Department of Pharmaceutical Chemistry, Faculty of Pharmacy, The British University in Egypt, El-Sherouk, Cairo, Egypt; Center of Drug Research and Development (CDRD), The British University in Egypt, El-Sherouk, Cairo, Egypt.
Center of Drug Research and Development (CDRD), The British University in Egypt, El-Sherouk, Cairo, Egypt; Department of Pharmacology, Faculty of Pharmacy, The British University in Egypt, El-Sherouk, Cairo, Egypt.
Eur J Med Chem. 2019 Mar 15;166:281-290. doi: 10.1016/j.ejmech.2019.01.068. Epub 2019 Jan 30.
Offering novel scaffolds targeting estrogen receptor creates huge necessity to overcome the evolving resistance developed by tumors. Structure-based drug design coupled with ring opening strategy of the steroids skeleton revealed the potential of indole-based analogs to be synthesized targeting the ligand binding domain of estrogen receptor-α. In vitro studies revealed the potential of the total sub-classes of the synthesized analogs to show anti-proliferative activity against estrogen receptor-dependent cancer cell lines at IC ranging from 28.23 to 57.13 μM. This was further validated by evaluating the potential of the synthesized analogs to compete along with estradiol via ER-α ELISA assay to show inhibitory profile at IC ranging from 1.76 to 204.75 nM. Two analogs (YMA-005 and YMA-006) showed significant reduction in tumor size at two dose levels with extensive degeneration and necrosis. Both YMA-005 and YMA-006 showed in-situ reduction of ER-α Immunohistochemical expression at both dose levels. Ultimately, novel analogs of indole-based biomimetic of estrone scaffolds were offered as estrogen receptor-α inhibitors.
提供针对雌激素受体的新型支架，这就产生了巨大的需求，以克服肿瘤产生的耐药性。基于结构的药物设计与甾体骨架的开环策略相结合，揭示了吲哚类类似物具有针对雌激素受体-α配体结合域进行合成的潜力。体外研究表明，所合成的类似物的全部子类具有在 IC 范围内从 28.23 到 57.13 μM 抑制依赖雌激素受体的癌细胞系增殖的潜力。通过评估合成类似物与雌二醇竞争的潜力，通过 ER-α ELISA 测定来显示在 IC 范围内从 1.76 到 204.75 nM 的抑制谱，进一步验证了这一点。两种类似物（YMA-005 和 YMA-006）在两个剂量水平下显示出肿瘤体积的显著减少，同时伴有广泛的退化和坏死。YMA-005 和 YMA-006 均在两个剂量水平下表现出 ER-α 免疫组织化学表达的原位减少。最终，提供了基于吲哚的雌酮支架的新型类似物作为雌激素受体-α抑制剂。
