Abstract:
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 (1) and echinosulfonic acids A-D (2-5). Our work includes the first synthesis of desulfato-echinosulfonic acid C, an α-hydroxy bis(3\'-indolyl) alkaloid (17), 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 (11-16) 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 (11, 14, and 17) 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 (11, 12, 14, and 15) were found to exhibit antibacterial activities against methicillin-sensitive and -resistant Staphylococcus aureus. 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.
摘要:
对复杂天然产物(NP)支架的合成努力是有用的,特别是那些旨在扩大其生物活性化学空间的人。这里,我们利用基于正交化学信息学的方法来预测一系列合成双吲哚生物碱的潜在生物活性,这些生物碱受到难以捉摸的海绵衍生的NP的启发,棘突砜A(1)和棘突磺酸A-D(2-5)。我们的工作包括首次合成脱硫-儿茶素磺酸C,α-羟基双(3'-吲哚基)生物碱(17),及其完整的NMR表征。该合成为棘突磺酸A-C的结构修正提供了确证。此外,我们展示了一个强大的合成策略,对不同范围的α-次甲基双(3'-吲哚基)酸和乙酸酯(11-16),而不需要在一个或两个步骤中进行基于二氧化硅的纯化。通过将我们的双吲哚合成库与2048种海洋吲哚生物碱的生物活性数据(报告至2021年底)整合,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,发现C-6二溴化α-羟基双(3'-吲哚基)和α-次甲基双(3'-吲哚基)类似物(11,14和17)与抗菌C-6二溴化海洋双吲哚,指导我们的生物学评估。验证我们的化学信息学分析的结果,发现二溴α-次甲基双(3'-吲哚基)生物碱(11、12、14和15)对甲氧西林敏感和耐药的金黄色葡萄球菌具有抗菌活性。Further,在研究双吲哚生物碱的其他合成方法时,鉴定出16种分配错误的合成α-羟基双(3'-吲哚基)生物碱。仔细分析他们报告的核磁共振数据后,并与本文报道的合成双吲哚获得的那些进行比较,所有的结构都被修改为α-次甲基双(3'-吲哚基)生物碱。