Estrogen is a significant factor in the maintenance and progression of hormone-dependent breast cancer. As well known, aromatase mediates the production of estrogen. Thus, inhibition of aromatase with chemical molecules has been considered to be an effective treatment for estrogen receptor-positive (ER+) breast cancer. In this work, we designed and synthesized a series of novel non-steroidal molecules containing 2-phenylindole scaffold and moiety of either imidazole or 1,2,4-triazole to enhance their binding capacity with the aromatase. Among these molecules, a compound named as 8o was confirmed experimentally to have the highest inhibitory activity to aromatase. Further cell activity assay proved that compound 8o has low cytotoxicity and is a promising lead for developing novel aromatase inhibitors. Molecular modeling and simulation techniques were performed to identify the binding modes of letrozole and 8o with the aromatase. Analysis of energy of the two compound-aromatase complexes revealed that the 8o has low binding energy (strong binding affinity) to the aromatase as compared to letrozole, which was in accordance with the experimental results. As concluded, a combination of experimental and computational approaches facilitates us to understand the molecular mechanism of inhibitory action and discover more potent non-steroidal AIs against aromatase, thereby opening up a novel therapeutic strategy for hormone-dependent breast cancer.

雌激素是激素依赖性乳腺癌的维持和发展的重要因素。众所周知，芳香酶介导雌激素的产生。因此，用化学分子抑制芳香酶被认为是雌激素受体阳性（ER +）乳腺癌的有效治疗方法。在这项工作中，我们设计和合成了一系列新型的非甾体分子，它们包含2-苯基吲哚骨架和咪唑或1,2,4-三唑部分，以增强它们与芳香酶的结合能力。在这些分子中，实验证实了一种名为8o的化合物对芳香化酶具有最高的抑制活性。进一步的细胞活性分析证明了化合物8o具有低细胞毒性，是开发新型芳香化酶抑制剂的有希望的先导。进行分子建模和模拟技术以鉴定来曲唑和8o与芳香化酶的结合模式。两种化合物-芳香化酶复合物的能量分析表明，与来曲唑相比，8o与芳香酶的结合能低（强结合亲和力），这与实验结果一致。综上所述，实验方法和计算方法的组合有助于我们理解抑制作用的分子机制，并发现针对芳香化酶的更有效的非甾体类AI，从而为激素依赖性乳腺癌开辟了新的治疗策略。