The macrocyclic tumonolide (1) with enamide functionality and the linear tumonolide aldehyde (2) are new interconverting natural products from a marine cyanobacterium with a peptide‐polyketide skeleton, representing a hybrid of apratoxins and palmyrolides or laingolides. The planar structures were established by NMR and mass spectrometry. The relative configuration of the stereogenically‐rich apratoxin‐like polyketide portion was determined using J‐based configuration analysis. The absolute configuration of tumonolide (1) was determined by chiral analysis of the amino acid units and computational methods, followed by NMR chemical shift and ECD spectrum prediction, indicating all‐R configuration for the polyketide portion, as in palmyrolide A and contrary to the all‐S configuration in apratoxins. Functional screening against a panel of 168 GPCR targets revealed tumonolide (1) as a selective antagonist of TACR2 with an IC50 of 7.0 μM, closely correlating with binding affinity. Molecular docking studies established the binding mode and rationalized the selectivity for TACR2 over TACR1 and TACR3. RNA sequencing upon treatment of HCT116 colorectal cancer cells demonstrated activation of the pulmonary fibrosis idiopathic signaling pathway and the insulin secretion signaling pathway at 20 μM, indicating its potential to modulate these pathways.

中文翻译：

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海洋蓝藻选择性 TACR2 拮抗剂 Tumonolide 及其醛的分离、结构解析和生物活性


具有烯酰胺官能团的大环 tumonolide (1) 和线性 tumonolide 醛 (2) 是来自具有肽聚酮化合物骨架的海洋蓝细菌的新型相互转化天然产物，代表 apratoxins 和 palmyrolides 或 laingolides 的杂合体。通过核磁共振和质谱建立平面结构。使用基于 J 的构型分析确定了富含立体异构的阿帕毒素类聚酮化合物部分的相对构型。 Tumonolide (1) 的绝对构型是通过氨基酸单元的手性分析和计算方法确定的，然后进行 NMR 化学位移和 ECD 谱预测，表明聚酮部分的全 R 构型，如 Palmyrolide A 中那样，与 Palmyrolide A 中的情况相反apratoxins 中的全 S 构型。针对一组 168 个 GPCR 靶点的功能筛选显示，tumonolide (1) 是 TACR2 的选择性拮抗剂，IC50 为 7.0 μM，与结合亲和力密切相关。分子对接研究建立了结合模式，并合理化了 TACR2 相对于 TACR1 和 TACR3 的选择性。 HCT116 结直肠癌细胞处理后的 RNA 测序表明，20 μM 时肺纤维化特发性信号通路和胰岛素分泌信号通路被激活，表明其调节这些通路的潜力。