Reddy R Gajendra, Dachavaram Soma Shekar, Reddy B Raghunath, Kalyankar Kondbarao Balasaheb, Rajan Wenson D, Kootar Scherazad, Kumar Arvind, Das Saibal, Chakravarty Sumana
Chemical Biology and Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Uppal Road, Hyderabad 500007, India.
Academy of Scientific and Innovative Research (AcSIR), Chennai 600113, India.
ACS Omega. 2018 Sep 30;3(9):10534-10544. doi: 10.1021/acsomega.8b00456. Epub 2018 Sep 5.
Fellutamide B is reported to have cytotoxic and proteasome inhibitory activity. Interestingly, fellutamide B and its simplified analogues have also been observed for the neurotrophic activity by stimulating the synthesis and secretion of neurotrophins. Owing to the interesting structural and potent neurotrophic role of fellutamide B (a lipopeptide aldehyde), we have assessed the synthetic path intermediates (compounds A-D) of fellutamide B for their neuroactive potential (in vitro and in vivo). We have observed few compounds (comp #A-D) to have potential neurite outgrowth activity in Neuro2a cells with no observable negative effect on the cell viability. In addition, most compounds (comp #A, C, and D) have shown neurogenic activity ex vivo in hippocampal neurosphere culture, with increased acetyl H3 and acetyl H4 induction ability (comp #C). Furthermore, the intermediate product comp #C has shown anxiolytic and antidepressant-like activity in novel tank test and social interaction test, in the chronic unpredictable stress model of zebrafish mood disorder, inducing BDNF gene expression in the telencephalon region of the fish brain. Our results thus demonstrate that the fellutamide B synthetic path intermediates have potential neurotrophic, neurogenic, and mood-elevating effects and thus good prospect to be developed as potential therapeutics to treat psychiatric disorders.
据报道，费卢他胺B具有细胞毒性和蛋白酶体抑制活性。有趣的是，通过刺激神经营养因子的合成和分泌，费卢他胺B及其简化类似物也表现出了神经营养活性。鉴于费卢他胺B（一种脂肽醛）有趣的结构和强大的神经营养作用，我们评估了费卢他胺B的合成路径中间体（化合物A - D）的神经活性潜力（体外和体内）。我们观察到少数化合物（化合物#A - D）在Neuro2a细胞中具有潜在的神经突生长活性，且对细胞活力没有明显的负面影响。此外，大多数化合物（化合物#A、C和D）在海马神经球培养中表现出离体神经生成活性，其中化合物#C的乙酰化组蛋白H3和乙酰化组蛋白H4诱导能力增强。此外，在斑马鱼情绪障碍的慢性不可预测应激模型中，中间产物化合物#C在新水箱试验和社交互动试验中表现出抗焦虑和抗抑郁样活性，可诱导鱼脑端脑区域的脑源性神经营养因子（BDNF）基因表达。因此，我们的结果表明，费卢他胺B合成路径中间体具有潜在的神经营养、神经生成和情绪提升作用，因此作为治疗精神疾病的潜在疗法具有良好的开发前景。
