Studies on BODIPY-conjugates of Copper and Zinc for Cellular Imaging and Photodynamic Therapy

Abstract

Cancer is a dreadful disease that occurs due to the uncontrolled division of abnormal cells. Though there are different therapeutic modalities available for cancer, chemotherapy is considered as the most practiced method. It is also well established that the transition metal-based chemotherapeutic agents provide several medicinal benefits in comparison to the purely organic counterparts. However, the efficacy of metal-based anticancer agents, especially the commercial platinum-based drugs is greatly reduced due to the dose-limiting toxicity and associated adverse effects. Shifting to photodynamic therapeutic treatment modality (PDT) may provide better spatio-temporal control on drug action but the clinically approved porphyrinic photosensitizers also show limited success owing to their hydrophobic nature and aggregation-induced photobiological deactivation-related issues under physiological conditions. Though Photofrin®, the FDA approved PDT drug, is found to be useful against a vast group of cancers, it suffers from additional drawbacks like skin photosensitivity and hepatotoxicity. It has been documented that the insertion of selective transition metals inside the porphyrinic core could result significant improvement in their photophysical and photobiological activities but even with the development of metallo-porphyrins, the challenges regarding the hydrophobic and aggregative-nature of these macrocyclic photosensitizers could not be addressed successfully. One possible way is the introduction of non-porphyrinic photosenstizers that should contain only the positive attributes of porphyrin or phthalocyanine-based classical PDT agents. BODIPY or boron-dipyrromethene-based dyes have recently emerged as the preferred alternatives, which are also known as ‘half of porphyrin’ or ‘porphyrin’s little sisters’ due to their close structural proximity with porphyrin unit. However, despite several promises, quite surprisingly, none of the BODIPY-based molecules have received clinical approval yet for the treatment of PDT. The limited success of BODIPY-based photosensitizers in clinical level could be attributed to their aqueous insolubility and limited physiological stability leading to poor pharmacokinetic behaviour under physiological conditions, especially applicable for the heavy atom (I, Br)-tethered BODIPY-based photosensitizers. Present thesis focuses to address these challenges alongside establishing the virtually unexplored chemistry of metallo-BODIPY conjugates as PDT photosensitizers. With the objective to explore the medicinal aspects of BODIPY dyes as the cellular imaging and photosensitizing unit inserted within the ligand system of transition metal complexes, we selected copper and zinc as our preferred choices since these cost-effective metals are essential for our survival and their usage can also circumvent the problem related with heavy-metal toxicity. Current work thus focuses on the design, synthesis, physicochemical and photobiological aspects of multiple Cu(II)-BODIPY and Zn(II)-BODIPY conjugates and evaluates their suitability as next-generation replacements of existing metallo-porphyrinoids as PDT agents, both from the therapeutic as well as diagnostic point of view. Taking the advantage of variable coordination number of copper and zinc and the flexible coordination geometry of Cu and Zn-based complexes, mixed ligand metallo-BODIPY conjugates are also developed to achieve additional benefits such as drug selectivity, intracellular organelle targeting, modulation of metal-centered redox activity and regulation in dark toxicity, simultaneous activation of multiple photodynamic pathways and augmented imaging-cum-photosensitizing activities. References: A. Bhattacharyya and A. R. Chakravarty et al., Med. Chem. Commun., 2015, 6, 846-851; RSC Adv., 2016, 6, 104474-104482; Dalton Trans., 2018, 47, 5019-5030; Dalton Trans., 2021, 50, 103-115; Eur. J. Med. Chem., 2021, 220, 113438.