Colorectal cancer (CRC) is the third leading cause of cancer deaths in the world. Standard drugs currently used for the treatment of advanced CRC—such as 5-fluorouracil (5FU)—remain unsatisfactory in their results due to their high toxicity, high resistance, and adverse effects. In recent years, mitochondria have become an attractive target for cancer therapy due to higher transmembrane mitochondrial potential. We synthesized gallic acid derivatives linked to a ten-carbon aliphatic chain associated with triphenylphosphonium (TPP+C10), a lipophilic cationic molecule that induces the uncoupling of the electron transport chain (ETC). Other derivatives, such as gentisic acid (GA-TPP+C10), have the same effects on colorectal cancer cells. Although part of our group had previously reported preparing these structures by a convergent synthesis route, including their application via flow chemistry, there was no precedent for a new methodology for preparing these compounds. In this scenario, this study aims to develop a new linear synthesis strategy involving an essential step of Steglich esterification under mild conditions (open flask) and a high degree of reproducibility. Moreover, the study seeks to associate GA-TPP+C10with 5FU to evaluate synergistic antineoplastic effects. In addition, we assess the antimigratory effect of GA-TPP+C10and TPP+C10using human and mouse metastatic CRC cell lines. The results show a new and efficient synthesis route of these compounds, having synergistic effects in combination with 5FU, increasing apoptosis and enhancing cytotoxic properties. Additionally, the results show a robust antimigratory effect of GATPP+C10 and TPP+C10, reducing the activation pathways linked to tumor progression and reducing the expression of VEGF and MMP-2 and MMP-9, common biomarkers of advanced CRC. Moreover, TPP+C10and GA-TPP+C10increase the activity of metabolic signaling pathways through AMPK activation. The data allow us to conclude that these compounds can be used for in vivo evaluations and are a promising alternative associated with conventional therapies for advanced colorectal cancer. Additionally, the reported intermediates of the new synthesis route could give rise to analog compounds with improved therapeutic activity.
结直肠癌是全球癌症死亡的第三大主要原因。目前用于治疗晚期结直肠癌的标准药物，如5-氟尿嘧啶，因其高毒性、高耐药性及不良反应，疗效仍不尽如人意。近年来，由于线粒体跨膜电位较高，已成为癌症治疗中备受关注的作用靶点。我们合成了与十碳脂肪链连接并偶联三苯基膦（TPP+C10）的没食子酸衍生物，该亲脂性阳离子分子可诱导线粒体电子传递链解偶联。其他衍生物如龙胆酸（GA-TPP+C10）对结直肠癌细胞具有相同作用。尽管本课题组先前曾报道通过汇聚式合成路线制备这些结构，包括采用流动化学技术进行应用，但尚无制备此类化合物的新方法学先例。在此背景下，本研究旨在开发一种新的线性合成策略，该策略包含在温和条件（开放容器）下进行的关键Steglich酯化步骤，并具有高度可重复性。此外，研究试图将GA-TPP+C10与5-氟尿嘧啶联用，以评估协同抗肿瘤效应。同时，我们使用人源及鼠源转移性结直肠癌细胞系评估了GA-TPP+C10和TPP+C10的抗迁移作用。研究结果显示：这些化合物具有新颖高效的合成路径，与5-氟尿嘧啶联用可产生协同效应，增强细胞凋亡并提升细胞毒性；GA-TPP+C10和TPP+C10表现出显著的抗迁移效果，能抑制肿瘤进展相关激活通路，降低晚期结直肠癌常见生物标志物VEGF及MMP-2、MMP-9的表达水平；TPP+C10和GA-TPP+C10还能通过激活AMPK增强代谢信号通路活性。这些数据表明，这些化合物可用于体内评估，是晚期结直肠癌常规治疗中具有潜力的替代方案。此外，新合成路线中报道的中间体可能衍生出具有更高治疗活性的类似化合物。
肿瘤(癌症)患者之家