天然产物Hoiamide A的全合成及其门控电压钠离子通道部分激动剂活性构效关系研究

Ion channels regulate the transportation of inorganic ions cross the cell membrane, and thus play a very important role for living creatures. Ion channels are well recognized as important therapeutic targets for treating over 50 different pathophysiologies, including therapy for pain, cardiovascular, and so on. Hoiamide A is a structurally novel cyclic depsipeptide, featured as a polyketide side chain bearing six contiguous stereogenic centers, a consecutive five-membered heterocycles of thiazoline-thiazoline-thiazole and high content of unnatural amino acids. Hoiamide A was isolated from marine natural product in 2009. It was found to be a potent partial agonist of the voltage-gated sodium channel (VGSC) acting on neurotoxin site 2 (IC50 = 3.9uM), which can produce a concentration-dependent reduction in batrachotoxin-induced sodium influx in neocortical neurons. Our research group has developed efficient routes for the construction of key fragments of hoiamide A, and also successfully completed the total synthesis of hoiamide C. Based on these preliminary results, this proposal intends to construct the C36-stereogenic center and the sterically-hindered C34-ester by employing the Evans-Tishchenko one-pot protocol. After the completion of the total synthesis of Hoiamide A, we will further establish a focused library of analogues and study the structure-activity relationship of Hoiamide A as VGSC regulator. The implementation of the project will demonstrate the ability to build esters, amides and similar natural products with relatively large steric-hindrance, and this will also be helpful for the future medicinal chemistry studies.

离子通道涉及无机离子的被动跨膜运输过程，是生命活动的基础，并成为重要的药物靶蛋白。离子通道调节剂可用于疼痛、心脑血管等50多种疾病的临床治疗。Hoiamide A是结构新颖的大环内酯肽类天然产物，含有一个连续六手性中心的侧链、三个串连的五元杂环和多个非天然氨基酸片断。Hoiamide A 具有针对门控电压钠离子通道神经毒位点-2的部分激动剂活性（IC50＝3.9uM），与蟾毒素联用可微调细胞内钠离子浓度。课题组设计高效的不对称合成路线，制备了关键片断并完成了Hoiamide C的全合成。本项目拟采用Evans-Tishchenko反应构建手性羟基的同时完成大位阻酯键的合成，在完成天然产物全合成的基础上制备聚焦型结构类似物库，并研究Hoiamide A作为钠离子通道调节剂的构效关系。项目的实施对于构建空间位阻较大的酯键、酰氨键、以及类似天然产物全合成提供借鉴，并为后续药物化学研究奠定基础。

项目在国家自然科学基金委经费支持下，利用不对称合成方法制备了Hoiamide A分子的所有非天然片段，探索并优化了噻唑啉和噻唑杂环的合成路线，采用Evans-Tishchenko方法构建了分子内大位阻酯键，通过关大环完成了Hoiamide A的全合成研究，该路线最长线性步骤为19步，总收率为2.9%。在完成Hoiamide A的全合成后，项目组合成了Hoiamide A的结构类似物。为了获得其他与离子通路调控有关的小分子化合物，通过文献调研选定Smenothiazole的两个分子进行合成。对于Hoiamide和Smenothiazole A和B钠离子通道抑制的活性研究还在测试中。.同时利用本基金的支持，课题组还展开了其他具有抗肿瘤等活性天然产物的全合成研究，先后完成了同样属于大环多肽结构类型的Banyasin A、Nannocystin A、Largamide B和Scytonemin A等的全合成。.在基金的资助下发表的论文数超过计划目标，现有Hoiamide A的全合成和Smenothiazole的研究论文2篇待发表；已发表与本项目有关的SCI论文4篇；另有致谢本基金支持的SCI论文9篇。项目先后参与的研究生共7人，全部为硕博连读研究生，博士后1人。其中在本项目执行期由硕士转为博士培养的学生7人，已毕业博士研究生5人，在读博士研究生2人。