School of Environment and Science, Griffith University, Southport, QLD 4222, Australia.
Griffith Institute for Drug Discovery, Griffith University, Nathan, QLD 4111, Australia.
Molecules. 2024 Jun 12;29(12):2806. doi: 10.3390/molecules29122806.
Synthetic efforts toward complex natural product (NP) scaffolds are useful ones, particularly those aimed at expanding their bioactive chemical space. Here, we utilised an orthogonal cheminformatics-based approach to predict the potential biological activities for a series of synthetic bis-indole alkaloids inspired by elusive sponge-derived NPs, echinosulfone A () and echinosulfonic acids A-D (-). Our work includes the first synthesis of desulfato-echinosulfonic acid C, an α-hydroxy bis(3'-indolyl) alkaloid (), and its full NMR characterisation. This synthesis provides corroborating evidence for the structure revision of echinosulfonic acids A-C. Additionally, we demonstrate a robust synthetic strategy toward a diverse range of α-methine bis(3'-indolyl) acids and acetates (-) without the need for silica-based purification in either one or two steps. By integrating our synthetic library of bis-indoles with bioactivity data for 2048 marine indole alkaloids (reported up to the end of 2021), we analyzed their overlap with marine natural product chemical diversity. Notably, the C-6 dibrominated α-hydroxy bis(3'-indolyl) and α-methine bis(3'-indolyl) analogues (, , and ) were found to contain significant overlap with antibacterial C-6 dibrominated marine bis-indoles, guiding our biological evaluation. Validating the results of our cheminformatics analyses, the dibrominated α-methine bis(3'-indolyl) alkaloids (, , , and ) were found to exhibit antibacterial activities against methicillin-sensitive and -resistant . Further, while investigating other synthetic approaches toward bis-indole alkaloids, 16 incorrectly assigned synthetic α-hydroxy bis(3'-indolyl) alkaloids were identified. After careful analysis of their reported NMR data, and comparison with those obtained for the synthetic bis-indoles reported herein, all of the structures have been revised to α-methine bis(3'-indolyl) alkaloids.
合成复杂天然产物（NP）支架的努力是有用的，特别是那些旨在扩大其生物活性化学空间的努力。在这里，我们利用正交化学信息学方法来预测一系列受难以捉摸的海绵衍生 NP、echinosulfone A（）和 echinosulfonic acids A-D（-）启发的合成双吲哚生物碱的潜在生物活性。我们的工作包括首次合成 desulfato-echinosulfonic acid C，一种 α-羟基双（3'-吲哚基）生物碱（）及其完整的 NMR 特征。这项合成提供了对 echinosulfonic acids A-C 结构修订的佐证。此外，我们还展示了一种针对各种 α-亚甲基双（3'-吲哚基）酸和醋酸盐（-）的强大合成策略，无需在一步或两步中进行基于硅胶的纯化。通过将我们的双吲哚合成文库与 2048 种海洋吲哚生物碱（截至 2021 年底报道）的生物活性数据相结合，我们分析了它们与海洋天然产物化学多样性的重叠。值得注意的是，C-6 二溴化 α-羟基双（3'-吲哚基）和 α-亚甲基双（3'-吲哚基）类似物（，，和）被发现与具有抗菌作用的 C-6 二溴化海洋双吲哚有显著重叠，指导了我们的生物学评估。验证我们化学信息学分析的结果，二溴化 α-亚甲基双（3'-吲哚基）生物碱（，，，和）被发现对耐甲氧西林和敏感的具有抗菌活性。进一步，在研究双吲哚生物碱的其他合成方法时，确定了 16 种错误分配的合成 α-羟基双（3'-吲哚基）生物碱。仔细分析它们报告的 NMR 数据，并与本文报道的合成双吲哚的那些进行比较后，所有结构都已修订为 α-亚甲基双（3'-吲哚基）生物碱。
