Sphingomyelins and glycerophospholipids are structurally related phospholipids. Nevertheless, glycerophospholipids analogs are known as antitumor agents while sphingomyelin analogs were reported as cytoprotective agents. Herein, we have addressed the development of 3-deoxysphingomyelin analogs as cytotoxic agents possessing modified sphingobases. Thus, pyrrolidine-based 3-deoxysphingomyelin analogs were synthesized and evaluated against a panel of cell lines representing four major types of cancers. Compounds 3d, 4d and 6d elicited better GI50 values than the FDA approved drug miltefosine. Investigation of their impact on Akt phosphorylation as a possible mechanism for the antiproliferative activity of this class of compounds revealed that these compounds might elicit a concentration-dependent mechanism via inhibition of Akt phosphorylation at the lower concentration. Molecular docking predicted their binding modes to Akt to involve polar head binding to the Pleckstrin homology domain and hydrophobic tail extension into a hydrophobic pocket connecting the Pleckstrin homology domain and the kinase domain. As a whole, the described work suggests compounds 3d, 4d and 6d as promising pyrrolidine-based 3-deoxysphingomyelin analogs for development of novel cancer therapies.

中文翻译：

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抗增殖的3-deoxysphingomyelin类似物：基于吡咯烷的3-deoxysphingomyelin类似物作为抗癌剂的设计，合成，生物学评估和分子对接。

鞘磷脂和甘油磷脂是结构上相关的磷脂。然而，甘油磷脂类似物被称为抗肿瘤剂，而鞘磷脂类似物被报告为细胞保护剂。在这里，我们已经解决了3-脱氧鞘磷脂类似物作为具有修饰的鞘氨醇碱基的细胞毒剂的开发。因此，合成了基于吡咯烷的3-脱氧鞘磷脂类似物，并针对代表四种主要类型癌症的一组细胞系进行了评估。化合物3d，4d和6d的GI50值优于FDA批准的药物米替福辛。作为这类化合物的抗增殖活性的可能机制，它们对Akt磷酸化的影响的研究表明，这些化合物可能通过在较低浓度下抑制Akt磷酸化而引发浓度依赖性的机制。分子对接预测它们与Akt的结合模式涉及与Pleckstrin同源结构域的极性头结合和疏水尾延伸至连接Pleckstrin同源结构域和激酶结构域的疏水口袋中。总体而言，上述工作表明化合物3d，4d和6d是有前途的基于吡咯烷的3-deoxysphingomyelin类似物，可用于开发新的癌症疗法。分子对接预测它们与Akt的结合模式涉及与Pleckstrin同源结构域的极性头结合和疏水尾延伸至连接Pleckstrin同源结构域和激酶结构域的疏水口袋中。总体而言，上述工作表明化合物3d，4d和6d是有前途的基于吡咯烷的3-deoxysphingomyelin类似物，可用于开发新的癌症疗法。分子对接预测它们与Akt的结合模式涉及与Pleckstrin同源结构域的极性头结合和疏水尾延伸至连接Pleckstrin同源结构域和激酶结构域的疏水口袋中。总体而言，上述工作表明化合物3d，4d和6d是有前途的基于吡咯烷的3-deoxysphingomyelin类似物，可用于开发新的癌症疗法。