STAT3信号通路的异常激活与多种肿瘤的发生发展密切相关，靶向STAT3磷酸化是治疗肿瘤的重要策略。紫檀芪作为天然的二苯乙烯类化合物，具有一定的STAT3抑制活性和一定的抗肿瘤作用。吲哚结构因其多样的药效团特性，在抗癌药物设计中备受关注。本研究通过分子杂交策略，将紫檀芪与取代的吲哚结合，旨在开发新型STAT3抑制剂，以增强紫檀芪的抗肿瘤作用。

基于紫檀芪在抗肿瘤方面的活性和机制，本论文以紫檀芪为母体化合物，通过分子杂交策略设计并合成了一系列紫檀芪-吲哚杂合分子。采用MTT法，以C6大鼠胶质瘤细胞和A549人非小细胞肺癌细胞作为测试肿瘤细胞株，Vorinostat为阳性对照药，对所合成的35个紫檀芪-吲哚杂合分子进行了体外抗肿瘤活性测试。测试结果表明，7个化合物表现出良好的抗肿瘤活性，其中化合物P17、P18和P22均对两种细胞系表现出微摩尔级的抗肿瘤活性，IC₅₀值在0.82 ~ 4.81 μM范围内。初步的构效关系研究表明，吲哚的5位引入可供电子基团或卤素原子可显著增强化合物的抗肿瘤活性。

本论文选取了抗肿瘤活性良好的P17开展了进一步的抗肿瘤活性评价与作用机制研究，DAPI染色实验和Annxexin V-APC/PI双染色法流式细胞术实验结果表明，化合物P17能显著诱导肿瘤细胞凋亡，尤其能促进晚期细胞凋亡。进一步的克隆形成实验和划痕实验结果显示，P17可以显著抑制肿瘤细胞的增殖和迁移，且作用效果与阳性对照Vorinostat相当。最后通过Western Blot对P17的抗肿瘤机制进行分析，发现P17能显著降低STAT3的磷酸化水平，并且能下调细胞凋亡相关蛋白Bcl-2的水平，促进caspase-3的切割和活化。以上结果表明，P17通过阻断STAT3信号通路从而诱导细胞凋亡，抑制肿瘤细胞增殖，发挥抗肿瘤作用。分子模拟对接结果显示化合物P17能结合与STAT3蛋白的SH2结构域，吲哚环上的氯原子能与Lys 658形成中等强度的氢键作用。细胞热位移实验进一步证实了化合物P17能直接结合与STAT3蛋白，与空白对照组相比，熔解温度提升了2.6 ℃。

综上所述，本课题设计并合成了35个紫檀芪衍生物，通过体外抗肿瘤活性评价与作用机制研究，从中获得了多个具有良好抗肿瘤作用的紫檀芪-吲哚类杂合化合物，为后续进一步的结构优化与抗肿瘤活性研究指明了方向。

The abnormal activation of the STAT3 signaling pathway is closely associated with the development and progression of various tumors, and targeting STAT3 phosphorylation represents a critical therapeutic strategy. Pterostilbene, a natural stilbene derivative, exhibits moderate STAT3 inhibitory activity and antitumor effects. The indole scaffold, known for its diverse pharmacophoric properties, has garnered significant attention in anticancer drug design. This study utilized a molecular hybridization strategy to combine pterostilbene with substituted indole moieties, aiming to develop novel STAT3 inhibitors with enhanced antitumor efficacy.

Based on the antitumor mechanisms of pterostilbene, a series of 35 pterostilbene-indole hybrid molecules were designed and synthesized. The in vitro antitumor activity of these compounds was evaluated using the MTT assay against C6 rat glioma cells and A549 human non-small cell lung cancer cells, with Vorinostat as the positive control. Seven compounds demonstrated potent antitumor activity, with P17, P18, and P22 showing micromolar-range IC₅₀ values (0.82 - 4.81 μM) against both cell lines. Structure-activity relationship (SAR) analysis revealed that introducing electron-donating groups or halogen atoms at the 5-position of the indole moiety significantly enhanced antitumor activity.