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设计具有强大体外和体内神经活性功能的咔唑基伏立诺他和类图巴他汀A组蛋白去乙酰化酶（HDAC）抑制剂。

Crafting Carbazole-Based Vorinostat and Tubastatin-A-like Histone Deacetylase (HDAC) Inhibitors with Potent in Vitro and in Vivo Neuroactive Functions.

作者信息

Reddy R Gajendra, Surineni Goverdhan, Bhattacharya Dwaipayan, Marvadi Sandeep Kumar, Sagar Arpita, Kalle Arunasree M, Kumar Arvind, Kantevari Srinivas, Chakravarty Sumana

机构信息

Applied Biology Division and Fluoro and Agrochemical Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Uppal Road, Hyderabad 500007, Telangana, India.

Academy of Scientific and Innovative Research (AcSIR), Chennai 600113, India.

出版信息

ACS Omega. 2019 Oct 7;4(17):17279-17294. doi: 10.1021/acsomega.9b01950. eCollection 2019 Oct 22.

DOI:10.1021/acsomega.9b01950
PMID:31656902
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6811854/
Abstract

Small-molecule inhibitors of HDACs (HDACi) induce hyperacetylation of histone and nonhistone proteins and have emerged as potential therapeutic agents in most animal models tested. The established HDACi vorinostat and tubastatin-A alleviate neurodegenerative and behavioral conditions in animal models of neuropsychiatric disorders restoring the neurotrophic milieu. In spite of the neuroactive pharmacological role of HDACi (vorinostat and tubastatin-A), they are limited by efficacy and toxicity. Considering these limitations and concern, we have designed novel compounds - as potential HDACi based on the strategic crafting of the key pharmacophoric elements of vorinostat and tubastatin-A into architecting a single molecule. The molecules - were synthesized through a multistep reaction sequence starting from carbazole and were fully characterized by NMR and mass spectral analysis. The novel molecules - showed remarkable pan HDAC inhibition and the potential to increase the levels of acetyl H3 and acetyl tubulin. In addition, few novel HDAC inhibitors -, , and exhibited significant neurite outgrowth-promoting activity with no observable cytotoxic effects, and interestingly, compound has shown comparably more neurite growth than the parent compounds vorinostat and tubastatin-A. Also, compound was evaluated for possible mood-elevating effects in a chronic unpredictable stress model of Zebrafish. It showed potent anxiolytic and antidepressant-like effects in the novel tank test and social interaction test, respectively. Furthermore, the potent in vitro and in vivo neuroactive compound has shown selectivity for class II over class I HDACs. Our results suggest that the novel carbazole-based HDAC inhibitors, crafted with vorinostat and tubastatin-A pharmacophoric moieties, have potent neurite outgrowth activity and potential to be developed as therapeutics to treat depression and related psychiatric disorders.

摘要

组蛋白去乙酰化酶（HDAC）的小分子抑制剂（HDACi）可诱导组蛋白和非组蛋白的超乙酰化，在大多数测试的动物模型中已成为潜在的治疗药物。已获批的HDACi伏立诺他和tubastatin - A可改善神经精神疾病动物模型中的神经退行性变和行为状况，恢复神经营养环境。尽管HDACi（伏立诺他和tubastatin - A）具有神经活性药理作用，但它们在疗效和毒性方面存在局限性。考虑到这些局限性和问题，我们基于将伏立诺他和tubastatin - A的关键药效基团进行策略性构建以设计单个分子，设计了新型化合物——作为潜在的HDACi。这些分子通过从咔唑开始的多步反应序列合成，并通过核磁共振和质谱分析进行了全面表征。新型分子显示出显著的泛HDAC抑制作用以及增加乙酰化H3和乙酰化微管蛋白水平的潜力。此外，少数新型HDAC抑制剂——、和表现出显著的促神经突生长活性且无明显细胞毒性作用，有趣的是，化合物显示出比母体化合物伏立诺他和tubastatin - A更强的神经突生长能力。此外，在斑马鱼慢性不可预测应激模型中评估了化合物的可能的情绪提升作用。它分别在新鱼缸试验和社交互动试验中显示出强效的抗焦虑和抗抑郁样作用。此外，强效的体外和体内神经活性化合物对II类HDAC的选择性高于I类HDAC。我们的结果表明，基于咔唑的新型HDAC抑制剂，结合了伏立诺他和tubastatin - A的药效基团，具有强大的神经突生长活性，有潜力开发为治疗抑郁症和相关精神疾病的药物。

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