Platinum(II)-BODIPY Conjugates for Organelle Targeted Photodynamic Therapy in Red Light

Abstract

The serendipitous discovery of Cisplatin (CP, Peyrone's chloride) as an anticancer agent in 1965 by Barnett Rosenberg led to the evolution of other platinum-based anticancer drugs, namely, Carboplatin in 1989 and Oxaliplatin in 2002 [1]. Researchers subsequently have tried to exploit the therapeutic potential of metal complexes for treatment of various diseases. And a chief focus is set to design metal-based therapeutics to circumvent of the drawbacks associated with the conventional platinum-based chemotherapeutic agents. Thus, as an alternative to chemotherapy, Photodynamic Therapy (PDT) has evolved as a new modality where selective killing of cancer cells can be achieved using a red light photosensitiser by generating singlet oxygen. The major challenge is to develop the combined effects of chemotherapeutic potential of platinum and a red light activatable photosensitiser for photodynamic therapeutic effect simultaneously. The fundamental aim of the thesis work is to design organelle targeted photodynamic therapeutic platinum(II) complexes for achieving near infra-red (NIR) light induced cellular apoptosis through singlet oxygen generation in cancer cells. The employment of dyes that have the ability to generate singlet oxygen and fluorescence emission properties concurrently enables to real time tracking of the drug mechanistic action by determining its cellular uptake, localisation inside cells and its drug action. The nuclear DNA being the major target for conventional chemotherapeutic drugs, in recent years researchers have focussed on targeting a specific organelle to increase the efficacy of the anticancer therapeutics [2]. This thesis deals with the design and synthesis of NIR light active platinum(II) complexes as photodynamic therapeutic agents starting with glucose appended platinum(II) BODIPY conjugates, which displayed selective uptake in cancer cells over healthy cells with notable red light induced cytotoxicity by mitochondrial localisation [3]. The morpholine appended dinuclear platinum(II) centred BODIPY complexes were developed for lysosome targeted PDT agent [3]. The morpholine appended mono-styryl BODIPY conjugated platinum(II) complexes were synthesised and studied for the heavy atom effect induced by iodine atoms for lysosome targeted PDT under red light [3]. A platinum(II) complex with two BODIPY units was found to localise in the endoplasmic reticulum of cancer cells and induce ER stress under red light irradiation to cause cytotoxicity. A cisplatin analogue with malonyl chloride derived BODIPY as O,O donor ligand, named as “Maloplatin” was found to display both DNA binding and mitochondria targeted red light induced PDT activity against cancer cells [3]. References: 1. Wang, D.; Lippard, S. J. Nat. Rev. Drug Discov. 2005, 4, 307-320; Kenny, R. G.; Marmion, C. J. Chem. Rev. 2019, 119, 1058-1137. 2. Qiu, K.; Chao, H. et al. Coord. Chem. Rev. 2019, 378, 66-86; Garai, A.; Ramu, V.; Chakravarty, A. R. et al. ACS Omega, 2018, 3, 9333-9338. 3. Ramu, V.; Chakravarty, A. R. et al. Inorg. Chem. 2018, 57, 1717-1726; Inorg. Chem. 2019, 58, 9067-9075; Eur. J. Inorg. Chem. 2021, 9, 831-839; Inorg. Chem. 2021, under revision (ic-2021-00124q).