Synthesis of novel zinc porphyrins with bioisosteric replacement of Sorafenib: Efficient theranostic agents for anti-cancer application

Novel zinc porphyrins (trans-A<inf>2</inf>B<inf>2</inf> and A<inf>3</inf>B type) are reported containing pharmacophoric groups derived from Sorafenib at the meso-positions. The pharmacophoric and bioisosteric modification of Sorafenib was done with 2-methyl-4-nitro-N-phenylaniline. The in-vitro photo-cytotoxicity studies of zinc porphyrins on HeLa cells revealed excellent PDT based autophagy inhibition of cancer cells, with IC<inf>50</inf> values between 6.2 to 15.4 μM. The trans-A<inf>2</inf>B<inf>2</inf> type zinc porphyrin with two bioisosteric groups gave better cytotoxicity than A<inf>3</inf>B type. Molecular docking studies revealed excellent binding with mTOR protein kinase of the designed porphyrins. The confocal studies indicated significant ER localization of trans-A<inf>2</inf>B<inf>2</inf> type zinc porphyrin in HeLa cells along with ROS generation. trans-A<inf>2</inf>B<inf>2</inf> type zinc porphyrin induced ER stress in cancer cells, thereby causing elevation of Ca⁺² ions in cytoplasm, which led to cancer cell death via autophagy pathway. The studies suggested that trans-A<inf>2</inf>B<inf>2</inf> and A<inf>3</inf>B type zinc porphyrins can be developed as theranostic agents for anti-cancer applications.