Breast cancer is the most frequently diagnosed cancers and the leading causes of cancer death among females worldwide. Estrogen receptor positive has been identified as the predominant internal reasons, involving in more than 70% breast cancer patients and SERMs which competes with estradiol for the binding to ERα in breast tissue are widely used in the treatment of ER+ breast cancer, such as tamoxifen, raloxifene. However, many SERMs may cause negative side effects due to their estrogenic activity in other tissues and approximate 50% of patients with ER-positive tumors either initially do not respond or become resistant to these drugs. Here, a series of designed 4,6-diaryl-2-pyrimidinamine derivatives had been synthesized to treat estrogen receptor positive breast cancer by simultaneously antagonizing ER and inhibiting VEGFR-2. Bioactivity evaluation showed that these compounds could significantly inhibit the proliferation of MCF-7, HUVEC and Ishikawa cells. Further studies identified compound III-3A could antagonize against estrogen action and inhibit the phosphorylation of VEGFR-2 as well as inhibit angiogenesis in vivo. The results indicated designed 4,6-diaryl-2-pyrimidinamine derivatives can be used to further study as anti-breast cancer drugs.

乳腺癌是全世界女性中最常被诊断出的癌症，也是导致癌症死亡的主要原因。雌激素受体阳性已被确定为主要原因，涉及70％以上的乳腺癌患者，SERM与雌二醇竞争与乳腺组织中ERα的结合，被广泛用于治疗ER +乳腺癌，例如他莫昔芬，雷洛昔芬。但是，许多SERM可能由于其在其他组织中的雌激素活性而引起负面副作用，大约50％的ER阳性肿瘤患者最初对这些药物没有反应或变得耐药。在这里，已经合成了一系列设计的4,6-二芳基-2-嘧啶胺衍生物，通过同时拮抗ER和抑制VEGFR-2来治疗雌激素受体阳性乳腺癌。生物活性评估表明，这些化合物可显着抑制MCF-7，HUVEC和Ishikawa细胞的增殖。进一步研究确定了化合物III-3A可以拮抗雌激素作用，并抑制VEGFR-2的磷酸化并抑制体内血管生成。结果表明设计的4,6-二芳基-2-嘧啶胺衍生物可作为抗乳腺癌药物用于进一步研究。