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

Abstract

Novel zinc porphyrins (trans-A2B2 and A3B 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 IC50 values between 6.2 to 15.4M. The trans-A2B2 type zinc porphyrin with two bioisosteric groups gave better cytotoxicity than A3B type. Molecular docking studies revealed excellent binding with mTOR protein kinase of the designed porphyrins. The confocal studies indicated significant ER localization of trans-A2B2 type zinc porphyrin in HeLa cells along with ROS generation.trans-A2B2 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-A2B2 and A3B type zinc porphyrins can be developed as theranostic agents for anti-cancer applications.