螳螂肠道碳壳菌新骨架化合物合成机制的研究

Experiencing a variety of chronic stimuli, liver fibrosis is a pathological response of the liver to these injuries. If not treated promptly, it may lead to the severe phenomenon of liver fibrosis, sometimes even to cirrhosis. Therefore, liver fibrosis has become a worldwide problem endangering human life and health. Unfortunately, there has been a lack of a well-tolerated and efficient medicament that impedes the progression of liver fibrosis so far, and thus, its prevention and treatment is still a challenging and key issue of the treatment of liver diseases. A new type of skeletons named dalepkons A-B (1–2) are isolated and characterized from Mantis symbiotic gut fungi Daldinia eschscholzii IFB-TL01 and demonstrated to have possessed a promising potential anti-fibrotic activity with their exhibition of a much stronger cell viability inhibition effect upon activated hepatic stellate cell line CFSC-8B than that upon quiescent phase of Lx-2 cells. Dalepkons A and B and their enantiomers are also observed to contribute to anticancer activities against human hepatoma carcinoma cell lines Hep G2 and SMMC-7721. Complete structural elucidation and enantiomer's absolute configuration determination of the dalepkons are elucidated by 1D and 2D NMR experiments combined with X-ray crystallography our single crystal X-ray diffraction with Cu Kα radiation and CD spectra. As the production of these compounds is very low, samples are insufficient for their further research concerning pharmacological mechanism. To resolve this problem, with chemical synthesis of these compounds conducted, we obtained these compounds in large quantities and looked forward to cognizing their synthesis mechanism. Only in this way can a solid material foundation be laid for the further in-depth studies and explorations of their new functions.

肝纤维化是各种慢性刺激引起肝脏的损伤和炎症，如不及时治疗，将引起严重的肝纤维化甚至导致肝硬化，肝纤维化已成为一个危害人类生命健康的世界性问题。直到目前为止，对肝纤维化的治疗尚无行之有效的方案，因此，肝纤维化的防治仍是肝病治疗的重点难点。我们从螳螂肠道共生真菌D. Eschscholzii IFB-TL01的大规模发酵产生的次生代谢产物中，分离得到一类具有全新骨架类型的化合物（命名为dalepkon），并完成了该类化合物的晶体结构解析、手性拆分和绝对构型测定。前期的系列研究表明，该类新骨架化合物具有很好的抗肝纤维化活性，并且对肝癌细胞也有比较出色的抑制作用。由于该类化合物的产量很低，对其进一步的药理机制研究以及其它相关研究缺乏样品保障，所以，我们对它们进行了化学合成研究，在大量获得该类化合物的同时，并期待解决该类化合物的合成机制，从而为其新功能的开发和深入研究奠定良好的物质基础。

基于真菌基因组信息，化合物dalesconol骨架是由萘酚单元通过逐步耦合构造而成。从生物合成中间体的互变异构可形成分流产物的观点来看，我们把dalesconol的生物合成途径选作本研究的主题。通过系统的实验，我们发现了一种多酚类新骨架化合物selesconol，它能够诱导大鼠骨髓间充质干细胞（rMSCs）向神经元细胞的分化，该发现对于开发基于细胞替代疗法是非常有价值的。另外，微生物合成次生代谢产物通常是以其生物合成基因簇（BGC）为基础，因此，不同BGC来源的中间体的组装往往被忽视。我们通过实验表明，Daldinia eschscholzi的dalesconol 类天然产物的生物合成途径，可“接纳”其它来源的生物合成中间体（即dalesconol生物合成基因簇以外的其它基因产生的结构单元）形成全新骨架的分子，如spirodalesol和dalescones，它们可能成为抑制NLRP3炎性体活化的强效抑制剂。