Effect Of Structure And Stereochemistry On Cytotoxicity Of Ruthenium Polypyridyl Complexes

Efforts to develop novel non-platinum, metal-based antitumor drugs have been pursued by many groups and ruthenium complexes have drawn a lot of attention as prospective transition metal-based antineoplastic agents. Recently, it was discovered that complex [(phen)2Ru(tatpp)Ru(phen)2]+4 shows biological activity both in vitro and in vivo. Expanding on this area of research, in depth cytotoxicity studies in human lung cancer cells and healthy cells were carried out in five different ruthenium(II) polypyridyl complexes as racemic mixtures and also their enantiopure forms. This study was carried out by performing MTT-cytotoxicity assays on non small cell lung cancer cells (NSCLC), H358 - Human Bronchioalveolar Carcinoma and H226 - Squamous Lung Carcinoma as well as noncancerous/normal cells, HAVSMC - Human Aorta Vascular Smooth Muscle Cells and HUVEC - Human Umbilical Vein Endothelial Cells. The complexes screened in this cytotoxicity assay include [Ru(phen)3]2+, [(phen)2Ru(tpphz)]2+ MZ2+, [(phen)2Ru(tpphz)Ru(phen)2]4+ Z4+, [(phen)2Ru(tatpp)]2+ MP2+ and [(phen)2Ru(tatpp)Ru(phen)2]4+ P4+, where, phen - 1,10-phananthroline, tpphz - tetrapyrido[3,2-a:2'3'-c:3"2"-h:2"3"-j]phenazine and tatpp - 9,11,20,22-tetraazatetrapyrido[3,2-a:2'3'-c:3",2"-l:2"',3"'-n]pentacene.
The study showed some promising results which are listed below. The type of the bridging ligand attached to the metal center played a vital role in determining the potency of the drug, the longer tatpp ligand being more effective. The benefit of working with two metal centers as compared to one center was minimal; MP2+ and P4+ have similar IC50 values. Stereochemistry had a measurable effect on cytotoxicity; the Δ/ΔΔ isomers were approximately twice more potent than the Λ/ΛΛ isomers. The stereochemistry around the dimeric complexes ought to be ΔΔ for it work best, meso complexes (ΔΛ) are equivalent in potency as the ΛΛ isomers. Complexes MP2+ and P4+ showed higher IC50 values in healthy cells and so they have a larger therapeutic window which can be very useful in designing new cancer therapy drugs.