title: Synthesis, biochemical evaluation and molecular modeling studies of novel rhodium complexes with nanomolar activity against Platelet Activating Factor.
abstract: Two square planar Rh(I) organometallic complexes namely [Rh(L(1))(cod)]Cl (cod = cycloocta-1,5-diene, L(1)=2,2'-pyridylquinoxaline (1-Cl), [Rh(L1)(cod)](NO3) (1-NO(3)) and a series of novel octahedral rhodium(III) complexes of the general formulae mer-[Rh(L(1))Cl(3)(MeOH)] (2) and cis-[Rh(L(2))(2)Cl(2)]Cl (L(2)=4 carboxy 2 (2' pyridyl)quinoline (3), L(3)=2,2' bipyridine 4,4' dicarboxylic acid (4) were synthesized and characterized spectroscopically. All the synthesized compounds including the previously prepared cis-[Rh(L(1))(2)Cl(2)]Cl complex (5) were biologically evaluated as potential inhibitors of the Platelet Activation Factor (PAF) and thrombin induced aggregation. In particular compounds 1-Cl and 1-NO(3) were found to be strong inhibitors of PAF with IC(50) values in the range of 16 nM and 15 nM rendering them good candidates for further investigation. Their potency is comparable to that of the widely used PAF receptor antagonists WEB2170, BN52021, and Rupatadine (IC(50) of 20, 30 and 260 nM respectively). Molecular docking calculations suggest that 1-Cl, 1-NO3 and 2 can be accommodated within the ligand-binding site of PAF receptor and block the activity of PAF. On the other hand, the octahedral rhodium(III) complexes 3-5 that cannot fit the ligand-binding domain, could potentially exhibit their activity at the extracellular domain of the receptor.
authors: Laboratory of Biochemistry, Faculty of Chemistry, National and Kapodistrian University of Athens, Athens 15771, Greece.
authors: Alexandros B
authors: AB
authors: Tsoupras
authors: Athanasios
authors: A
authors: Papakyriakou
authors: Constantinos A
authors: CA
authors: Demopoulos
authors: Athanassios I
authors: AI
authors: Philippopoulos
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D012238:Rhodium / Q000737:chemistry; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology
chemical_list: D001381:Azepines; D009942:Organometallic Compounds; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D014230:Triazoles; C063964:bepafant; D012238:Rhodium; D013917:Thrombin