Marine, Ecology Research Centre, School of Environment, Science and Engineering, Southern Cross University, Lismore, NSW, 2480, Australia.
Melbourne Centre for Nanofabrication, Victorian Node of the Australian National Fabrication Facility, Clayton, VIC, 3168, Australia.
Sci Rep. 2019 Aug 26;9(1):12342. doi: 10.1038/s41598-019-48533-2.
Indole derivatives are a structurally diverse group of compounds found in food, toxins, medicines, and produced by commensal microbiota. On contact with acidic stomach conditions, indoles undergo condensation to generate metabolites that vary in solubility, activity and toxicity as they move through the gut. Here, using halogenated ions, we map promising chemo-preventative indoles, i) 6-bromoisatin (6Br), ii) the mixed indole natural extract (NE) 6Br is found in, and iii) the highly insoluble metabolites formed in vivo using desorption/ionisation on porous silicon-mass spectrometry imaging (DIOS-MSI). The functionalised porous silicon architecture allowed insoluble metabolites to be detected that would otherwise evade most analytical platforms, providing direct evidence for identifying the therapeutic component, 6Br, from the mixed indole NE. As a therapeutic lead, 0.025 mg/g 6Br acts as a chemo-preventative compound in a 12 week genotoxic mouse model; at this dose 6Br significantly reduces epithelial cell proliferation, tumour precursors (aberrant crypt foci; ACF); and tumour numbers while having minimal effects on liver, blood biochemistry and weight parameters compared to controls. The same could not be said for the NE where 6Br originates, which significantly increased liver damage markers. DIOS-MSI revealed a large range of previously unknown insoluble metabolites that could contribute to reduced efficacy and increased toxicity.
吲哚衍生物是一类结构多样的化合物，存在于食物、毒素、药物中，也由共生微生物群产生。在与酸性胃条件接触时，吲哚会发生缩合，生成的代谢物在通过肠道时在溶解度、活性和毒性方面存在差异。在这里，我们使用卤化离子来绘制有前途的化学预防吲哚，i）6-溴靛蓝（6Br），ii）6Br 存在于混合吲哚天然提取物（NE）中，iii）在体内用解吸/离子化在多孔硅质谱成像（DIOS-MSI）上形成的高度不溶性代谢物。功能化的多孔硅结构允许检测到原本会逃避大多数分析平台的不溶性代谢物，从而为从混合吲哚 NE 中鉴定治疗成分 6Br 提供了直接证据。作为一种治疗先导化合物，0.025mg/g 的 6Br 可作为 12 周遗传毒性小鼠模型中的化学预防化合物；在该剂量下，6Br 可显著降低上皮细胞增殖、肿瘤前体（异常隐窝焦点；ACF）；并且与对照组相比，肿瘤数量减少，而对肝脏、血液生物化学和体重参数的影响最小。对于 6Br 起源的 NE 来说，情况并非如此，因为它会显著增加肝脏损伤标志物。DIOS-MSI 揭示了大量以前未知的不溶性代谢物，这些代谢物可能导致疗效降低和毒性增加。
