光化性角化病新药ingenol mebutate及其类似物的化学合成研究

Ingenol mebutate is a novel topical drug for actinic keratosis approved by FDA in 2012. Compared with the other drugs for actinic keratosis, ingenol mebutate has the advantages of good efficacy, fast onset, short course, and fewer side effects. However, the high price of ingenol mebutate, due to the low content in E. peplus and the difficulties of separation and purification, imposes heavy economic burdens on both patients and their families. In order to solve the problem, we plan to develop an efficient, scalable chemical synthesis route for ingenol mebutate without using toxic reagents, and lay a solid foundation for the industrial synthesis of ingenol mebutate. In addition, the chemical instability of ingenol mebutate limited its wider applications such as oral dosing. We plan to explore bioisosteric modification to the chemically labile site in pursuit of potent and chemically stable ingenol mebutate analogues.

Ingenol mebutate是2012由美国FDA批准上市的新药，用于光化性角化病的皮肤局部治疗，具有疗效好、起效快、疗程短、副作用少等优点。但是由于自然含量稀少、分离提纯困难，导致价格高昂，给患者带来沉重的经济负担。本课题拟对ingenol mebutate开展合成研究，旨在发展一条简单高效、不使用剧毒物质、有工业化应用前景的化学合成路线，为最终实现ingenol mebutate的工业化合成，降低生产成本奠定基础。另外，由于ingenol mebutate存在化学不稳定性，限制其应用范围，需要进一步的结构优化改进。本课题拟利用所发展的合成路线合成新型的ingenol mebutate类似物，为进一步研究其构效关系，得到稳定性更好、应用范围更广的药物提供合成保障。

巨大戟醇甲基丁烯酸酯（ingenol mebutate，1）是一个从巨大戟属植物E. peplus的茎中分离得到的具有四环结构的二萜化合物，对光化性角化病、鳞状细胞癌、基底细胞癌、表皮内癌都有良好的治疗效果。课题组于2016-2018 年对ingenol mebutate进行合成研究，但可惜的是由于关键步骤（串联的烯烃复分解开环-关环反应）没有按照预期发生，我们尝试了几种其他方法，都未能解决该问题，导致项目未能按预期计划进行。

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