Liu Linyi, Tang Zhichao, Wu Chengze, Li Xinyu, Huang Ali, Lu Xiang, You Qidong, Xiang Hua
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
Bioorg Med Chem Lett. 2018 Apr 1;28(6):1138-1142. doi: 10.1016/j.bmcl.2017.12.066. Epub 2017 Dec 30.
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.
乳腺癌是全球女性中最常被诊断出的癌症，也是癌症死亡的主要原因。雌激素受体阳性已被确定为主要的内在原因，超过70%的乳腺癌患者与之相关，而在乳腺组织中与雌二醇竞争结合ERα的选择性雌激素受体调节剂（SERM）被广泛用于治疗雌激素受体阳性（ER+）乳腺癌，如他莫昔芬、雷洛昔芬。然而，许多SERM由于其在其他组织中的雌激素活性可能会引起负面副作用，并且约50%的ER阳性肿瘤患者最初要么对这些药物无反应，要么会产生耐药性。在此，通过同时拮抗雌激素受体（ER）和抑制血管内皮生长因子受体-2（VEGFR-2），合成了一系列设计的4,6-二芳基-2-嘧啶胺衍生物以治疗雌激素受体阳性乳腺癌。生物活性评估表明，这些化合物可显著抑制MCF-7、人脐静脉内皮细胞（HUVEC）和石川细胞的增殖。进一步研究确定化合物III-3A可拮抗雌激素作用，抑制VEGFR-2的磷酸化，并在体内抑制血管生成。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进一步研究。
