Grant: Discovery Grants Program - Individual

Estrogen binding to the Estrogen Receptors (ERs) initiates a series of molecular events leading to effects that vary from one body part to another. The stimulation of these processes undoubtedly has various health benefits, but stimulation of certain tissues such as breast and uterus increases the risk of cancer at these sites. The phenolic hydroxyl moieties present in natural estrogens play a key role in binding with ERs. The estrogens also serve as scavengers of reactive oxygen species thereby exhibiting protective roles against degenerative diseases including cardiovascular disease and neurodegenerative disease by virtue of their phenolic hydroxyl moiety. Recent literature suggests that the substitution of an N for a C in phenols can be used to modulate the reactivity of the phenolic hydroxyls. Based on this hypothesis, the overall goal of this proposal is to contribute knowledge towards a better understanding of the fundamental mechanism underlying the chemical interaction between ligands and ERs using novel pyridine and pyrimidine based probes. These molecules bearing hydroxyl groups on the heteroaromatic rings are expected to possess significantly different physicochemical properties than known phytoestrogens (such as resveratrol, quercetin and curcumin) and synthetic non-steroidal selective estrogen receptor modulators (such as tamoxifen, raloxifene etc). The synthesized molecules will be evaluated for some of their physicochemical properties, ER-binding affinities, and cytotoxicity potentials against tumour cells. The proposed program places special emphases on the training of highly qualified personnel, organic synthesis, and property determination. The outcome of these studies will be extremely valuable for understanding the basic chemistry of ER receptor binding and will have direct impact on the development of therapeutic agents for the treatment/prevention of degenerative diseases such as cancer and cardiovascular and neurodegenerative diseases.