具有抗肿瘤活性愈创木烷型倍半萜类天然产物全合成

The naturally occurring guaianoid type sesquiterpenoid natural products have attracted a great deal of interest not least because the majority of the compounds isolated to date exhibit some biological activity. Representative guaianoids include Curcumol, Isocurcumenol, Curcumenol, 4-epi-Curcumenol and Englerin A. Curcumol, which is isolated from the extracts of Zedoaria Rhizoma, exhibits potent antibiotic, antitumor, antiinflammation and HIV inhibitory activity. Englerin A, a new guaianoid sesquiterpenes, isolation from the root bark and stem bark of Phyllanthus engleri Pax (Euphorbiaceae), displays remarkable potency and selectivity in its inhibition of renal cancer cell line growth. Englerin A has been under intensive preclinical investigation and has the potency to become a new antitumor drug. We will plan to develop a novel strategy to prepare guaianoid type sesquiterpene Curcumol, Isocurcumenol, Curcumenol and 4-epi-Curcumenol base on the asymmetric synthetic pathway. The key step is the rhodium(II)-catalyzed tandem cascade intramolecular cyclization-cycloaddition reaction of carbonyl ylid with allene. We will also explore the asymmetric total synthesis of Englerin. Derivatives and analogues of Curcumol, Isocurcumenol, Curcumenol and 4-epi-Curcumenol will be prepared base on the above strategy for further biological studies.

愈创木烷型倍半萜类天然产物是自然界广泛存在且具有广泛生物活性的化合物，代表性分子包括莪术醇（Curcumol）、Isocurcumenol，Curcumenol和4-epi-Curcumenol。莪术醇从中药温郁金的挥发油中分离得到，具有抗肿瘤、消炎，抗菌和HIV抑制性等生物活性。愈创木烷型新型倍半萜天然产物Englerin A对肾癌细胞表现出高效和高选择性的抑制活性，有可能成为新型的治疗癌症的药物先导化合物。 本项目首次开展针对愈创木烷型倍半萜类天然产物的不对称全合成研究，实现代表性分子莪术醇（Curcumol），Isocurcumenol，Curcumenol和4-epi-Curcumenol的不对称全合成，并在此基础上探索(-)-Englerin A的全合成新途径，具有重要的学术意义,为评估和筛选此类天然产物的药用活性奠定了研究基础，具有潜在的应用价值。

愈创木烷型倍半萜类天然产物是自然界广泛存在且具有广泛生物活性的化合物，代表性分子包括莪术醇（Curcumol）、Isocurcumenol，Curcumenol和4-epi-Curcumenol。莪术醇从中药温郁金的挥发油中分离得到，具有抗肿瘤、消炎，抗菌和HIV抑制性等生物活性。本项目首次开展愈创木烷型倍半萜类天然产物的不对称全合成研究，已完成天然产物莪术醇（（-）-Curcumol）的不对称全合成，该研究工作被国际知名专业期刊Organic Chemistry Frontiers 作为“Synthetic Approaches to Natural Products via Catalytic Processes”专题而特邀撰稿，研究工作受到了国际同行的关注。另外，天然产物异莪术烯醇（-）-Isocurcumenol，莪术烯醇（-）-Curcumenol和表莪术烯醇（-）- 4-epi-Curcumenol已完成整体分子骨架的构建，再经官能团转化和分子内重排等两步反应就将完成其不对称全合成，研究工作将于近期撰文发表。后期将着重解决此类化合物水溶性差的问题，提高生物利用度，并利用PROTAC技术进行结构修饰和改造，合成具有全新结构的双功能抗肿瘤靶向分子。综上所述，本项目开发了以手性铑催化羰基叶立德的环加成环合串联反应为关键反应的愈创木烷型倍半萜类天然产物的全合成新方法，取得了预期的研究结果，为今后评估和筛选此类天然产物的药用活性奠定了研究基础，具有重要的科学研究意义和潜在的应用价值。