Antidiabetic profiling of veramycins,polyketides accessible by biosynthesis,chemical synthesis and precursor-directed modification  

作　　者：Denis Dardić Nils Böhringer Alberto Plaza Florian Zubeil Juliane Pohl Svenja Sommer Leo Padva Jonathan Becker Maria A.Patras Mona-Katharina Bill Michael Kurz Luigi Toti Sven W.Görgens Sören M.M.Schuler AndréBillion Oliver Schwengers Paulus Wohlfart Alexander Goesmann Norbert Tennagels Andreas Vilcinskas Peter E.Hammann Till F.Schäberle Armin Bauer 

机构地区：[1]Fraunhofer Institute for Molecular Biology and Applied Ecology(IME),Branch for Bioresources,35392 Gießen,Germany [2]Justus-Liebig-University Gießen,35392 Gießen,Germany [3]Sanofi-Aventis Deutschland GmbH,R&D Integrated Drug Discovery,65926 Frankfurt am Main,Germany [4]Sanofi-Aventis Deutschland GmbH,R&D German Hub,65926 Frankfurt am Main,Germany [5]German Center of Infection Research(DZIF),Partner Site Gießen-Marburg-Langen,35392 Gießen,Germany

出　　处：《Organic Chemistry Frontiers》2022年第6期1604-1615,共12页有机化学前沿（英文）

摘　　要：Seven new polyketides,termed veramycins,were isolated from a Streptomyces sp.from the Sanofi microbial strain collection along with their known congeners NFAT-133 and TM-123.Veramycin A,anα-pyrone congener of TM-123 and NFAT-133 showed an increased baseline deoxy-glucose uptake in the absence of insulin in a modified L6 rat skeletal muscle cell line(L6 GLUT4 AS160-like cells).In addition,both compounds slightly increased the sensitivity to insulin in this cell line.Total syntheses of NFAT-133,TM-123 and veramycin A were accomplished starting from a central building block,which bears the three contiguous stereogenic centers of this polyketide family.Our approach enables an efficient,selective and flexible access to all possible isomers of the stereotriad for further exploration of this series as a potential anti-diabetic lead structure as exemplified by the synthesis of an NFAT-133 epimer.Finally,the corresponding biosynthetic gene cluster(BGC)was identified by genome sequencing and gene inactivation.Based on feeding experiments,a biosynthetic pathway was proposed,which enabled access to new veramycin A analogs by precursor-directed biosynthesis.

关 键 词：synthesis directed ISOMERS 

分 类 号：O62[理学—有机化学]