Medicinal Chemistry

Synthesis of Novel Palladacycles Inhibitors of the Cathepsin B Activity and Antitumoral Agents

Abstract

Abdel-Sattar S Hamad Elgazwy, Mohamed R Shehata, Myssoune Y Zaki, Dalia H S Solima and Marwa M Elbakkry

The reaction of 2-bromo-3,4,5-trimethoxybenzaldehyde 1 with Pd(dba) 2 ; dba=dibenzylideneacetone) in the presence of a stoichiometric amount of nitrogen donor ligands, such as N,N,N’,N’ -tetramethyl-ethane-1,2-diamine (TMEDA), 2,2’-bipyridine (bpy) 4,4’-dimethyl-2,2’-bipyridine (dmbpy) and an 1,10-phenanthroline (Phen), should be added to with equimolar ratio in degassed acetoneunder nitrogen to give mononuclear σ-aryl palladium (II) complexes cis-[2- Pd{C 6 H(CHO)-6-(OMe) 3 -3,4,5}BrL 2 ] 3a-d, where L 2 =TMEDA (3a); L 2 =bpy (3b); L 2 =dmbpy (3c); L 2 =Phen (3d) in good yields 48-65%. The reaction of the synthesized five-membered C,N -palladacycle cis-[2-Pd{C 6 H(CHO)-6-(OMe) 3 -3,4,5} BrL 2 ] 3a-d, where L 2 =TMEDA (3a); L=bpy (3b); L 2 =dmbpy (3c); L 2 =Phen (3d), with an1-naphthylisocyanates (C 10 H 7 - NCO) and an 1-naphthylisothiocyanates (C 10 H 7 -NCS), leads to the formation of novel palladacycle 4a-d and 5a-d, which was characterized in solution by 1 H NMR spectroscopy. The solid products were characterized by satisfactory elemental analysis and spectra studies. All the resulting complexes 3a-d, 4a-d and 5a-d were tested in vitro against a number of cell lines. For example, it inhibited K562 leukaemia cells with an IC 50 value in the range of (3.00 -4.3) μM (1 h exposure) and displayed cathepsin B inhibitory action with an IC 50 value in the range of (0.045-0.055 μM)