Phenothiazine-based CaaX competitive inhibitors of human farnesyltransferase bearing a cysteine, methionine, serine or valine moiety as a new family of antitumoral compounds

Diazaphenoxazines and Diazaphenothiazines: Synthesis of the “Correct” Isomers Reveals They Are Highly Reactive Radical-Trapping Antioxidants

“…Phenoxazines and phenothiazines (i.e., 1 and 2 , Figure ) figure prominently in medicinal chemistry, − and their photophysical properties have enabled their use in dye-sensitized solar cells, − organic light emitting diodes, − and as photoredox catalysts . Phenothiazines have also long been known to possess potent antioxidant activity and have been pursued as additives to protect petroleum-derived products, including lubricants, rubber, and fuels from (peroxyl) radical-mediated autoxidation.…”

Pegylation of phenothiazine – A synthetic route towards potent anticancer drugs

“…The investigation of the antitumor activity of various phenothiazine based derivatives demonstrated that the mechanism of their tumour growth inhibition involves the inhibition of farnesyltransferase (FT) enzyme, which plays a key role in the tumour cell proliferation [48] , [49] . More precisely, the inhibition mechanism consists in the binding of thiol units or coordination of Zn 2+ or Mg 2+ sites of FT [50] , [51] . As no specific sites for binding thiol units were present in the structure of the studied PEGylated phenothiazines, their ability to inhibit FT was verified by experiments of complexation with Zn 2+ or Mg 2+ metals (see Supporting Information Figures S5-S11 and explanations therein).…”

Development of Phenothiazine Hybrids with Potential Medicinal Interest: A Review

“…Among the hybrids synthesized, the carboxylic acids were found to have relevant in vitro activity, supporting the notion that the carboxyl group has a higher zinc chelating capacity, acting as a haptophore group. The strongest FTase inhibition was achieved by compounds 16a , 16b , 16c and 16d ( Figure 10 ) [ 36 ]. Docking studies revealed that the phenothiazine derivative 16a should be placed on the same side of the protein active site and is oriented in the same direction of the derivative 16d .…”

“…Quantitative SAR studies show that the phenothiazine skeleton plays an important role in the human farnesyltransferase inhibition. Therefore, FTase inhibitory properties are critically influenced by carboxylic acid locations near zinc atoms of proteins, which is an interaction important for the inhibitory properties of the enzyme [ 36 ].…”