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  2. Antiproliferative 3-deoxysphingomyelin analogs: Design, synthesis, biological evaluation and molecular docking of pyrrolidine-based 3-deoxysphingomyelin analogs as anticancer agents

Antiproliferative 3-deoxysphingomyelin analogs: Design, synthesis, biological evaluation and molecular docking of pyrrolidine-based 3-deoxysphingomyelin analogs as anticancer agents

  • Bioorg Chem. 2019 Mar:84:444-455. doi: 10.1016/j.bioorg.2018.11.040.
Ahmed H E Hassan 1 Hye Rim Park 2 Yoon Mi Yoon 2 Hye In Kim 2 Sung Yeun Yoo 2 Kun Won Lee 2 Yong Sup Lee 3
Affiliations

Affiliations

  • 1 Medicinal Chemistry Laboratory, Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
  • 2 Department of Life and Nanopharmaceutical Science, Kyung Hee University, Kyung Hee University, Seoul 02447, Republic of Korea.
  • 3 Medicinal Chemistry Laboratory, Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea; Department of Life and Nanopharmaceutical Science, Kyung Hee University, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address: kyslee@khu.ac.kr.
Abstract

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.

Keywords

3-Deoxysphingomyelin analogs; Akt phosphorylation; Antiproliferative agents; Bioactive lipids.

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