Angiogenesis inhibitors and photosensitizers are pivotal in tumor clinical treatment, yet their utilization is constrained. Herein, eleven novel angiogenesis inhibitors were developed through hybridization strategy to overcome their clinical limitations. These title compounds boast excitation wavelengths within the “therapeutic window”, enabling deep tissue penetration. Notably, they could generate superoxide anion radicals via the Type I mechanism, with compound showed the strongest superoxide anion radical generating capacity. Biological evaluation demonstrated remarkable cellular activity of all the title compounds, even under hypoxic conditions. Among them, compound stood out for its superior anti-proliferative activity in both normoxic and hypoxic environments, surpassing individual angiogenesis inhibitors and photosensitizers. Compound induced cell apoptosis via superoxide anion radical generation, devoid of dark toxicity. Molecular docking revealed that the target-recognizing portion of compound was able to insert into the ATP binding pocket of the target protein similar to sorafenib. Collectively, our results suggested that hybridization of angiogenesis inhibitors and photosensitizers was a potential strategy to address the limitations of their clinical use.

中文翻译：

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具有超氧阴离子自由基放大作用的新型血管生成抑制剂：克服血管生成抑制剂和光敏剂的致命弱点


血管生成抑制剂和光敏剂在肿瘤临床治疗中至关重要，但其应用受到限制。在此，通过杂交策略开发了十一种新型血管生成抑制剂，以克服其临床局限性。这些标题化合物拥有“治疗窗口”内的激发波长，能够穿透深层组织。值得注意的是，它们可以通过I型机制产生超氧阴离子自由基，其中化合物表现出最强的超氧阴离子自由基产生能力。生物学评价表明，即使在缺氧条件下，所有标题化合物也具有显着的细胞活性。其中，该化合物在常氧和缺氧环境中均具有优异的抗增殖活性，超过了单个血管生成抑制剂和光敏剂。化合物通过超氧阴离子自由基的产生诱导细胞凋亡，无暗毒性。分子对接表明，与索拉非尼类似，化合物的靶标识别部分能够插入靶蛋白的 ATP 结合袋中。总的来说，我们的结果表明，血管生成抑制剂和光敏剂的杂交是解决其临床使用局限性的潜在策略。