Enantioselective, organocatalytic synthesis of the secoiridoid natural product Patriridosid D and evaluation of its potential as an antitumoral agent

现代天然产物和药物合成将合成方法问题（合成经济;高度特异性和立体选择性的转化;反应性的平衡）与结构美学方面（高度功能化的分子;新型结构）和医学化学主题（作用特征;搜索，优化和简化先导结构）相结合。申请的项目包括许多这些方面。主要目标是有效的，对映选择性的，和第一个全合成的天然产物Patriridoside D，它具有一个新的开环环烯醚萜骨架与四个连续的立体中心。基于我们的初步工作，最新的，环境友好的有机催化转化将被用作密集官能化中间体的关键步骤，例如在三醛物种上，其也以类似的形式存在于自然界中。Patriridoside D是从多年生草本植物糙叶败酱（Patrinia Scabra Bunge）中分离得到的天然产物，其提取物在传统中药中用于治疗白血病和胃癌，并且其显示出对顺铂抗性胃癌细胞系MKN-45的特异性细胞毒性。因此，进一步的目标是评估其对不同类型癌症的作用特征，并合成用于结构活性研究的衍生物，以提高特异性抗肿瘤活性。如果拟议的项目成功，将获得新的合成知识，并将获得一种新的，易于获得的潜在抗癌药物的先导结构。

Modern natural product and drug synthesis combines synthetic-methodical questions (synthetic economy; highly specific and stereoselective transformations; balancing of reactivities) with structural-aesthetic aspects (highly functionalized molecules; novel architectures) and medical-chemical topics (action profile; search, optimization, and simplification of lead structures). The project applied for comprises many of these aspects. Primary goal is the efficient, enantioselective, and first total synthesis of the natural product Patriridosid D, which possesses a novel secoiridoid skeleton with four consecutive stereogenic centres. Based on our preliminary work, up-to-date, environmentally friendly organocatalytic transformations will be used as the key steps on densely functionalized intermediates, e.g. on a trialdehyde species, which also exists in similar form in nature. The natural product Patriridosid D was isolated from the perennial herb Patrinia Scabra Bunge, the extracts of which were applied in traditional Chinese medicine for treatment of leukaemia and gastric cancer, and it shows a specific cytotoxicity against the cisplatin resistant gastric cancer cell line MKN-45. Further goals are therefore the evaluation of its action profile against different types of cancer and the synthesis of derivatives for structure-activity studies and for improving the specific antitumoral activity.If the proposed project is successful, new synthetic knowledge will be gained and a novel, easily accessible lead structure for a potential anti-cancer drug will be obtained.