Abstract：
Small molecule drugs sourced from natural products are pivotal for novel therapeutic discoveries. However, their clinical deployment is often impeded by non-specific activity and severe adverse effects. This study focused on 3-fluoro-10-hydroxy-Evodiamine (F-OH-Evo), a potent derivative of Evodiamine, whose development is curtailed due to suboptimal tumor selectivity and heightened cytotoxicity. By harnessing the remarkable stability, specificity, and αvβ3 integrin affinity of c(RGDFK), a novel prodrug by conjugating F-OH-Evo with cRGD was synthesized. This innovative prodrug substantially enhanced the tumor-specific targeting of F-OH-Evo and improved the anti-tumor activities. Among them, compound 3c demonstrated the best selective inhibitory activity toward U87 cancer cells in vitro. It selectively enterd U87 cells by binding to αvβ3 integrin, releasing the parent molecule under the dual response of ROS and GSH to exert inhibitory activity on topo I. The results highlight the potential of cRGD-conjugated prodrugs in targeted cancer therapy. This approach signifies a significant advancement in developing safer and more effective chemotherapy drugs, emphasizing the role of prodrug strategies in overcoming the limitations of traditional cancer treatments.
摘要：
来自天然产物的小分子药物对于新的治疗发现至关重要。然而,他们的临床部署通常受到非特异性活动和严重不良反应的阻碍。本研究集中于3-氟-10-羟基-乙二胺（F-OH-Evo），一种有效的伊沃二胺衍生物，由于肿瘤选择性欠佳和细胞毒性增强，其发展受到限制。通过利用非凡的稳定性，特异性，和c(RGDFK)的αvβ3整联蛋白亲和力，通过将F-OH-Evo与cRGD结合合成了一种新型前药。这种创新的前药实质上增强了F-OH-Evo的肿瘤特异性靶向并提高了抗肿瘤活性。其中,化合物3c在体外对U87癌细胞表现出最佳的选择性抑制活性。它通过与αvβ3整合素结合选择性地进入U87细胞，在ROS和GSH的双重反应下释放母体分子以发挥对topoI的抑制活性。该结果强调了cRGD缀合的前药在靶向癌症治疗中的潜力。这种方法标志着在开发更安全，更有效的化疗药物方面取得了重大进展，强调前药策略在克服传统癌症治疗局限性方面的作用。
