Resorcylic acid lactones (RALs) with a cis-enone moiety, represented by hypothemycin (1) and (5Z)-7-oxozeaenol (2), are fungal secondary metabolites with irreversible inhibitory activity against protein kinases, with particularly selective activity for inhibition of TAK1 (transforming growth factor beta-activated kinase 1). Gram-scale quantities of these compounds were needed as feedstock for semi-synthesizing RAL-analogues in a step-economical fashion. To do so, this study had three primary goals: identifying fungi that biosynthesized 1 and 2, enhancing their production by optimizing the fermentation conditions on the lab scale, and developing straight forward purification processes. After evaluating 536 fungal extracts via an in-house dereplication protocol, three strains were identified as producing cis-enone RALs (i.e., MSX78495, MSX63935, MSX45109). Screening these fungal strains on three grain-based media revealed enhanced production of 1 by strain MSX78495 on oatmeal medium, while rice medium increased the biosynthesis of 2 by strain MSX63935. Furthermore, the purification processes were improved, moving away from HPLC purification to utilizing two to four cycles of resuspension and centrifugation in small volumes of organic solvents, generating gram-scale quantities of these metabolites readily. In addition, studying the chemistry profiles of strains MSX78495 and MSX63935 resulted in the isolation of ten other RALs (3-12), two radicinin analogues (13-14), and six benzopyranones (15-20), with 19 and 20 being newly described chlorinated benzopyranones.

具有顺式-烯酮部分的间苯二甲酸内酯 (RALs)，以小霉素 ( 1 ) 和 ( 5Z )-7-氧代玉米烯醇 ( 2 ) 为代表，是对蛋白激酶具有不可逆抑制活性的真菌次级代谢产物，具有特别的选择性抑制活性TAK1（转化生长因子 β 活化激酶 1）。需要克级数量的这些化合物作为以分步经济方式半合成 RAL 类似物的原料。为此，这项研究有三个主要目标：识别生物合成1和2的真菌，通过优化实验室规模的发酵条件和开发直接的纯化工艺来提高它们的产量。在通过内部去复制方案评估了 536 种真菌提取物后，确定了三个菌株产生顺-烯酮 RAL（即 MSX78495、MSX63935、MSX45109）。在三种谷物培养基上筛选这些真菌菌株显示，菌株MSX78495在燕麦培养基上的产量增加，而水稻培养基增加了2的生物合成通过菌株 MSX63935。此外，纯化过程也得到了改进，从 HPLC 纯化转向在小体积有机溶剂中使用两到四个再悬浮和离心循环，很容易产生克级数量的这些代谢物。此外，通过研究菌株 MSX78495 和 MSX63935 的化学特征，分离出了其他 10 个 RAL（3-12 个）、 2个radicinin 类似物（13-14个）和 6 个苯并吡喃酮（15-20个），其中19 个和20个是新的描述了氯化苯并吡喃酮。