the sole exception of the bis-PTA complex.
5. Comparing the IC50 values obtained in the two different lines, we can observe that compounds coordinating the fumaronitrile maintain their antiproliferative activity. A similar trend is found in the complexes with maleic anhydride. The analogous complexes with tmetc, except for 15b, 15d and 19d, instead reduce their activity passing from the cisplatin-sensitive line to the resistant one.
Pro-apoptotic effect
In Table 3.8 the percentage of total apoptosis was reported for some representative compounds (15b, 16a, 17a, 20a, 24a, 25 and 26) and each data was compared to the analysis of untreated cells (negative control, C-), in which the observed total apoptosis was less than 5%.
COMPLEX Total apoptosis (%) Table 3.8 Pro-apoptotic effects of Pd(0) olefin complexes (C-: untreated cells)
The analysis of the results obtained for the A2780 line shows that compounds 16a, 24a and 26 have a good pro-apoptotic activity at concentrations between 5 and 8 M. In particular, the total apoptosis (early and late) remains between 63% and 99%.
Also in the case of the A2780-R cell line, complexes 16a, 24a and 26 are those with the greater percentages of total apoptosis; however, the value between 30 and 35% is smaller than that found for the cisplatin-sensitive line.
3.9. Conclusions
In this chapter we have presented the synthesis and characterization of palladium 3-allyl, 2-olefin and palladacyclopentadienyl complexes containing purine-based NHC ligands. These complexes, which are stable both in the solid state and in solution, were tested toward ovarian cancer cell lines both cisplatin-sensitive and cisplatin-resistant. The results of the antiproliferative activity have highlighted that 3-allyl palladium and palladacyclopentadienyl complexes are generally more active than 2-olefn palladium (0) derivatives. Among the most active species, 3-allyl complexes containing a NHC ligand and a triphenylphosphine and mixed NHC/PTA palladacyclopentadienyl compounds are especially promising. In fact, they display an excellent antiproliferative activity on the ovarian cancer lines and, at the same time, they are almost inactive on normal cells.
Moreover, the analysis of the proapoptotic activity showed that the most active complexes are able to promote programmed cell death (apoptosis). This process, unlike necrosis, is preferred because the system can recycle the cellular material avoiding or reducing inflammatory processes.
Encouraged by the results regarding the compounds with purine-based NHCs, we decided to extend our study also to 3-allyl-palladium and palladacyclopentadienyl complexes stabilized by other types of NHCs. The synthesis of these classes of compounds and their biological activity will be presented in the successive chapters.
3.10. References
[1] (a) T.A.K. Al-Allaf, L.J. Rashan, Eur. J. Med. Chem., 1998, 33, 817; (b) A. Valentini, F.
Conforti, A. Crispini, A. De Martino, R. Condello, C. Stellitano, G. Rotillo, M. Ghedini, G.
Federici, S. Bernardini, D. Pucci, J. Med. Chem., 2009, 52, 484; (c) A. Monney, M. Albrecht, Coord. Chem. Rev., 2013, 257, 2420; d) M. Tanaka, H. Kataoka, S. Yano, H. Ohi, K.
Kawamoto, T. Shibahara, T. Mizoshita, Y. Mori, S. Tanida, T. Kamiya, T. Joh, BMC Cancer, 2013, 13, 327.
[2] H. Rosemeyer, Chem. Biodivers., 2004, 1 (3), 361.
[3] T.W. Stone, H.A. Simmonds, Purines: Basic and Clinical Aspects. Springer Netherlands, 1991.
[4] J.W. Daly, Cell. Mol. Life Sci., 2007, 64, 2153.
[5] T.T. Hansel, R.C. Tennant, A.J. Tan, L.A. Higgins, H. Neighbour, E.M. Erin, P.J. Barnes, Drugs Today, 2004, 40, 55.
[6] (a) D. Petch, R.J. Anderson, A. Cunningham, S.E. George, D.E. Hibbs, R. Liu, S.P. Mackay, A. Paul, D.A.P. Small, P.W. Groundwater, Bioorg. Med. Chem., 2012, 20, 5901; (b) C.
Siering, H. Kerschbaumer, M. Nieger, S. R. Waldvogel, Org. Lett., 2006, 8, 1471; (c) F. G.
Lupascu, O. M. Dragostin, L. Foia, D. Lupascu, L. Profire, Molecules, 2013, 18, 9684.
[7] (a) E.I. Ivanov, G.D. Kalayanov, I.M. Yaroshchenko, D.E. Stepanov, Khim. Geterotsikl.
Soedin, 1989, 11, 1570; (b) J. Schutz, W.A. Herrmann, J. Organomet. Chem., 2004, 689, 2995.
[8] E. Mohammadi, B. Movassagh, J. Mol. Cat. A, 2016, 418, 158.
[9] V.R. Landaeta, R.E. Rodriguez-Lugo, E.N. Rodriguez-Arias, D.S. Coll-Gomez, T. Gonzalez, Transition Met. Chem., 2010, 35, 165.
[10] J. Schutz, W.A. Herrmann, J. Organomet. Chem., 2004, 689, 2995.
[11] J.J. Zhang, J.K. Muenzner, M.A. Abu El Maaty, B. Karge, R. Schobert, S. Wolfl, I. Ott, Dalton Trans., 2016, 45, 13161.
[12] (a) A.K. Nebioglu, A. Melaiye, K.M Hindi, S. Durmus, M.J. Panzner, L.A. Hogue, R.J.
Mallet, C.E. Hovis, M. Coughenour, S.D. Crosby, A. Milsted, D.L. Ely, C.A. Tessier, C.L.
Cannon, W.J. Youngs, J. Med. Chem., 2006, 49, 6811; (b) H.A. Mohamed, B.R.M. Lake, T.
Laing, R.M. Phillips, C.E. Willians, Dalton Trans., 2015, 44, 7563.
[13] K.M. Hindi, M.J. Panzner, C.A. Tessier, C.L. Cannon, W.J. Youngs, Chem. Rev., 2009, 109 (8), 3859.
[14] A. Szadkowska, S. Staszko, E. Zaorska, R. Pawlowski, RSC Adv., 2016, 6, 44248.
[15] (a) J.J. Zhang, C.M. Che, I. Ott, J. Organomet. Chem., 2015, 782, 37; (b) M. Skander, P.
Retailleau, B. Bourriè, L. Schio, P. Mailliet, A. Marinetti, J. Med. Chem., 2010, 53, 2146.
[16] B. Bertrand, L. Stefan, M. Pirrotta, D. Monchaud, E. Bodio, P. Richard, P.L. Gendre, E.
Warmerdam, M.H. De Jager, G.M.M. Groothuis, M. Picquet, A. Casini, Inorg. Chem., 2014, 53, 2296.
[17] E. Mohammadi, B. Movassagh, J. Organomet. Chem., 2016, 822, 62.
[18] H. E. Affsprung, V.S. Archer, Anal. Chem., 1964, 36 (13), 2512-2513; (b) M.J. Smith, S.E.
Manahan, Anal. Chim. Acta, 48, 1969, 315.
[19] P. de Fremont, N.M. Scott, E.D. Stevens, T. Ramnial, O.C. Lightbody, C.L.B. Macdonald, J.A.C. Clyburne, C.D. Abernethy, S.P. Nolan, Organometallics, 2005, 24, 6301.
[20] I. J. B. Lin, C. S. Vasam, Coord. Chem. Rev., 2007, 251, 642.
[21] L. Canovese, F. Visentin, G. Chessa, P. Uguagliati, G. Bandoli, Organometallics, 2005, 24, 3297.
[22] S. N. Sluijter, S. Warsink, M. Lutzc, C. J. Elsevier, Dalton Trans., 2013, 42, 7365.
[23] (a) L. Canovese, F. Visentin, G. Chessa, P. Uguagliati, A. Dolmella, J. Organomet. Chem, 2000, 601, 1; (b) L. Canovese, F. Visentin, P. Uguagliati, B. Crociani, J. Chem. Soc. Dalton Trans., 1996, 1921; (c) L. Canovese, C. Santo, F. Visentin, Organometallics, 2008, 27, 3577;
(d) L. Canovese, F. Visentin,C. Biz,T. Scattolin, C. Santo, V. Bertolasi, Polyhedron, 2015, 102, 94.
[24] (a) L. Canovese, F. Visentin, G. Chessa, P. Uguagliati, C. Levi, A. Dolmella, Organometallics, 2005, 24, 5537; (b) L. Canovese, F. Visentin, P. Uguagliati, G. Chessa, A.
Pesce, J. Organomet. Chem., 1998, 566, 61.
[25] L. Canovese, C. Santo, T. Scattolin, F. Visentin, V. Bertolasi, J. Organomet. Chem., 2015, 794, 288.
[26] (a) E. Guerrero, S. Miranda, S. Luttenberg, N. Frohlich, J.M. Koenen, F. Mohr, E. Cerrada, M. Laguna, A. Mendia, Inorg. Chem., 2013, 52, 6635; (b) M. Carreira, R. Calvo-Sanjuaı`n, M. Sanauı`, I. Marzo, M. Contel, Organometallics, 2012, 31, 5772.
[27] ECACC (European Collection of authenticated cell cultures) (http://www.pheculture collections.org.uk/products/celllines/generalcell/detail.jsp?refId=93112519&collection=ecac c_gc).
[28] T.T. Fong, C. Lock, C.Y. Chung, Y.E. Fung, P. Chow, P. Wan, C. Che, Angew. Chem. Int.
Ed., 2016, 55, 11935.
The figures proposed at the beginning of the chapter are related to these sources: https://rickardha.deviantart.com/art/Roman-Bridge-363826754 and http://greece.greekreporter.com/2014/07/14/10-must-see-ancient-greek-temples/