Studies on Photocytotoxic Iron(III) and Cobalt(III) Complexes Showing Structure-Activity Relationship

Abstract

Photodynamic therapy(PDT) has recently emerged as a promising new non-invasive treatment modality for a large number of neoplastic and non-neoplastic lesions. Photoexcitation of a photosensitizing drug in the tumor tissue causes generation of reactive oxygen species which results in cell death. The current porphyrinic photosensitizers suffer a wide range of drawbacks leading to the development of the chemistry of alternative photosensitizing agents in PDT. Among them, the 4d and 5d transition metal-based photosensitizers have been explored extensively with the exception of the 3d metal complexes. The objective of this thesis work is to design and synthesize photoactive iron(III) abd cobalt(III) complexes and evalutate their photonuclease and photocytotoxic potential.

Bioessential 3d metal ions provide an excellent platform for metal-based PDT drug designing as because of its varied spectral, magnetic and redox properties, with its complexes possessing rich photochemical behavior in aqueous and non-aqueous media. We have synthesized binary iron(III) complexes as netropsin mimics using amino acid Schiff bases derived from salicylaldehyde/napthaldehyde and arginine/lysine. The complexes were found to be good AT selective DNA binders and exhibited significant DNA photocleavage activity. To enhance the photodynamic potential, we further synthesized iron(III) complexes of phenolate-based ligand and planar phenanthroline bases. The DNA photocleavage activity of these complexes and their photocytotoxic potential in cancer models were studied. ROS generated by these complexes were found to induce apoptotic cell death. Ternary cobalt(III) complexes were synthesized to study the effect of the central metal atom. The diamagnetic cobalt(III) complexes were structurally dissimilar to their iron(III) analogues. Although the Co(III)/Co(II) redox couple is chemically and photochemically accessible but the Co(III)-dppz complex, unlike its iron(III)-dppz analogue, exhibited selective damage to hTSHR expressing cells but not in HeLa cells. A structure-activity relationship study on iron(III) phenolates having modified dppz ligands was carried out and it was found that electron donating group on the phenazine unit and an increase of the aromatic surface area largely improved the PDT efficiency. Finally, SMVT targeted iron(III) complexes with biotin as targeting moiety were synthesized and the in vitro efficacy of the complexes was tested in HepG2 cells over-expressing SMVTs and compared to HeLa amd HEK293 cells. The complexes exhibited higher phytocytotoxicity in HepG2 than in HeLa and cells and HEK293 cells. An endocytotic mode of uptake took place in HepG2 cells whereas in HEK293 cells, uptake is purely by diffusion. This is expected to reduce the side-effects and have less effect on cells with relatively less SMVTs.

In summary, the present research work opens up novel strategies for the design and development of primarily iron-based photosensitizers for their potential applications in PDT with various targeting moieties.