Development of a Redox-Sensitive Spermine Prodrug for the Potential Treatment of Snyder Robinson Syndrome,Journal of Medicinal Chemistry

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Development of a Redox-Sensitive Spermine Prodrug for the Potential Treatment of Snyder Robinson Syndrome
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-10-25 , DOI: 10.1021/acs.jmedchem.1c00419
Mukund P Tantak ₁ , Vandana Sekhar ₁ , Xianzun Tao ₂ , R Grace Zhai ₂ , Otto Phanstiel ₁

Affiliation

Snyder Robinson Syndrome (SRS) is a rare disease associated with a defective spermine synthase gene and low intracellular spermine levels. In this study, a spermine replacement therapy was developed using a spermine prodrug that enters cells via the polyamine transport system. The prodrug was comprised of three components: a redox-sensitive quinone “trigger”, a “trimethyl lock (TML)” aryl “release mechanism”, and spermine. The presence of spermine in the design facilitated uptake by the polyamine transport system. The quinone–TML motifs provided a redox-sensitive agent, which upon intracellular reduction generated a hydroquinone, which underwent intramolecular cyclization to release free spermine and a lactone byproduct. Rewardingly, most SRS fibroblasts treated with the prodrug revealed a significant increase in intracellular spermine. Administering the spermine prodrug through feeding in a Drosophila model of SRS showed significant beneficial effects. In summary, a spermine prodrug is developed and provides a lead compound for future spermine replacement therapy experiments.

中文翻译：

开发用于潜在治疗 Snyder Robinson 综合征的氧化还原敏感性精胺前药

斯奈德罗宾逊综合征 (SRS) 是一种罕见的疾病，与精胺合酶基因缺陷和细胞内精胺水平低有关。在这项研究中，使用精胺前药开发了一种精胺替代疗法，该前药通过多胺运输系统。前药由三部分组成：氧化还原敏感的醌“触发器”、“三甲基锁 (TML)”芳基“释放机制”和精胺。设计中精胺的存在促进了多胺转运系统的吸收。醌-TML 基序提供了一种氧化还原敏感剂，它在细胞内还原后产生对苯二酚，该对苯二酚经历分子内环化以释放游离精胺和内酯副产物。值得庆幸的是，用前药处理的大多数 SRS 成纤维细胞显示细胞内精胺显着增加。通过喂食果蝇来施用精胺前药SRS 模型显示出显着的有益效果。总之，开发了一种精胺前药，并为未来的精胺替代疗法实验提供了先导化合物。

更新日期：2021-11-11

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