Cytotoxic and antibacterial polyketide-indole hybrids synthesized from indole-3-carbinol by Daldinia eschscholzii
Cytotoxic and antibacterial polyketide-indole hybrids synthesized from indole-3-carbinol by Daldinia eschscholzii
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Daldinia eschscholzii 从吲哚-3-甲醇合成的细胞毒性和抗菌性聚酮化合物-吲哚杂种
DOI：
10.1016/j.apsb.2018.09.011
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发表时间：
2019-03-01
影响因子：
14.5
通讯作者：
Tan, Renxiang
中科院分区：
文献类型：
--
作者：
Lin, Liping;Jiang, Nan;Tan, Renxiang
吲哚-3-甲醇（I3 C）在真菌培养物（Daldinia eschscholzii）中产生了两个未描述的聚酮-吲哚杂合物（PIH），命名为indolchromins A和B。吲哚色满的结构主要通过一维和二维核磁共振谱进行了鉴定，其中一维核磁共振谱由单晶X射线晶体学分析证实。每个indolchromin生物碱手性分离成四个异构体，其绝对配置分配通过比较记录的圆二色性（CD）光谱与电子CD（ECD）曲线计算所有可选的立体异构体。通过酶抑制实验、前体补料实验和能量计算，进一步阐明了真菌培养中吲哚染色质的构建途径。8-氨基-7-氧代壬酸合成酶（AONS）催化的脱羧Claisen缩合、C（sp（3））-H活化、双键迁移和Michael加成等级联反应在真菌培养过程中均发生相容性反应。在1.3-8.6 μ mol/L的MIC范围内，（2S，4 R）-和（2 R，4S）-吲哚色胺A和（2 R，4S）吲哚色胺B对彼得弗林氏梭菌、艰难梭菌、韦荣氏球菌属、脆弱拟杆菌和化脓性链球菌。(2R（2S，4S）-吲哚色明A和（2S，4S）-吲哚色明B对人乳腺癌细胞系MDA-MB-231具有细胞毒性，IC（50）值分别为27.9和131.2 nmol/L，前者对另一种人乳腺癌细胞系MCF-7具有额外活性（IC（50）94.4 nmol/L）。(C)2019中国药学会、中国医学科学院药物研究所。制作和主办：Elsevier B. V.
Two skeletally undescribed polyketide-indole hybrids (PIHs), named indolchromins A and B, were generated from indole-3-carbinol (I3C) in the fungal culture (Daldinia eschscholzii). The indolchromin structures were elucidated mainly by their 1D and 2D NMR spectra with the former confirmed by the single-crystal X-ray crystallographic analysis. Each indolchromin alkaloid was chirally separated into four isomers, whose absolute configurations were assigned by comparing the recorded circular dichroism (CD) spectra with the electronic CD (ECD) curves computed for all optional stereoisomers. Furthermore, the indolchromin construction pathways in fungal culture were clarified through enzyme inhibition, precursor feeding experiment, and energy calculation. The cascade reactions, including decarboxylative Claisen condensation catalyzed by 8-amino-7-oxononanoate synthase (AONS), C(sp(3))-H activation, double bond migration, and Michael addition, all undergone compatibly during the fungal cultivation. In an MIC range of 1.3-8.6 mu mol/L, (2S,4R)- and (2R,4S)-indolchromin A and (2R,45)indolchromin B are inhibitory against Clostridium petfringens, Clostridium difficile, Veillonella sp., Bacteroides fragilis, and Streptococcus pyogenes. (2R,4S)-Indolchromin A and (2S,4S)-indolchromin B were cytotoxic against the human breast cancer cell line MDA-MB-231 with IC(50 )values of 27.9 and 131.2 nmol/L, respectively, with the former additionally active against another human breast cancer cell line MCF-7 (IC(50 )94.4 nmol/L). (C) 2019 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.