Tin(II) and Tin(IV) Complexes Incorporating the Oxygen Tripodal Ligands [(η5-C5R5)Co{P(OEt)2O}3]−, (R = H, Me; Et = -C2H5) as Potent Inflammatory Mediator Inhibitors: Cytotoxic Properties and Biological Activities against the Platelet-Activating Factor (PAF) and Thrombin

Abstract

Metal complexes displaying antiplatelet properties is a promising research area. In our methodology, Platelet-Activating Factor (PAF), the most potent lipid pro-inflammatory mediator, serves as a biological probe. The antiplatelet activity is exerted by the inhibition of the PAF-induced aggregation in washed rabbit platelets (WRPs) and in rabbit plasma rich in platelets (rPRPs). Herein, the synthesis and biological investigation of a series of organometallic tin(II) and tin(IV) complexes, featuring the oxygen tripodal Kläui ligands [(η5-C5R5)Co{P(OEt)2O}3]−, {R = H, (LOEt−); Me (L*OEt−)}, are reported. Reaction of NaLOEt (1a) and NaL*OEt (1b) with SnCl2, yielded the rare four-coordinate LOEtSnCl (2a) and L*OEtSnCl (2b) complexes. Accordingly, LOEtSnPh3 (3a) and L*OEtSnPh3 (3b) were prepared, starting from Ph3SnCl. Characterization includes spectroscopy and X-ray diffraction studies for 2a, 2b and 3b. The antiplatelet activity of the lead complexes 2b and 3a (IC50 = 0.5 μΜ) is superior compared to that of 1a and 1b, while both complexes display a pronounced inhibitory activity against thrombin (IC50 = 1.8 μM and 0.6 μM). The in vitro cytotoxic activities of 3a and 2b on human Jurkat T lymphoblastic tumor cell line is higher than that of cisplatin.

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

“…These findings are in accord with the well-established general trend known as the synergetic effect, indicating that coordination of the ligand precursor to a metal center, results in an increase in the antiplatelet activity of the relevant compound [28]. As recently demonstrated [32], this trend can be clearly attributed to the overall structure of the obtained complexes, signifying that an efficient combination of the ligand and metal precursors, providing the target molecule, is the key component for increased activity against the PAFR.…”

“…Complementary, the size of the target molecule (relevant metal-based inhibitors) seems to affect, the biological activity expressed. Our findings based on theoretical docking calculations propose that the less bulky inhibitor that fits well within the binding site of the PAF receptor is more potent as opposed to the bulkier one, which could bind to the extracellular domain of the receptor, antagonizing the substrate's entrance to PAFR [25,32]. Accordingly, within the series of the complexes studied, we can propose that the Mn(II) complex 5 is the bulkiest, rendering it less effective against the PAF-induced aggregation (IC 50 = 39 µM), a result which is in favor of the preliminary structure-activity relationship established [32].…”

“…Our findings based on theoretical docking calculations propose that the less bulky inhibitor that fits well within the binding site of the PAF receptor is more potent as opposed to the bulkier one, which could bind to the extracellular domain of the receptor, antagonizing the substrate's entrance to PAFR [25,32]. Accordingly, within the series of the complexes studied, we can propose that the Mn(II) complex 5 is the bulkiest, rendering it less effective against the PAF-induced aggregation (IC 50 = 39 µM), a result which is in favor of the preliminary structure-activity relationship established [32]. This also corroborates with previously reported results [17,25], as for example the square-planar rhodium(I) complex [Rh(cod)(pqx)]Cl (less bulky) that exhibits a considerably increased anti-PAF activity (IC 50 = 15 nM), compared to the bulkier, octahedral rhodium(III) complex mer-[Rh(pqx)Cl 3 (MeOH)] (IC 50 = 0.125 µM)].…”

“…Following the strategy reported above, several coordination compounds and organometallic complexes have been investigated in our group, while preliminary structure-activity relationships have been established [17]. Existing complexes expand from rhodium [25][26][27][28] and iridium [29], to ruthenium [30,31] and tin-based inhibitors, with inhibitory effects of the PAF-induced aggregation in WRPs [32], in the nanomolar and sub-micromolar range. It would be very useful to mention here, that the term "metal-based inflammatory mediators" has been recently coined in the literature [33], indicating our contributions in the field.…”

Anti-Inflammatory and Antithrombotic Potential of Metal-Based Complexes and Porphyrins

“…In this respect, a series of chromium(III), manganese(II), iron(II), cobalt(II), nickel(II), copper(II), zinc(II), ruthenium(II) and (III), rhodium(I) and (III), and recently tin(II) and (IV) have been synthesized and structurally characterized and have shown strong anti-inflammatory and antithrombotic properties against the PAF-related pathways and other thrombo-inflammatory pathways, such as those related to thrombin, collagen and ADP [13,[16][17][18][19]. The ability of such metal-based compounds to inhibit platelet activation and aggregation by affecting each or more of these thrombo-inflammatory pathways, through specific structure-activity relationships related to their inhibitory binding on the specific receptors of either platelet agonists and/or thrombo-inflammatory mediators, further indicates that these bioactive metal-based antiplatelet compounds can serve as inhibitors of the inflammatory processes induced by such agonists in several other cell types and tissues that express these receptors on their membranes, including leucocytes, endothelial cells, mesangial cells, neural cells, etc.…”