The serendipitous discovery of Cisplatin in 1965 by Barnett Rosenberg and its FDA approval led to the evolution of metal-based anticancer drugs in cancer treatment [1]. The decisive facts regarding the mechanism of cisplatin had revealed that the drug struggles to perform efficiently due to three main reasons: (a) increased efflux or lesser uptake of cisplatin leads to deduction in its cellular accumulation; (b) inactivity of the drug by thiols present inside the cell; (c) broad nuclear DNA mechanisms specifically nucleotide excision repair (NER) which restore the Pt-DNA adducts. A new development is the use of photo-luminescent compounds giving low IC50 values and high therapeutic index values along with the display of emission band thus making them suitable for cellular imaging and causing cellular damage. Contemporarily, the organelle targeting compounds have emerged out as alternatives for better efficacy of the metal-based drugs as anticancer agents [2].
The cationic monofunctional complexes specially imidazoplatin, pyriplatin, and phenanthriplatin exhibit dynamic cytotoxicity by restoring resistant Pt-DNA mono adducts which stall RNA polymerase II. The imidazoplatin and pyriplatin analogs conjugated to boron-dipyrromethene (BODIPY) are developed for targeting the mitochondrial DNA [3,4]. The nuclear excision repair (NER) mechanism which operates for nuclear DNA is absent for mitochondrial DNA. The DNA crosslinking properties of these monofunctional complexes with 9-ethylguanine as a model nucleobase suggested the formation of Pt-DNA adducts from 1H NMR and mass spectral studies. The results revealed that a combination of PDT with DNA cross-linking property augmented the anticancer potential of these mono-functional BODIPY conjugates by showing cells through in vitro and in vivo studies suggest that mitochondria is favourable for drug-resistant cancer therapy application by means of chemotherapeutic and PDT dual activity.
References:
1. (a) Wang, D.; Lippard, S.  J. Nat. Rev. Drug Discov. 2005, 4, 307-320. (b) Raza, M. K.; Mitra, K.; Shettar, A.; Basu, U.; Kondaiah, P.; and Chakravarty, A. R., Dalton Trans. 2016, 45, 13234-13243.
2. (a) Garai; A.; Gandhi, A.; Ramu, V.; Raza, M. K.; Kondaiah, P.; and Chakravarty, A. R. ACS Omega, 2018, 3, 9333-9338. (b) Bhattacharyya, U.; Verma, B.; Saha, R.; Mukherjee, N.; Raza, M. K.; Sahoo, S.; Kondaiah, P.; and Chakravarty, A. R. ACS Omega, 2020, 5, 4282-4292. (c) Pandey, V.; Raza, M. K.; Joshi, P.; and Gupta, I. J. Org. Chem. 2020, 85, 6309-6322.
3. Raza, M. K.; Gautam, S.; Garai; A.; Mitra, K.; Kondaiah, P.; and Chakravarty, A. R. Inorg. Chem. 2017, 56, 11019-11029.
4. Raza, M. K.; Gautam, S.; Howlader, P.; Bhattacharyya, A.; Kondaiah, P.; and Chakravarty, A. R. Inorg. Chem., 2018, 57, 14374-14385.

Mitochondria-targeting Pt(II) Complexes in Photodynamic Therapy

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