天然产物来源的抗疟药物在疟疾的临床治疗中一直扮演着重要角色。在前期研究中，我们从前沟藻属甲藻南海新发现种Amphidinium gibbosum中分离得到了具有抗恶性疟活性的新型中分子长链聚酮化合物AY-60-2，其分子式为C75H142O32，并确定了它的平面结构。本申请项目拟重点对该前沟藻进行室内大规模培养，并基于超高压液相-质谱联用和高效液相色谱技术对AY-60-2及其类似物进行化学指纹追踪分离。在累积化合物量的前提下，利用Grubbs’ Catalyst II和HIO4/NaBH4试剂将AY-60-2及其类似物分别定向裂解成3至4个主要片段。运用基于J耦合常数的构型分析等先进NMR技术、Mosher酯衍生化方法确定各裂解片段的相对和绝对立体化学，并最终完整确立长链聚酮化合物的绝对立体化学。此外，对长链聚酮化合物及其各裂解片段进行体外抗恶性疟筛选，发现具有抗疟活性的重要结构基序片段。

Antimalarial drugs that were derived from natural products have been playing an important role in the clinical treatment of malaria. Previously, we obtained a medium-molecule compound, named AY-60-2, which had a molecular formula of C75H142O32, from Amphidinium gibbosum, the newly discovered species of the dinoflagellate genus Amphidinium in the South China Sea. AY-60-2, of which the planar structure was established, belongs to a new type of long-chain polyketides with antimalarial activity against Plasmodium falciparum. Based on Ultra-High Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS) and High Performance Liquid Chromatography (HPLC) techniques, this proposal aims to achieve indoor large-scale culture of A. gibbosum and chemical fingerprint-guided separation of AY-60-2 and its analogs. Based on the quantity accumulation of compounds, AY-60-2 and its analogs were directionally cleaved into three to four main fragments by Grubbs’ Catalyst II and HIO4/NaBH4 reagents, respectively. Advanced NMR techniques, including J-based configurational analysis, and the Mosher’s ester derivatization method were utilized to determine the relative and absolute configurations of the main fragments. Finally, absolute configurations of whole long-chain polyketide compounds were established. In addition, antimalarial screening in vitro against P. falciparum was carry out on long-chain polyketide compounds and their main cleaved fragments in order to find important structural motif fragments with antimalarial activity.