计算机辅助设计、合成基于胀果甘草查尔酮类先导物的新型抗多药耐药宫颈癌化合物及其体内外活性和耐药逆转机制研究

子宫颈癌是重大妇科肿瘤，新疆地方性高发疑难症。化疗毒性和肿瘤多药耐药是临床治疗失败的主要原因。近期研究显示，部分查尔酮衍生物对多药耐药肿瘤仍有效，多药耐药肿瘤细胞对紫杉醇等常规化疗药产生“泵药”时对这些查尔酮不产生泵药，这可能通过肿瘤多药耐药的多个机制产生作用，显示深入研究潜力。课题组在前期研究中筛选出抗宫颈癌活性显著的胀果甘草查尔酮衍生物。本课题中：1.构建查尔酮类化合物库，对宫颈癌候选靶点进行分子对接，设计合成30～50个新型查尔酮；2.研究查尔酮对多药耐药宫颈癌细胞抑制活性及作用机制；3.选定候选药物，研究体内抗药肿瘤药效、对多药耐药相关ABC转运蛋白的作用、对多药耐药基因MDR1和MDR2表达的影响、对肿瘤多药耐药相关MAPK和Wnt/β-catenin信号通路的作用、做构效关系分析。本研究为有效低毒的新型逆转肿瘤多药耐药创新药物筛选及对地区重大疑难症的有效药物干预研究奠定基础。

Cervical cancer is a major gynecological tumor, and endemic disease in Xinjiang. Chemotherapy toxicity and multidrugs resistance are the main reasons of the failure of cancer clinical treatment. Recent studies have shown that some chalcone derivatives have a certain proliferation inhibitory activity against multidrug-resistant tumors, with low toxicity to normal cells, and they can act with different pathway to tumor multidrug resistance, showed a deeply study interest. In the preliminary study, our research group has screened a series of licorice chalcone derivatives with significant anti-cervical cancer effects and low toxicity to normal cells. In this study: 1. We construct a library of chalcone compounds, carry out molecular docking of cervical cancer potential drug targets with computer-aided drug design technology; design and synthesis of 30-50 new chalcone derivatives. 2. Study the inhibitory activity of these compounds to the multidrugs resistant tumor cells, and its mechanism. 3. Screening 1-2 candidate drugs, study the in vivo pharmacodynamic property to multidrug resisted tumor animal model; in-depth study on the effect to cancer multidrug resistance-related ABC transporter proteins, and the expression of multidrug resistance MDR1 and MDR2 genes; study the mechanism of candidate drugs on tumor multidrug resistance-related MAPK, Wnt/β-catenin and PI3K/Akt signaling pathways, and performe the structure-activity relationship analysis. This research lays the foundation for the screening of effective and low-toxic new innovative drugs for reversing tumor multidrug resistance and performing the effective drug interventions for major endemic disease cervical cancers in the region.