浅蓝霉素H的发酵优化与浅蓝苷K的化学合成
收稿日期: 2022-04-14
修回日期: 2022-06-06
网络出版日期: 2022-06-17
基金资助
国家自然科学基金委员会-山东省人民政府联合基金(U1906213); 天然产物有机合成化学院重点实验室开放基金(SIOC-2021-7)
Fermentation Optimization of the Caerulomycin H and the Synthesis of Cyanogriside K
Received date: 2022-04-14
Revised date: 2022-06-06
Online published: 2022-06-17
Supported by
National Natural Science Foundation of China-Shandong Union Foundation(U1906213); Open Fund Projects from Key Laboratory of Synthetic Chemistry of Natural Substances(SIOC-2021-7)
浅蓝霉素H (2)及其4-基α-L-吡喃鼠李糖苷[即浅蓝苷K (1)]是从海洋来源的浅蓝异壁放线菌WH1-2216-6的发酵产物中分离获得的天然产物, 浅蓝苷K (1)具有良好的肿瘤细胞增殖抑制活性, 但其产率低, 合成未见报道. 因此, 首先对浅蓝霉素H (2)的主产菌株浅蓝异壁放线菌WH1-2216-6突变株CRM05进行发酵优化, 采用放线菌5号与玉米配制的固体培养基发酵培养CRM05菌株, 将浅蓝霉素H (2)的产量提高到272 mg/L(提高了5倍), 获得了足量的浅蓝霉素H (2). 接着, 通过脱肟、鼠李糖苷化、成肟及脱乙酰保护等6步反应, 以25.6%的总收率从浅蓝霉素H (2)合成了浅蓝苷K (1). 通过高分辨质谱、核磁共振和比旋光等数据确认了浅蓝苷K (1)的结构, 与报道的天然产物为同一化合物. 浅蓝苷K (1)具有较强的肿瘤细胞抗增殖活性, 对肿瘤细胞株PATU8988T、786-O、5673、DU145、A-375、FaDu和SF126的半数抑制浓度(IC50)为1.07~1.78 μmol/L.
罗云 , 高谕康 , 燕鹏程 , 朱伟明 . 浅蓝霉素H的发酵优化与浅蓝苷K的化学合成[J]. 有机化学, 2022 , 42(9) : 2840 -2849 . DOI: 10.6023/cjoc202204035
Caerulomycin H (2) and its 4-yl α-L-rhamnopyranoside [cyanogriside K (1)] are two microbial natural products from marine-derived Actinoalloteichus cyanogriseus WH1-2216-6. Cyanogriside K (1) shows good antiproliferative activity against tumor cells, whereas the yield is very low and the synthesis has not been reported. Thus, enough caerulomycin H (2) was first obtained by optimazing the fermentation condition of the mutant strain CRM05 of A. cyanogriseus WH1-2216-6. The yield of caerulomycin H (2) reached 272 mg/L (increased by 5 times) in the optimal solid medium consisted of corn pellets (80 g) and liqiud medium 5# for actinomycetes (100 mL). Then cyanogriside K (1) was synthesized with 25.6% total yield from caerulomycin H (2) by six steps reactions including deoximation, rhamnosylation, oximation and deacetylation. The structure of cyanogriside K (1) was identified by NMR, HRESIMS and specific rotation data. It is the same compound as the reported natural product. Furthermore, cyanogriside K (1) showed good bioactivity against the proliferation of the tumor cell lines PATU8988T, 786-O, 5673, DU145, A-375, FaDu and SF126, with the half maximal inhibitory concentration (IC50) values ranging from 1.07 μmol/L to 1.78 μmol/L.
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