Investigation of organopalladium indenyl, butadienyl and imidoyl complexes: synthesis and anticancer properties

The discovery of cisplatin paved the way for the investigation of metallodrugs for chemotherapy applications. The goal of researchers is the design of water-soluble molecules which are able to exhibit their activity with reduced side-effects. Therefore, the aim of this project is the development of new organopalladium compounds form the synthesis to their anticancer properties, in collaboration with Università degli Studi di Ferrara, KAUS Arabia Saudita, CRO Aviano, PLS-Chimie Paris Tech, Elettra Sincrotrone. We investigated three new organometallic fragments: Pd(II)-indenyl, Pd(II)-butadienyl and Pd(II)-imidoyl. We chose to test all compounds on ovarian cancer cells: cisplatin sensitive and resistant celle lines, to and High Grade Serous Ovarian Cancer cell lines, which are classified as aggressive forms. Palladium butadienyl complexes were also tested on a triple breast cancer cell line. In the following paragraph an overview of the project will be presented, divided for compounds classes. 1) Cationic Palladium Indenyl complexes bearing phosphines, isocyanides and N-heterocyclic carbene ligands (NHC). The panel of cationic complexes [Pd(PR3)2(Ind)]ClO4, [Pd(NHC)(PR3)(Ind)]ClO4, [Pd(CNR’)(PR3)(Ind)]ClO4, [Pd(NHC-CH2Py)(Ind)]A, [Pd(NHC^NHC)(Ind)]ClO4 and [Pd(NHC)2(Ind)]A were synthesized by the protocols developed by prof. Visentin group. The most promising compound [Pd(NHC-CH2Pyr)(Ind)]A has been deeply investigated on a wide panels of HGCOC cell lines and on ovarian tumoroids deriving from real patients. The uptake test determined that the selectivity towards cancer cells starts immediately after the administration. Immunofluorescence techniques and caspases activation assays have been revealed that [Pd(NHC-CH2Pyr)(Ind)]A and [Pd(NHC^NHC)(Ind)]ClO4 firstly damage DNA, the biscarbene class [Pd(NHC)2(Ind)]A achieves mithocondria. 2) Palladium butadienyl complexes DPPF with different halides. The synthesis has been developed starting from the precursor with tioquinoline ligand, which can be easily exchanged with the chelate phosphine ligand DPPF. The complexes were tested in vitro during the period abroad in Paris. 3) Palladium imidoyl complexes bearing phosphines as ancillary ligands. The imidoyl organometallic fragment was obtained by the insertion of the isocyanide (DIC and TOSMIC) in Pd-Me or Pd-tolyl bond. A panel of trans-PTA, trans-DAPTA and DPPF chelate compounds was obtained employing two different precursors in the exchange of ligands reactions. The complexes were tested in vitro and Annexin V test has been done to understand the trigger role of these compounds for apoptotic pathways. For each class we are able to determine the most promising compounds. More in detail, palladium indenyl complexes bearing NHC ligands and the palladium butadienyl compound featured by the presence of two chloride atoms showed great activity and selectivity toward cancer cells. Concerning palladium imidoyl complexes, the presence of iodide atom seems to influence the selectivity. Moreover, a particular combination of a palladium imidoyl fragment with PTA phosphine induces apoptosis. Finally, the combination of the steric hindrance of the imidoyl ligand and the nature of the phosphine, influences the activity and selectivity trend.