Complexes of medicinal interest in terapy and diagnostics, involving the elements Au, Pd, Pt, Re and Tc with S,N,S-tridentate thiosemicarbazones

Author(s)

Pedro Ivo da Silva Maia

• Document type: Doctoral Thesis
• Press: São Carlos.
• Institution: Universidade de São Paulo (USP). Instituto de Química de São Carlos (IQSC/BT)
• Defense date: 2011-12-01

Examining board members

Victor Marcelo Deflon; Alzir Azevedo Batista; Antonio Eduardo Mauro

• Advisor: Victor Marcelo Deflon

Abstract

This thesis presents the synthesis of a new class of thiosemicarbazones/thiosemicarbazides (H2L1) potentially S,N,S-donors, obtained by reactions of N-[N\',N\'-diethylamino(thiocarbonyl)]benzimidoyl chloride and 4,4-dialkylthiosemicarbazides, which were found to present a remarkable antiproliferative effect against human MCF-7 breast cancer cells. These thiosemicarbazones were used to prepare new transition metal complexes, including the elements Au, Pd, Pt, Re and Tc; which have been characterized based on IR, UV-vis absorption, mass, 1H- and 31P-NMR spectroscopies, elemental analysis, X-ray diffractometry from single crystals and theoretical calculations. <br />The results obtained with the gold complexes were highlighted. They were synthesized by reactions of Na[AuCl4]&bullet;2H2O with the thiosemicarbazone ligands H2L1, under formation of air-stable green [AuCl(L1)] complexes. Small amounts of gold(I) complexes of the composition [AuCl(L3)] were formed as side-products, where L3 is the 5-diethylamino-3-phenyl-1-thiocarbamoyl-1,2,4-triazole ligand. A pathway of the reduction reaction was proposed on the basis of mass spectroscopy and crystal structure analysis. Substitution reactions on the complexes were also investigated. DFT calculations carried out on [AuCl(L1)] and the products of the exchange reactions showed that the fourth ligand in the coordination sphere strongly influences the electron density on the metal center. The metal center\'s electron deficiency seems to be related with the cell growth inhibition against breast cancer cells of these gold(III) complexes. The gold complexes described in this work represent the first examples of fully characterized neutral Au(III) thiosemicarbazone complexes. <br />Platinum(II) and palladium(II) complexes containing the H2L1 ligands have also been prepared in order to compare their biological activity with those of the gold(III) analogs. H2L1 ligands react under single deprotonation with [PdCl2(MeCN)2] or [PtCl2(COD)] to form air-stable chelate complexes with general formula [M(HL1)Cl] (M = Pd or Pt). The presence of an ionizable hydrogen atom in the structure of the monodeprotonated ligands of the [M(HL1)Cl] complexes allowed the investigation of reactions with addition of base, which afforded oligomeric complexes. Furthermore, it has been shown that the chlorido ligand in [PdCl(HL1)] may be replaced by a thiophenolato ligand (tfol-) without additional deprotonation of the HL1- ligand, forming [Pd(HL1)(tfol)] type complexes. <br />Oxorhenium(V) complexes of the general composition [ReOCl(L1)], which are formed by reactions of H2L1 with (NBu4)[ReOCl4], have also been synthesized and characterized. The chorido ligand the [ReOCl(L1)] complexes was also replaced by other monodentade ligands. However, changes in the stoichiometry as well as in the reaction conditions may result in different products, so that two units of the monodentate ligand may coordinate, with the second one trans positioned to the oxo group. In addition, oxorhenium(V) complexes of the type \"3+2\" [ReO(L1)(Ph2btu)], where Ph2btu- = N,N-phenyl-N\'-benzoylthiourea, have also been obtained. The antiproliferative effects of the [ReO(X)(L)] system, where X is a monodentade or a bidentate ligand, on breast cancer cells was extensively investigated in in vitro experiments, which showed that the lability of the chlorido ligand plays a key role in the cytotoxic activity. <br />Finally, Re(V) complexes containing the phenylimido core Re(NPh)3+ and H2L1 ligands have been synthesized and fully characterized, including X-ray diffraction analysis. As well, complexes with Tc(NPh)3+ (99Tc isotope) were also prepared and characterized by spectroscopic methods. A comparison of the rhenium and the technetium complexes showed that they present structural analogy. The strong chelate ability of the H2L1 as well as the anticancer properties, indicate their technetium derivatives for future applications as radiopharmaceutical. (AU)

• FAPESP's process: 07/02594-4 - Synthesis and characterization of vanadium, molybdenum, nickel, palladium and platinum complexes with bioactive binders to obtain potential drugs
• Grantee: Pedro Ivo da Silva Maia
• Support Opportunities: Scholarships in Brazil - Doctorate