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

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 15.4 µM. 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.

Luminescent iridium(III) dipyrrinato complexes: synthesis, X-ray structures, and DFT and photocytotoxicity studies of glycosylated derivatives.

A series of luminescent Ir(III) dipyrrinato complexes were synthesized having various aromatic chromophores at the C-5 position of dipyrrin ligands. The presence of different chromophores on the Ir(III) dipyrrinato complexes altered their optical properties and produced strong emission in the red to NIR region (680-900 nm) with huge Stokes shifts (5910-7045 cm-1). TD-DFT studies indicated significant charge distribution between dipyrrin ligands and Ir-cyclometalated units in all the molecules. X-ray crystal structures revealed an octahedral geometry of the Ir(III) center in the complex. The in vitro studies of the glycosylated Ir(III) complexes revealed strong photoluminescence with maximum Stokes shifts, and they showed significant photocytotoxicity in skin keratinocyte (HaCaT) and lung adenocarcinoma (A549) cells. The singlet oxygen generation quantum yields of glycosylated Ir(III) complexes were in the range of 70-78% in water. The estimated IC50 values were between 17 and 25 µM after light exposure, and confocal microscopy revealed significant localization of the glycosylated Ir(III) complexes in the endoplasmic reticulum (ER) of cancer cells. The neutral Ir(III) dipyrrinato complexes are promising tracking agents for cellular imaging in the biological window and for photodynamic therapy (PDT) applications.

Systemic review on B-RafV600E mutation as potential therapeutic target for the treatment of cancer.

Cancer is one of the major public catastrophes worldwide and as per WHO, cancer is the leading cause of death universally after CVS disorders accounting for 9.6 million deaths in 2018. WHO statistics revealed five dangerous types of cancer viz. lung, breast, colorectal, prostate and skin. In male, lung cancer causes highest death, while in female, breast cancer causes the most. Alteration in MAPK signalling pathway plays a significant role in majority of cancer cases. Raf protein is activated by phosphorylation via downstream regulation of the MAPK pathway. Raf composed of 3 subtypes, viz. A-Raf, B-Raf, and C-Raf. B-Raf kinase plays a significant role in healthy cell growth in the MAPK pathway and the problem associated with B-Raf mutation leads to the development of cancer and other diseases. The progression of mutant B-Raf (B-RafV600E) protein is higher in cancer as compare to other diseases. In 2002, B-RafV600E mutation was identified for the first time in the development of cancer. The frequency of B-RafV600E mutation is higher in melanoma, thyroid, colorectal and ovarian cancer. We have covered small molecule B-RafV600E inhibitors reported in various literatures; from 2002 to 2020 and also covered clinical trial data. To widen the scope of readers, we compiled details of small molecules, specifically inhibiting B-RafV600E mutant and showing anti-proliferative activity against various cancer cell lines along with in-vivo data. We believe that the information covered here will be important in signifying the potentials of B-RafV600E mutation and its inhibitors as potent anticancer agents.