10.1016/j.ejmech.2014.02.051
This research investigates the synthesis and evaluation of arylmethyloxyphenyl derivatives as modulators of the P-glycoprotein (P-gp) pump, a key ATP-binding cassette transporter involved in multidrug resistance in cancer and certain neurological disorders. The study aimed to optimize the activity of lead compounds and understand the structure-activity relationships of these compounds. Various derivatives were synthesized to explore the effects of electron-donor groups, substitutions with electron-withdrawal groups, replacement of certain rings with heteroaromatic cycles, and molecular constriction on P-gp modulating activity. The research concluded that P-gp inhibition potency is strongly correlated with the number of methoxy groups in the A-ring, while methoxylation of the C-ring has a minimal effect. The most potent P-gp ligand identified was compound 10, which displayed nanomolar affinity and selectivity towards P-gp and was inactive against the MRP1 pump. Key chemicals used in the synthesis process included arylmethyloxyphenyl scaffolds, various substituted phenols, and reagents such as KOH, DMSO, and arylmethylchlorides, as well as other specific starting materials and intermediates detailed in the chemistry section of the article.
