Studies on BODIPY Appended Ruthenium(II) Complexes for Bioimaging and Photodynamic Therapy Applications

Abstract

Photodynamic therapy (PDT) is a medical technique that utilizes light, oxygen, and a photosensitizer to treat several medical conditions, including cancer. Because of the limitations and side effects of traditional anticancer therapies like surgery, chemotherapy, and radiation therapy, PDT has been recognized as an adjuvant and, in some cases, a mainstream alternative. Currently, clinical PDT utilizes tetrapyrrolic photosensitizers that possess several drawbacks. Even worldwide approved gold standard photosensitizer Photofrin® requires a high dose for the therapeutic effect that results in undesirable side effects like skin sensitivity and hepatotoxicity. In recent years, transition metal complexes are gaining interest as new photosensitizers with their fine-tuned photophysical and biological properties. This thesis work presents the results from a systematic study on the design and synthesis of new boron-dipyrromethene (BODIPY) appended ruthenium(II)complexes to study their photoinduced reactive oxygen species (ROS) generation ability, light-induced cytotoxicity and cellular imaging ability. Here, a wide range of ruthenium coordination units are connected to BODIPY chromophore with various linkers, and their effect on photophysical and photobiological properties investigated. New ruthenium(II) complexes with formulations [Ru(L1/2)(L3/4)Cl]Cl where L1, L2 (having biotin) are NN-donor bidentate phenanthroline derivatives and L3, L4 (contain BODIPY) are NNN-donor tridentate dipicolylamine derivative, were synthesized, characterized and their photocytotoxicity evaluated. The complex having both BODIPY and cancer targeting biotin showed cancer cells elective PDT effect giving respective IC50 value of 0.98±0.04 and 3.9±0.4 μM in A549 (lung cancer) and HPL1D (noncancerous) cell lines in visible light of 400-700 nm, while being non-toxic in the dark. Analogous complexes containing di-styryl BODIPY were prepared and their PDT activity with redlight activation was evaluated. The active complex produced a remarkable photocytotoxicity index (PI, ratio of IC50 in dark and with light exposure) of >5000 with red light (600- 720 nm) activation. Next, a series of bichromophoric systems having a heteroleptic [Ru(tpy)2] (tpy = terpyridine) moiety covalently linked to a BODIPY pendant were prepared, characterized and their photophysical and photobiological properties were evaluated. In a following study, a series of biotin-conjugated compounds containing BODIPY or Ru(II)-bis-tpy or both chromophoric units were developed and the difference of multichromophoric Ru-BODIPY conjugates with structurally similar compounds having a single chromophore were investigated highlighting the importance of constructing such bichromophoric systems. These bichromophoric systems produced both superoxide and singlet oxygen via dual type-I/II photosensitization processes and exerted potent apoptotic PDT effect with visible light activation. Finally, two homoleptic complexes with formulation [Ru(tpy-BODIPY)2]Cl2,where the connection between the BODIPY unit and the Ru(II)-bis-tpy scaffold differs by a phenylacetylene spacer, were prepared as PDT agents with simple molecular design and the effect of the spacer was studied in terms of structure-activity relationship. In summary, this thesis work presents systematic developments of Ru(II)-BODIPY conjugates as novel photosensitizers and photodetection agents for phototherapeutic applications.