Novel phenolic biheteroaryls as bioactive molecules

雌激素与雌激素受体(ER)的结合启动了一系列分子事件，导致不同身体部位的作用不同。这些过程的刺激无疑对健康有各种好处，但刺激某些组织，如乳房和子宫，会增加这些部位患癌症的风险。天然雌激素中存在的酚羟基在与ER结合中起着关键作用。雌激素还可以作为活性氧的清除剂，从而通过其酚羟基部分对包括心血管疾病和神经退行性疾病在内的退行性疾病表现出保护作用。最近的文献表明，酚类中的N取代C可以用来调节酚羟基的反应活性。基于这一假设，这一提议的总体目标是贡献知识，以更好地理解配体与内质网之间使用新型吡啶和嘧啶类探针进行化学相互作用的基本机制。这些杂芳环上带有羟基的分子有望具有与已知的植物雌激素(如白藜芦醇、栎素和姜黄素)和合成的非甾体选择性雌激素受体调节剂(如他莫昔芬、雷洛昔芬等)显著不同的物理化学性质。将对合成的分子的一些物理化学性质、ER结合亲和力和对肿瘤细胞的细胞毒性潜力进行评估。

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.