Actein的构效关系研究和治疗乳腺癌候选药物的发现

In recent years, investigations on anti-breast cancer activities and their mechanisms of Actein have attracted global attentions. The relevant research results showed the potential druggability of Actein in anti-breast cancer. Based on the previous investigations, our group has conducted preliminary researches on anti-breast cancer activity of animal level and its druggability. The results showed that Actein was not better than the first-line drugs, such as Taxol, although it was active to animal model (human triple-negative breast cancer cell line MDA-MB-231) both oral administration or intravenous injection. Besides, its bioavailability is low. We think that Actein's anti-breast cancer activity and bioavailability need to be improved. In order to obtain a candidate molecule of activites (in vitro and in vivo), bioavailability obviously improved and then build a solid foundation for later druggability research, some pharmacophores would be introduced to Actein scaffold to build a Actein-analogue library with skeletal diversity through structure modification of chemical transformation, and then evaluate their bioactivities and summary primary structure-activity relationships. After quadratic optimization of Actein analogues, evaluations of efficacy of tri-negative breast cancer cell bearing animal model and bioavailability of SD rats would be carried out.

近年来，Actein的抗乳腺癌活性和作用机制成为了国内外的研究热点。研究显示Actein在抗乳腺癌方面具有成药潜力。基于前期的研究基础，申请者所在的研究组对其体内药效和成药性进行了初步的研究。结果表明，Actein对人三阴性乳腺癌细胞MDA-MB-231裸鼠移植瘤无论是灌胃给药或静脉注射都表现出了显著的肿瘤抑制活性，但与一线药物紫杉醇相比无显著优势，且生物利用度偏低。申请者认为Actein的抗乳腺癌活性和生物利用度需要提高。因此，申请者从结构改造出发，采用化学合成的方式合理地把一些药效团引入Actein骨架中，构建结构多样的衍生物库，并进行抗三阴性乳腺癌细胞活性评价，总结构效关系并通过二次优化，得到活性提高的候选化合物，并对其进行初步的三阴性乳腺癌细胞裸鼠模型的体内药效和SD大鼠的生物利用度评价，以期得到活性和生物利用度明显提高的候选药物分子，为后期的成药性研究奠定坚实的基础。

目前，Actein的抗乳腺癌活性和作用机制成为了国内外的研究热点。研究显示Actein在抗乳腺癌方面具有成药潜力。但Actein存在活性中等，水溶性差等问题。项目以升麻中的大量成分Actein为母体化合物，根据保留主体骨架和结构多样性的原则合理地引入一些药效团，设计并合成了近30个Actein衍生物，通过体外抗三阴性乳腺癌活性筛选，获得了6个活性明显提高的衍生物，其中1个衍生物活性与顺铂相当，解决了Actein活性和水溶性差的问题，总结了Actein衍生物的构效关系。其中1个衍生物可以作为先导化合物，为后期的成药性研究奠定了良好的基础。

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