Structural diversification of phenylspirodrimane lactams by employing a biosynthetic intermediate  

作　　者：Jimei Liu Zhenfei Wang Jun Wu Yaotian Han Fei Ye Tiantai Zhang Haibo Yu Zhengshun Wen Jungui Dai 

机构地区：[1]State Key Laboratory of Bioactive Substance and Function of Natural Medicines,CAMS Key Laboratory of Enzyme and Biocatalysis of Natural Drugs,NHC Key Laboratory of Biosynthesis of Natural Products,and Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China [2]Zhejiang Provincial Engineering Technology Research Center of Marine Biomedical Products,School of Food Science and Pharmaceutics,Zhejiang Ocean University,Zhoushan316022,China

出　　处：《Chinese Chemical Letters》2023年第12期141-145,共5页中国化学快报（英文版）

基　　金：financially supported by National Natural Science Foundation of China(No.81803403);CAMS Innovation Fund for Medical Sciences(Nos.CIFMS-2022-I2M-JB-011 and CIFMS-2021-12M-1-029).

摘　　要：Phenylspirodrimanes are a kind of meroterpenoids with structural diversity and complexity,exhibiting a wide of biological properties,especially for the lactam derivatives consisting a y-lactam moiety and N-linked side chains.These compounds were derived from multi-step combination of enzymatic and non-enzymatic conversions of intermediates in their biosynthetic pathways.Stachbotrydial(2)with an o-phthalaldehyde unit was supposed as the high-reactivity intermediate of phenylspirodrimane lactams via nonenzymatic reaction with amines.In the present work,an effective and non-enzymatic diversification strategy was developed for the structural diversification of phenylspirodrimane lactams including monomers and dimers from 2 by feeding structurally various mono-and diamines in the fungus Stachybotrys chartarum cultures.In total,24 phenylspirodrimane lactams(1,3-25)including 18 new compounds were synthesized.Among them,stachybocin A(1),a bioactive phenylspirodrimane lactam dimer,was produced with the yield of 18.7 mg/g of cell dry weight.The structures of these compounds were elucidated by extensive spectroscopic data,single-crystal X-ray diffraction(Cu Kα),and calculated electronic circular dichroism(ECD)analyses.Bioassay revealed that compounds 1,17,and 24 displayed significant inhibitory effect on the inactivated state of hNav 1.2 channels with IC_(50) values of 0.22,2.08,and 0.53μmol/L,respectively.In addition,1 showed potent protein tyrosine phosphatase 1B(PTP1B)inhibitory N-methyl-b-aspartate(NMDA)receptor antagonistic,and anti-inflammatory activities.

关 键 词：Phenylspirodrimane lactams Stachbotrydial Nonenzymatic reaction hNav 1.2channels inhibitoryactivity Stachybotrys chartarum 

分 类 号：O625.525[理学—有机化学]