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Synthesis of Chiral Sphingolipids and their Stereochemical Effects on Induction of Neurite Outgrowth and Sphingomyelin Synthase Activity
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| Title: | Synthesis of Chiral Sphingolipids and their Stereochemical Effects on Induction of Neurite Outgrowth and Sphingomyelin Synthase Activity |
| Other Titles: | キラルスフィンゴ脂質の合成とその立体化学による神経突起伸長及びスフィンゴミエリン合成酵素活性への影響について |
| Authors: | SAJEER, KOOLATH Browse this author |
| Issue Date: | 25-Mar-2020 |
| Publisher: | Hokkaido University |
| Abstract: | Sphingolipids are class of lipids having a backbone of sphingoid base with amide linked fatty acids and having different polar head groups. They are first discovered from the brain extract in the 1870s. Sphingolipids are named after the mythological Sphinx because of their enigmatic nature. They are known to protect cell surface by forming plasma membrane lipid bilayer. These sphingolipids play an important role in signal transmission and cell recognition, involved in many cellular processes such as apoptosis, senescence, differentiation, autophagy etc. Sphingolipids are important biomolecules and they are chiral. Chirality of sphingolipids and understanding their stereochemical effects is very important because they play a very crucial role in the biological system. Most of the drugs are chiral. Naturally the stereochemistry of most common sphingolipid, ceramide has D-erythro stereochemistry. So, the Chirality of sphingolipids plays key role in the drug discovery because one enantiomer of the drug may be useful medicine for a disease, but another isomer may be inactive or may be toxic to that disease. The second chapter of the thesis consists of the study of stereochemical effects of chiral GM3 on induction of neurite outgrowth and their comprehensive synthesis. The synthesis of different isomers of GM3 was performed from possible stereoisomers of sphingosine and study their stereochemical effects on induction of neurite outgrowth with or without NGF in PC12 cells. Neurite outgrowth activity was measured by staining with Coomassie brilliant blue (CBB) and fluorescence imaging with an inverted microscope and fluorescence microscope. All four isomers are enhancing the neurite outgrowth in the presence of NGF and without NGF. The result of the neurite outgrowth assay suggests that L-erythro GM3 inducing more neurite outgrowth as compared to the other three isomers.
Chapter 3 mainly focusing the importance of stereochemistry of ceramides and it was confirmed by creating the chiral ceramide library. To create the ceramide library, four different isomers of sphingosine was used and derivatize with different types of carboxylic acids by using solid-phase synthesis. Total of 128 chiral ceramides was synthesized and performed the sphingomyelin synthase (SMS) assay to understand the inhibitory activity towards SMS1 and SMS2. The cell-based assay of sphingomyelin synthase in the presence of unique chiral ceramides suggested that L-threo type ceramides showing higher inhibitory activities towards SMS1 and SMS2.
In chapter 4, novel ceramide library was created by using different types of sphingoid bases with variety of acyl chains. By using solid-phase synthesis, 132 ceramides were created to investigate their inhibitory activities against sphingomyelin synthase1 and 2 (SMS1 &2) using a cell-based assay. We have screened 95 ceramides so far and found two selective and potent inhibitors of SMS2 (DM-16 and DS-8) shows more than 100-fold selectivity. The libraries of this sort will be a rich source of biologically active synthetic molecules. |
| Conffering University: | 北海道大学 |
| Degree Report Number: | 甲第13943号 |
| Degree Level: | 博士 |
| Degree Discipline: | 生命科学 |
| Examination Committee Members: | (主査) 教授 門出 健次, 教授 比能 洋, 招へい教員（客員准教授） 臼杵 靖剛（先端生命科学研究院）, 助教 村井 勇太 |
| Degree Affiliation: | 生命科学院（生命科学専攻） |
| Type: | theses (doctoral) |
| URI: | http://hdl.handle.net/2115/89206 |
| Appears in Collections: | 課程博士 (Doctorate by way of Advanced Course) > 生命科学院(Graduate School of Life Science)
学位論文 (Theses) > 博士 （生命科学）
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