Synthesis, biochemical evaluation and molecular modeling studies of novel rhodium complexes with nanomolar activity against Platelet Activating Factor

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-NO3) 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-NO3 were found to be strong inhibitors of PAP with IC50 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 (IC50 3 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 PAP receptor and block the activity of PAP. 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. (C) 2012 Elsevier Inc. All rights reserved.