First-Row Transition Metal Complexes Incorporating the 2-(2'-pyridyl)quinoxaline Ligand (pqx), as Potent Inflammatory Mediators: Cytotoxic Properties and Biological Activities against the Platelet-Activating Factor (PAF) and Thrombin.

Inflammatory mediators constitute a recently coined term in the field of metal-based complexes with antiplatelet activities. Our strategy targets Platelet-Activating Factor (PAF) and its receptor, which is the most potent lipid mediator of inflammation. Thus, the antiplatelet (anti-PAF) potency of any substance could be exerted by inhibiting the PAF-induced aggregation in washed rabbit platelets (WRPs), which internationally is a well-accepted methodology. Herein, a series of mononuclear ( mer -[Cr(pqx)Cl 3 (H 2 O]) ( 1 ), [Co(pqx)Cl 2 (DMF)] ( 2 ) (DMF = N , N '-dimethyl formamide), [Cu(pqx)Cl 2 (DMSO)] ( 3 ) (DMSO = dimethyl sulfoxide), [Zn(pqx)Cl 2 ] ( 4 )) and dinuclear complexes ([Mn(pqx)(H 2 O) 2 Cl 2 ] 2 ( 5 ), [Fe(pqx)Cl 2 ] 2 ( 6 ) and [Ni(pqx)Cl 2 ] 2 ( 7 )) incorporating the 2-(2'-pyridyl)quinoxaline ligand (pqx), were biologically evaluated as inhibitors of the PAF- and thrombin-induced aggregation in washed rabbit platelets (WRPs). The molecular structure of the five-co-ordinate analog ( 3 ) has been elucidated by single-crystal X-ray diffraction revealing a trigonal bipyramidal geometry. All complexes are potent inhibitors of the PAF-induced aggregation in WRPs in the micromolar range. Complex ( 6 ) displayed a remarkable in vitro dual inhibition against PAF and thrombin, with IC 50 values of 1.79 μM and 0.46 μM, respectively. Within the series, complex ( 5 ) was less effective (IC 50 = 39 μM) while complex ( 1 ) was almost 12-fold more potent against PAF, as opposed to thrombin-induced aggregation. The biological behavior of complexes 1 , 6 and 7 on PAF's basic metabolic enzymatic pathways reveals that they affect key biosynthetic and catabolic enzymes of PAF underlying the anti-inflammatory properties of the relevant complexes. The in vitro cytotoxic activities of all complexes in HEK293T (human embryonic kidney cells) and HeLa cells (cervical cancer cells) are described via the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The results reveal that complex 3 is the most potent within the series.