A series of O-substituted analogues of the B,C-ring truncated scaffold of deguelin were designed as C-terminal inhibitors of heat shock protein 90 (HSP90) and investigated as novel antiproliferative agents against HER2-positive breast cancer. Among the synthesized compounds, compound 80 exhibited significant inhibition in both trastuzumab-sensitive and trastuzumab-resistant breast cancer cells, whereas compound 80 did not show any cytotoxicity in normal cells. Compound 80 markedly downregulated the expression of the major client proteins of HSP90 in both cell types, indicating that the cytotoxicity of 80 in breast cancer cells is attributed to the destabilization and inactivation of HSP90 client proteins and that HSP90 inhibition represents a promising strategy to overcome trastuzumab resistance. A molecular docking study of 80 with the homology model of a HSP90 homodimer showed that 80 fit nicely in the C-terminal domain with a higher electrostatic complementary score than that of ATP.

设计了一系列的deguelin B，C环截短支架的O取代类似物作为热休克蛋白90（HSP90）的C末端抑制剂，并被研究作为针对HER2阳性乳腺癌的新型抗增殖药。在合成的化合物中，化合物80在曲妥珠单抗敏感和曲妥珠单抗耐药的乳腺癌细胞中均表现出显着的抑制作用，而化合物80在正常细胞中未显示任何细胞毒性。化合物80在两种细胞类型中均显着下调了HSP90主要客户蛋白的表达，表明80的细胞毒性乳腺癌细胞中的HSP90归因于HSP90客户蛋白的失稳和失活，并且HSP90的抑制代表了克服曲妥珠单抗的有前途的策略。对80与HSP90同型二聚体的同源性模型进行的分子对接研究表明，80与C末端结构域非常吻合，静电互补得分高于ATP。