41 results on '"Dong Jae Baek"'
Search Results
2. Synthesis and Cytotoxic Activity of Fingolimod (FTY720) Analogs with Various Amide Head Groups
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Su Bin Kim, Kwang Joon Kim, Jitendra Shrestha, Yoon Sin Oh, Joo-Youn Lee, Seungyeon Lee, Eun-Young Park, and Dong Jae Baek
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Pharmacology ,Drug Discovery - Published
- 2022
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Catalog
3. SK1 Inhibitor RB005 Induces Apoptosis in Colorectal Cancer Cells through SK1 Inhibition Dependent and Independent Pathway
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Maftuna Shamshiddinova, Jitendra Shrestha, Yong-Moon Lee, Dong Jae Baek, Yoon Sin Oh, and Eun Young Park
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Ceramide ,Programmed cell death ,Fingolimod Hydrochloride ,Colorectal cancer ,Activator (genetics) ,Angiogenesis ,Cell growth ,Sphingosine kinase ,Apoptosis ,General Medicine ,Ceramides ,medicine.disease ,chemistry.chemical_compound ,chemistry ,Colonic Neoplasms ,medicine ,Cancer research ,Humans ,RNA, Small Interfering ,Colorectal Neoplasms - Abstract
Background and Objective: Colorectal cancer (CRC) is the fourth leading cause of cancer- related death globally, with a high incidence rate in economically fast-growing countries. Sphingosine- 1-phosphate (S1P) is a bioactive lipid mediator that plays critical roles in cancer cell proliferation, migration, and angiogenesis converted by the isoforms of sphingosine kinase (SK1 and SK2). SK1 is highly expressed in colorectal cancer; its inhibitors suppress the formation of S1P and increase ceramide levels having a pro-apoptotic function. RB005 is a selective SK1 inhibitor and a structural analog of PP2A activator FTY720. The purpose of this study is to test whether RB005, an SK1 inhibitor, can be used as an anticancer agent by inhibiting the growth of colon cancer cells. Methods: We performed MTT and colony-forming assay using colon cancer cell lines HT29 and HCT116 cells to examine the cell toxicity effect of RB005. To determine whether apoptosis of RB005 in colon cancer cell line is due to SK1 inhibition or other mechanisms due to its structural similarity with FTY720, we conducted LC/MS, siRNA knockdown, and PP2A activity experiments. Results: RB005 notably inhibited CRC cell growth and proliferation compared to PF543 and ABC294640 by inducing the mitochondria-mediated intrinsic apoptotic pathway. Apoptotic cell death is caused by increased mitochondrial permeability Initiated by the activation of pro-apoptotic protein BAX, increased ceramides, and activation of PP2A. Also, RB005 treatment in HT29 cells did not change the expression level of SK1, but strikingly decreased SK1 activity and S1P levels. All these events of cell death and apoptosis were less effective when SK1 was knocked down by siRNA. Conclusion: This result indicates that RB005 shows the in-vitro anti-CRC effect by inhibiting SK1 activity and PP2A activation, increasing proapoptotic ceramide levels following the activation of the intrinsic apoptotic pathway. more...
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- 2022
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4. Synthesis of PF-543 Derivatives Using Simple Synthetic Methods and Their Biological Effect Analysis for the Development of Anticolorectal Cancer Agents
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Eun Young Park, Joo-Youn Lee, Jitendra Shrestha, and Dong Jae Baek
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Simple (abstract algebra) ,Chemistry ,Drug Discovery ,medicine ,Pharmaceutical Science ,Molecular Medicine ,Cancer ,Biological effect ,medicine.disease ,Combinatorial chemistry - Abstract
Background: Sphingolipids, even in extremely low doses, regulate various physiological functions. Particularly, immune and cancer cells might be controlled by changes in the sphingosine- 1-phosphate (S1P) levels, and S1P has been studied for a long time as a major target for new drug development. Sphingosine kinase (SK) phosphorylates sphingosine to produce S1P. An increase in the S1P levels promotes the growth of cancer cells. SK has 2 isoforms, SK1 and SK2, both of which are involved in the growth of cancer cells. Objective: PF-543 has been developed as an SK1 inhibitor and has a non-lipid structure that differs from those of general SK inhibitors. While PF-543 has a potent SK1 inhibitory effect, and has low anticancer activity in some types of cancer cells. Therefore, the development of other PF-543 derivatives is needed. Methods: We designed a structurally simplified derivative of PF-543. To primarily demonstrate that the designed structure was biologically active, 8 derivatives were synthesized by a 2-step method using the commercial starting material, and their biological activities were evaluated. Results: The SK1-inhibitory effects of the synthesized derivatives were not higher than that of PF- 543. However, the anticancer activity and apoptotic effect of the derivatives were similar to those of PF-543, despite their fabrication from a simple modification of the PF-543 structure. In a docking study, the derivatives were found to bind SK1 in a form similar to PF-543. Conclusion: Our analogs, which are similar to PF-543, showed comparable anticancer activity, indicating that the synthesized derivatives are structurally more efficient for anticancer activity than PF-543. Therefore, our study provides important information that may be useful for developing new anticancer substances that target SK1. more...
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- 2021
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5. Allomyrina dichotoma larval extract attenuates intestinal barrier disruption by altering inflammatory response and tight junction proteins in lipopolysaccharide-induced Caco-2 cells
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Gong-Deuk Bae, Kyong Kim, Chul Young Kim, Se-Eun Jang, Yoon Sin Oh, Eun Young Park, and Dong Jae Baek
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Lipopolysaccharides ,Male ,0301 basic medicine ,Lipopolysaccharide ,Biophysics ,Inflammation ,AMP-Activated Protein Kinases ,Diet, High-Fat ,Models, Biological ,Biochemistry ,Permeability ,Nitric oxide ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Adenosine Triphosphate ,0302 clinical medicine ,Edible Insects ,medicine ,Animals ,Humans ,Intestinal Mucosa ,Phosphorylation ,Protein kinase A ,Molecular Biology ,Cell damage ,Tight Junction Proteins ,Intestinal permeability ,Tight junction ,Cell Biology ,medicine.disease ,Cell biology ,Coleoptera ,Mice, Inbred C57BL ,030104 developmental biology ,chemistry ,Caco-2 ,Larva ,030220 oncology & carcinogenesis ,Caco-2 Cells ,medicine.symptom ,Reactive Oxygen Species ,human activities - Abstract
Intestinal epithelial cells form a barrier between the intestinal lumen and host connective tissues and play an important role in maintaining intestinal nutrient homeostasis. This study investigated effects of Allomyrina dichotoma (rhinoceros beetle) larval extract (ADLE) on the intestinal barrier damage and explored mechanisms for reversing intestinal barrier dysfunction in lipopolysaccharide (LPS)-stimulated Caco-2, human intestinal epithelial cells. LPS reduced intestinal epithelial barrier function by increasing transepithelial electrical resistance, and this effect was significantly attenuated by ADLE treatment. ADLE also significantly countered the inhibition of tight junction-related protein expression in both LPS-induced Caco-2 cells and intestine from HFD-induced mice. Moreover, ADLE significantly decreased expression and production of inflammatory factors, such as iNOS, cox-2, nitric oxide, and cytokines induced by LPS stimulus. Reduction in phosphorylation of adenosine monophosphate-activated protein kinase was averted by ADLE treatment in LPS treated INS-1 cells. Finally, reactive oxygen stress level was decreased and ATP production was increased by ADLE treatment. ADLE appears to display gut health-promoting effects by reducing inflammation and inducing tight junction proteins in Caco-2 cells. Therefore, ADLE might be useful for preventing or treating intestine cell damage in inflammatory bowel disease. more...
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- 2020
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6. Mediating Effect of Drug Burden on the Relationship between Household Income and Health-related Quality of Life of the Elderly with Hypertension
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Hong Seop Moon, Eun-Young Park, Dong Jae Baek, and Jeong Min Choi
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Drug ,Health related quality of life ,business.industry ,media_common.quotation_subject ,Environmental health ,Household income ,Medicine ,General Medicine ,business ,media_common - Published
- 2019
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7. Synthesis and Biological Evaluation of PF-543 Derivative Containing Aliphatic Side Chain
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Sanghee Kim, Tae-Ho Lee, Seon Woong Kim, Eun Young Park, Sang Mi Shin, Yoon Sin Oh, Dong Jae Baek, and Joo-Youn Lee
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Pyrrolidines ,Cell Survival ,Stereochemistry ,Sphingosine kinase ,Antineoplastic Agents ,010402 general chemistry ,Inhibitory postsynaptic potential ,01 natural sciences ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,Catalytic Domain ,Cell Line, Tumor ,Drug Discovery ,Side chain ,Humans ,Moiety ,Sulfones ,IC50 ,Biological evaluation ,Sulfonyl ,chemistry.chemical_classification ,Binding Sites ,010405 organic chemistry ,Chemistry ,Methanol ,General Chemistry ,General Medicine ,0104 chemical sciences ,Molecular Docking Simulation ,Phosphotransferases (Alcohol Group Acceptor) ,Docking (molecular) - Abstract
The PF-543 is known as a potent and selective inhibitor of sphingosine kinase (SK) 1 amongst all the SK inhibitors known to date. In a recently reported study by Pfizer on the synthesis of PF-543 derivatives and the SK inhibitory effects, the introduction of propyl moiety into sulfonyl group of PF-543 in the case of 26b revealed an excellent result of 1.7 nM of IC50 of SK1, suggesting the potential substitution of chain structure for benzenesulfonyl structure. In the present work, we aimed for identification of antitumor activity and inhibitory effects of PF-543 derivative containing aliphatic long chain (similar to known SK inhibitors) on SK1. The synthesized compound 2 exhibited an inhibitory effect on SK1 in a manner similar to that of PF-543; the PF-543 derivative manifested similar antitumor activity on HT29, HCT116 (colorectal cancer cell line), and AGS (gastric cancer cell line) cells. Also, from the docking study conducted with PF-543 and compound 2, it was apparent that the aliphatic chain in compound 2 could probably replace benzenesulfonyl structure of PF-543. more...
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- 2019
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8. Mebendazole Impedes the Proliferation and Migration of Pancreatic Cancer Cells through SK1 Inhibition Dependent Pathway
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Khem Raj Limbu, Rashmi Bhandari Chhetri, Yoon Sin Oh, Dong Jae Baek, and Eun-Young Park
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Chemistry (miscellaneous) ,Organic Chemistry ,Drug Discovery ,Molecular Medicine ,Pharmaceutical Science ,Physical and Theoretical Chemistry ,mebendazole ,pancreatic ductal adenocarcinoma ,sphingosine kinase ,sphingosine 1-phosphate ,Analytical Chemistry - Abstract
Pancreatic ductal adenocarcinoma (PDAC) has one of the highest mortality rates and requires the development of highly efficacious medications that can improve the efficiency of existing treatment methods. In particular, in PDAC, resistance to conventional chemotherapy reduces the effectiveness of anticancer drugs, decreasing the therapeutic efficiency. Sphingosine 1-phosphate (S1P), produced by sphingosine kinase (SK), plays a vital role in cancer growth, metastasis, chemotherapy, and drug resistance. Focusing on the structural characteristics of mebendazole (MBZ), we studied whether MBZ would affect metastasis, invasion, and drug resistance in cancer by lowering S1P production through inhibition of SK activity. MBZ selectively inhibited SK1 more than SK2 and regulated the levels of sphingolipids. MBZ inhibited the proliferation and migration of cancer cells in other PDAC cell lines. To determine whether the effect of MBZ on cancer cell growth and migration is S1P-mediated, S1P was treated, and the growth and migration of cancer cells were observed. It was found that MBZ inhibited S1P-induced cancer cell growth, and MBZ showed a growth inhibitory effect by regulating the JAK2/STAT3/Bcl-2 pathway. The phosphorylation of focal adhesion kinase (FAK), a transcription factor that regulates migration, was inhibited by MBZ, so it was found that the effect of MBZ regulates the migration of cancer cells through the S1P/FAK/vimentin pathway. In conclusion, our study suggests that the anthelmintic MBZ can be used as a potential therapeutic agent for treating PDAC and for structural synthesis studies of its analogs. more...
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- 2022
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9. In vitro anticancer evaluation of micelles containing N-(4-(2-((4-methoxybenzyl)amino)ethyl)phenyl)heptanamide, an analogue of fingolimod
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Jin Tae Hong, Dae Hwan Shin, Yu Jin Lee, Dong Jae Baek, Moon Sup Yoon, and Chun-Woong Park
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0301 basic medicine ,Stability test ,Polymers ,Antineoplastic Agents ,Micelle ,03 medical and health sciences ,0302 clinical medicine ,Drug Stability ,Cell Line, Tumor ,mental disorders ,Drug Discovery ,medicine ,Humans ,Particle Size ,Micelles ,chemistry.chemical_classification ,Drug Carriers ,Aqueous solution ,Polymeric micelles ,Fingolimod Hydrochloride ,Organic Chemistry ,Water ,Polymer ,Combinatorial chemistry ,Fingolimod ,In vitro ,Drug Liberation ,030104 developmental biology ,chemistry ,Solubility ,030220 oncology & carcinogenesis ,Molecular Medicine ,Particle size ,Drug Screening Assays, Antitumor ,human activities ,medicine.drug - Abstract
Fingolimod has been evaluated for use as an anticancer agent. However, many steps are required to synthesize fingolimod because of its intricate structure. A fingolimod analogue, N-(4-(2-((4-methoxybenzyl)amino)ethyl)phenyl)heptanamide (MPH), also has anti-cancer effects and is easier to synthesize but is poorly soluble in water. To compensate for its poor water solubility, MPH-loaded polymeric micelles were prepared by thin film hydration method using various polymers and the physicochemical properties of the MPH-loaded micelles such as particle size, drug-loading (DL, %), and encapsulation efficiency (EE, %) were evaluated. A storage stability test was conducted to select the final formulation and the release profile of the MPH-loaded micelles was confirmed by in vitro release assay. MPH-loaded mPEG-b-PLA micelles were selected for further testing based on their stability and physicochemical properties; they were stable for stable for 14 days at 4 °C and 25 °C and for 7 days at 37 °C. They showed anti-cancer efficacy against both A549 and U87 cancer cells. Encapsulation of MPH in polymeric micelles did not decrease the in vitro cytotoxicity of MPH. The findings of this study lay the groundwork for future formulations that enable the effective and stable delivery of poorly water-soluble agents. more...
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- 2020
10. Synthesis and Biological Evaluation of PF-543 Derivative
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Hee-Sook Jun, Dong Jae Baek, Sanghee Kim, Joo-Youn Lee, Tae-Ho Lee, Seon Woong Kim, and Eun Young Park
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0301 basic medicine ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,chemistry ,Organic Chemistry ,Biochemistry ,Combinatorial chemistry ,Derivative (chemistry) ,Biological evaluation - Abstract
PF-543 has been known as a substance that strongly inhibits SK1. However, it also exhibits antineoplastic activity that is lower than other inhibitors of SK1. In this study, we compared PF-543 and synthesized a newly designed derivative of PF-543 (compound 2) in which two aromatic structures were connected in para-form. The synthesized derivative showed inhibitory effect on SK1, similar to that of PF-543. However, it was more cytotoxic to HT29, AGS, and PC3 cells than PF-543. We also carried out a docking study for SK1 and demonstrated that the synthesized derivative showed interaction with SK1 similar to PF-543. Results obtained from this study suggest that the structure of compound 2 may be well substituted for the structure of PF-543 in terms of biological activity, providing us important structural information for the design of new derivatives of PF-543. more...
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- 2018
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11. Antitumor activity of PF-543 and PF-543 derivative (22c) as sphingosine kinase 1 inhibitors
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Dong Jae Baek and Eun-Young Park
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Antitumor activity ,chemistry.chemical_compound ,Sphingosine kinase 1 ,biology ,Chemistry ,medicine ,Sphingosine kinase ,Cancer research ,biology.protein ,Cancer ,General Medicine ,medicine.disease ,Derivative (chemistry) - Published
- 2018
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12. Determining the Anticancer Activity of Sphingosine Kinase Inhibitors Containing Heteroatoms in Their Tail Structure
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Jitendra Shrestha, Seong Woong Kim, Su-Bin Kim, Yoon Sin Oh, Sung Hwan Ki, Taeho Lee, Sang-Bum Kim, Taeuk Park, Dong Jae Baek, and Eun-Young Park
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RS1-441 ,Pharmacy and materia medica ,derivative ,Pharmaceutical Science ,colorectal cancer ,SK inhibitor ,S1P ,anticancer agent ,PP2A ,Article - Abstract
Sphingosine kinase (SK) enzyme, a central player of sphingolipid rheostat, catalyzes the phosphorylation of sphingosine to the bioactive lipid mediator sphingosine 1 phosphate (S1P), which regulates cancer cell proliferation, migration, differentiation, and angiogenesis through its extracellular five G protein-coupled S1P receptors (S1PR1–5). Recently, several research studies on SK inhibitors have taken place in order use them for the development of novel anticancer-targeted therapy. In this study, we designed and synthesized analog derivatives of known SK1 inhibitors, namely RB005 and PF-543, by introducing heteroatoms at their tail structure, as well as investigated their anticancer activities and pharmacokinetic parameters in vitro. Compounds 1–20 of RB005 and PF-543 derivatives containing an aliphatic chain or a tail structure of benzenesulfonyl were synthesized. All compounds of set 1 (1–10) effectively reduced cell viability in both HT29 and HCT116 cells, whereas set 2 derivatives (11–20) showed poor anticancer effect. Compound 10, having the highest cytotoxic effect (48 h, HT29 IC50 = 6.223 µM, HCT116 IC50 = 8.694 µM), induced HT29 and HCT116 cell death in a concentration-dependent manner through the mitochondrial apoptotic pathway, which was demonstrated by increased annexin V-FITC level, and increased apoptotic marker cleaved caspase-3 and cleaved PARP. Compound 10 inhibited SK1 by 20%, and, thus, the S1P level decreased by 42%. Unlike the apoptosis efficacy, the SK1 inhibitory effect and selectivity of the PF-543 derivative were superior to that of the RB005 analog. As a result, compounds with an aliphatic chain tail exhibited stronger apoptotic effects. However, this ability was not proportional to the degree of SK inhibition. Compound 10 increased the protein phosphatase 2A (PP2A) activity (1.73 fold) similar to FTY720 (1.65 fold) and RB005 (1.59 fold), whereas compounds 11 and 13 had no effect on PP2A activation. Since the PP2A activity increased in compounds with an aliphatic chain tail, it can be suggested that PP2A activation has an important effect on anticancer and SK inhibitory activities. more...
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- 2022
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13. Synthesis of FTY720 (Fingolimod) Derivatives Containing Serine Structure
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Jitendra Shrestha, Sang Mi Shin, Eun Young Park, Tae-Ho Lee, Doohyun Lee, Yoon Sin Oh, and Dong Jae Baek
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0301 basic medicine ,Sphingosine ,Chemistry ,Stereochemistry ,General Chemistry ,Fingolimod ,Serine ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,Fingolimod fty720 ,030220 oncology & carcinogenesis ,medicine ,medicine.drug - Published
- 2018
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14. Synthesis and Biological Evaluation of FTY720 (Fingolimod) Derivatives with Aromatic Head Group as Anticancer Agents
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Joo-Youn Lee, Hong Seop Moon, Jitendra Shrestha, Sanghee Kim, Sang Mi Shin, Seon Woong Kim, Tae-Ho Lee, Eun Young Park, and Dong Jae Baek
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0301 basic medicine ,Cell Survival ,Sphingosine kinase ,Antineoplastic Agents ,Pharmacology ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,0302 clinical medicine ,Drug Discovery ,medicine ,Tumor Cells, Cultured ,Phenyl group ,Humans ,Cell Proliferation ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Fingolimod Hydrochloride ,Multiple sclerosis ,General Chemistry ,General Medicine ,Protein phosphatase 2 ,medicine.disease ,Fingolimod ,Molecular Docking Simulation ,030104 developmental biology ,Docking (molecular) ,Apoptosis ,030220 oncology & carcinogenesis ,Cancer cell ,Drug Screening Assays, Antitumor ,medicine.drug - Abstract
FTY720 is employed for the treatment of multiple sclerosis and exerts apoptotic effects on various cancers through protein phosphatase 2A (PP2A) activation. In compound 4, the dihydroxy head group of FTY720 was modified into dihydroxy phenyl group. The cell survival in compound 4 treated colorectal and gastric cancer cells was significantly reduced as compared with control, 34.6 and 25.1%, respectively. The docking study of compound 4 showed that the aromatic head group effectively binds to PP2A. more...
- Published
- 2018
15. Synthesis of dansyl labeled sphingosine kinase 1 inhibitor
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Tae-Ho Lee, Sanghee Kim, Joo-Youn Lee, Yoon Sin Oh, GeunHyung Jo, Jitendra Shrestha, Dong Jae Baek, Eun Young Park, Yun Ji Jin, Seung Woo Hong, Gil Tae Hwang, and Dong-Sul Han
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0301 basic medicine ,Pyrrolidines ,Structural similarity ,Sphingosine kinase ,Xylenes ,Inhibitory postsynaptic potential ,Biochemistry ,03 medical and health sciences ,Structure-Activity Relationship ,Sulfones ,Molecular Biology ,Inhibitory effect ,Protein Kinase Inhibitors ,Fluorescent Dyes ,Binding Sites ,biology ,Molecular Structure ,Chemistry ,Methanol ,Organic Chemistry ,Cell Biology ,Molecular Docking Simulation ,Phosphotransferases (Alcohol Group Acceptor) ,030104 developmental biology ,Spectrometry, Fluorescence ,Sphingosine kinase 1 ,Docking (molecular) ,biology.protein ,Phosphatidylcholines ,Animal studies ,Selectivity ,Protein Binding - Abstract
PF-543 is a non-sphingosine analogue with inhibitory effect against SK1, based on a Ki of 4.3 nM and 130-fold selectivity for SK1 over SK2. Since the development of PF-543, animal studies demonstrated its valuable role in multiple sclerosis, myocardial infarction, and colorectal cancer. We synthesized labeled PF-543 for biochemical studies involving SK1. Overall, the 8-step synthetic route used 3,5-dimethylphenol as the starting material. A docking study of SK1 and SK1 inhibitory activity confirmed the structural similarity between the synthetic dansyl-PF-543 and PF-543. We also provide fluorescence spectra of dansyl-PF-543. more...
- Published
- 2018
16. Efficient solid-phase synthesis of 2,4-disubstituted 5-carbamoyl-thiazole derivatives using a traceless support
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Daehun Kim, Tae-Ho Lee, Kyung Hoon Min, Kwang-Hyeon Liu, Doohyun Lee, Jong-Sup Bae, Young-Dae Gong, and Dong Jae Baek
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chemistry.chemical_classification ,Sulfide ,Organic Chemistry ,Cleavage (embryo) ,Biochemistry ,Combinatorial chemistry ,Merrifield resin ,chemistry.chemical_compound ,Solid-phase synthesis ,chemistry ,Nucleophile ,Drug Discovery ,Organic chemistry ,Thiazole ,Linker - Abstract
An efficient protocol for the solid-phase synthesis of 2,4-disubstituted 5-carbamoyl-thiazole derivatives has been developed. After the reaction scopes were investigated in solution-phase, the polymer-supported synthesis route was progressed using a sulfide linker in a traceless manner. The solid-phase synthetic protocol started with the Thorpe-Ziegler type cyclization of 2-chloroacetamide and polymer-bound cyanocarboimidodithioate, which is derived from Merrifield resin. The resulting 5-carbamoyl-thiazole was introduced to one substitution by N-acylation. After the oxidation of sulfides to sulfones for subsequent cleavage, nucleophilic desulfonative substitution with amines and thiols gave the target 2,4-disubstituted 5-carbamoyl-thiazole derivatives in good purities and overall yields. more...
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- 2015
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17. Liquiritigenin prevents palmitate-induced beta-cell apoptosis via estrogen receptor-mediated AKT activation
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Eun Young Park, Dong Jae Baek, Hee-Sook Jun, Yoon Sin Oh, and Gong Deuk Bae
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0301 basic medicine ,Cell Survival ,Palmitates ,Estrogen receptor ,Apoptosis ,Cell Line ,03 medical and health sciences ,chemistry.chemical_compound ,eIF-2 Kinase ,Downregulation and upregulation ,Insulin-Secreting Cells ,Animals ,Viability assay ,Phosphorylation ,Protein kinase A ,Protein kinase B ,Fulvestrant ,Pharmacology ,Estradiol ,Caspase 3 ,Endoplasmic reticulum ,General Medicine ,Endoplasmic Reticulum Stress ,Cell biology ,Rats ,030104 developmental biology ,chemistry ,Receptors, Estrogen ,Flavanones ,Unfolded protein response ,Liquiritigenin ,Poly(ADP-ribose) Polymerases ,Proto-Oncogene Proteins c-akt ,Transcription Factor CHOP - Abstract
Liquiritigenin (LQ) is a major active component of licorice root, which is a flavone used for treating many diseases, including diabetes. LQ has been shown to exhibit a glucose-lowering effect in diabetic mice. Therefore, we investigated the potential of LQ to protect against lipotoxicity-induced beta-cell apoptosis and the underlying molecular mechanisms. Exposure of INS-1 rat insulinoma cells to LQ significantly increased cell viability and blocked palmitate (PA)-induced apoptosis, as evidenced by the reduction of Annexin-V-stained cells, cleaved caspase-3 levels, and poly (ADP-ribose) polymerase (PARP) activity, as well as upregulation of Bcl-2 expression. Moreover, LQ treatment significantly reduced the endoplasmic reticulum (ER) stress response by reducing phosphorylated protein kinase RNA-like endoplasmic reticulum kinase (PERK), phosphorylated eIF-2a, and CHOP expression in PA-treated INS-1 cells. The anti-apoptotic effect of LQ treatment was reversed through co-treatment with fulvestrant, a specific inhibitor of the estrogen receptor. LQ also increased AKT phosphorylation, and inactivation of this molecular event failed to decrease PERK phosphorylation with LQ treatment in PA-treated INS-1 cells. This effect was further accompanied by an inability to recover cell viability. These results suggest that LQ protects INS-1 cells from lipotoxicity-induced apoptosis by suppressing ER stress. We conclude that estrogen receptor-mediated AKT phosphorylation is one of the mechanisms contributing to the anti-apoptotic effect of LQ. more...
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- 2017
18. Membrane properties of cholesterol analogs with an unbranched aliphatic side chain
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Robert Bittman, Daniel Huster, Andreas Herrmann, Ivan Haralampiev, Thomas Meyer, Holger A. Scheidt, Dong Jae Baek, and Peter Müller
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Androstenols ,Magnetic Resonance Spectroscopy ,Chemistry ,Stereochemistry ,Organic Chemistry ,Phospholipid ,Cell Biology ,Nuclear magnetic resonance spectroscopy ,Permeation ,Biochemistry ,Permeability ,Sterol ,Diffusion ,chemistry.chemical_compound ,Cholesterol ,Membrane ,Alkanes ,Phosphatidylcholines ,Side chain ,Proton NMR ,lipids (amino acids, peptides, and proteins) ,Lipid bilayer ,Molecular Biology ,Phospholipids ,Unilamellar Liposomes - Abstract
The interactions between cholesterol and other membrane molecules determine important membrane properties. It was shown that even small changes in the molecular structure of cholesterol have a crucial influence on these interactions. We recently reported that in addition to alterations in the tetracyclic ring structure, the iso-branched side chain of cholesterol also has a significant impact on membrane properties (Scheidt et al., 2013). Here we used synthetic cholesterol analogs to investigate the influence of an unbranched aliphatic side chain of different length. The (2)H NMR order parameter of the phospholipid chains and therefore the molecular packing of the phospholipid molecules shows a significant dependence on the sterol's alkyl side chain length, while, membrane permeation studied by a dithionite ion permeation assay and lateral diffusion measured by (1)H MAS pulsed field gradient NMR are less influenced. To achieve the same molecular packing effect similar to that of an iso-branched aliphatic side chain, a longer unbranched side chain (n-dodecyl instead of n-octyl) at C17 of cholesterol is required. Obviously, sterols having a branched iso-alkyl chain with two terminal methyl groups exhibit altered cholesterol-phospholipid interactions compared to analogous molecules with a straight unbranched chain. more...
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- 2014
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19. Synthesis and Biological Evaluation of BODIPY-PF-543
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Gil Tae Hwang, Sanghee Kim, Eun Young Park, Yongseok Kwon, Hong Seop Moon, Seon Woong Kim, Tae-Ho Lee, Jitendra Shrestha, Yoon Sin Oh, Dong Jae Baek, and Seung Woo Hong
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Boron Compounds ,Pyrrolidines ,Sphingosine kinase ,Pharmaceutical Science ,Chemistry Techniques, Synthetic ,confocal microscopy ,Article ,Analytical Chemistry ,law.invention ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,BODIPY ,Confocal microscopy ,law ,Drug Discovery ,Sulfones ,Enzyme Inhibitors ,Physical and Theoretical Chemistry ,030304 developmental biology ,0303 health sciences ,Molecular Structure ,Sphingosine ,Methanol ,Spectrum Analysis ,Organic Chemistry ,PF-543 ,Fluorescence ,In vitro ,Cell biology ,inhibitor ,Phosphotransferases (Alcohol Group Acceptor) ,Cytosol ,chemistry ,sphingosine kinase ,Chemistry (miscellaneous) ,030220 oncology & carcinogenesis ,Cancer cell ,Molecular Medicine - Abstract
Sphingosine-1-phosphate (S1P) regulates the proliferation of various cells and promotes the growth of cancer cells. Sphingosine kinase (SK), which transforms sphingosine into S1P, has two isotypes: SK1 and SK2. To date, both isotypes are known to be involved in the proliferation of cancer cells. PF-543, an SK1 inhibitor developed by Pfizer, strongly inhibits SK1. However, despite its strong SK1 inhibitory effect, PF-543 shows low anticancer activity in vitro. Therefore, additional biological evidence on the anticancer activity of SK1 inhibitor is required. The present study aimed to investigate the intracellular localization of PF-543 and identify its association with anticancer activity by introducing a fluoroprobe into PF-543. Boron&ndash, dipyrromethene (BODIPY)-introduced PF-543 has a similar SK1 inhibitory effect as PF-543. These results indicate that the introduction of BODIPY does not significantly affect the inhibitory effect of SK1. In confocal microscopy after BODIPY-PF-543 treatment, the compound was mainly located in the cytosol of the cells. This study demonstrated the possibility of introducing fluorescent material into an SK inhibitor and designing a synthesized compound that is permeable to cells while maintaining the SK inhibitory effect. more...
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- 2019
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20. Design and Evaluation of ω-Hydroxy Fatty Acids Containing α-GalCer Analogues for CD1d-Mediated NKT Cell Activation
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Chang-Yuil Kang, Sanghee Kim, Won Jae Cho, Chaemin Lim, Yoon-Sook Lee, Joo Youn Lee, Dong Jae Baek, Minjae Cho, Jae Hyun Kim, and Doo Hyun Chung
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chemistry.chemical_classification ,Molecular model ,Hydrogen bond ,Organic Chemistry ,Fatty acid ,chemical and pharmacologic phenomena ,Biology ,Ligand (biochemistry) ,Biochemistry ,Combinatorial chemistry ,Amino acid ,carbohydrates (lipids) ,Glycolipid ,chemistry ,CD1D ,Drug Discovery ,biology.protein ,Molecule ,lipids (amino acids, peptides, and proteins) - Abstract
CD1d molecules recognize glycolipid antigens with straight chain fatty acid moieties. Although most of the residues in the CD1d binding groove are hydrophobic, some of the amino acids can form hydrogen bonds. Consequently, we have designed ω-hydroxy fatty acid-containing glycolipid derivatives of the prototypical CD1d ligand α-GalCer. The potency of the ω-hydroxy analogues of the proper length is comparable to that of α-GalCer. We propose, based on the biological results and molecular modeling studies, that a hydrogen bonding interaction is involved between the ω-hydroxy group and a polar amino acid residue in the hydrophobic binding groove. more...
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- 2014
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21. Die aliphatische Seitenkette von Cholesterol bestimmt essenzielle Membraneigenschaften
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Ivan Haralampiev, Andreas Herrmann, Daniel Huster, Robert Bittman, Peter Müller, Jörg Nikolaus, Dong Jae Baek, Holger A. Scheidt, Lars Thomas, and Thomas Meyer
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General Medicine - Published
- 2013
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22. Cholesterol’s Aliphatic Side Chain Modulates Membrane Properties
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Peter Müller, Andreas Herrmann, Robert Bittman, Holger A. Scheidt, Jörg Nikolaus, Thomas J. Meyer, Ivan Haralampiev, Daniel Huster, Lars Thomas, and Dong Jae Baek
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technology, industry, and agriculture ,Phospholipid ,Biological membrane ,General Chemistry ,Catalysis ,chemistry.chemical_compound ,symbols.namesake ,Membrane ,chemistry ,Membrane protein ,polycyclic compounds ,Membrane fluidity ,symbols ,Side chain ,Biophysics ,Organic chemistry ,lipids (amino acids, peptides, and proteins) ,van der Waals force ,Sphingomyelin - Abstract
The composition and chemical structures of the membrane forming molecules determine all essential properties of nature’s most important interface. Cellular membranes are subject to a hierarchical domain organization on the mesoscopic length scale.[1] This is triggered by preferential interactions between the major constituents of the membrane, e.g. phospholipids, cholesterol (Chol), glycolipids, and membrane proteins.[2] In particular, the attractive interactions between Chol and sphingolipids or saturated phospholipids and/or membrane proteins have been identified as the driving force for membrane domain formation.[3] Key to the lipid phase separation phenomena is the preferential interaction of Chol with saturated lipid chains.[4] Numerous examples of the specific interaction between Chol and saturated phospholipids or sphingomyelin have been reported.[5] The interaction between Chol and saturated lipid chains is thought to originate by attractive van der Waals interactions between Chol’s planar and rigid ring system (particularly the smooth α-face) and the saturated phospholipid chains.[6] This leads to a stiffening of the lipid chains, as indicated by an order increase, which is referred to as area condensation.[7] This increased packing density decreases membrane permeability.[8] Surprisingly, the influence of the aliphatic Chol side chain on lipid condensation and membrane domain formation is still not fully understood. Therefore, we have systematically studied the influence of the methyl-branched (iso-series) side chain of Chol with 5 to 14 carbon atoms[9] (Figure 1A) on important membrane properties. more...
- Published
- 2013
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23. Synthesis and bioactivity of α-galactosylceramide analogues bearing an aryl group within the fatty amide chain
- Author
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Chang-Yuil Kang, Joo-Youn Lee, Chaemin Lim, Dong Jae Baek, Junseok Park, and Robert Bittman
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chemistry.chemical_classification ,biology ,Stereochemistry ,Aryl ,Organic Chemistry ,Sonogashira coupling ,Biochemistry ,chemistry.chemical_compound ,chemistry ,Chain (algebraic topology) ,Group (periodic table) ,CD1D ,Amide ,Drug Discovery ,biology.protein ,Phenyl group ,Alkyl - Abstract
We describe the synthesis and bioactivity of analogues of α-galactosylceramide (1) bearing a long-chain alkyl group substituted at the meta or para position of an aryl group embedded within the amide chain. We compared the ability of these compounds and of 1 and C6Ph (2, which has a phenyl group at the amide chain terminus) to stimulate murine invariant Natural Killer T cells and to dock with human CD1d. more...
- Published
- 2013
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24. Synthesis of cholesterol analogs having varying length alkyl side chains including cholesterol-23, 23, 24, 24, 25, 26, 26, 26, 27, 27, 27-d11 as probes of cholesterol's functions and properties
- Author
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Robert Bittman and Dong Jae Baek
- Subjects
chemistry.chemical_classification ,Alkylation ,Chemistry ,Cholesterol ,Membrane lipids ,Organic Chemistry ,Chemistry Techniques, Synthetic ,Cell Biology ,Biochemistry ,Toluene ,Sterol ,Membrane Lipids ,Sterols ,chemistry.chemical_compound ,Molecular Probes ,Side chain ,Organic chemistry ,lipids (amino acids, peptides, and proteins) ,Molecular Biology ,Crown ether ,Alkyl - Abstract
Cholesterol-23, 23, 24, 24, 25, 26, 26, 26, 27, 27, 27-d11 and nondeuterated long-chain analogs of cholesterol were prepared by alkylation of cyano-containing sterols with isopentyl-d11 4-methylbenzenesulfonate (1.0equiv.) or with isoalkyl bromides, followed by reductive decyanation with excess potassium metal and a crown ether in toluene. The products are potentially useful probes of the role of the side-chain of cholesterol in the sterol's interactions with membrane lipids and proteins. more...
- Published
- 2013
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25. IgG Antibody Response Elicited by a Fully Synthetic Two-Component Carbohydrate-Based Cancer Vaccine Candidate with α-Galactosylceramide as Built-in Adjuvant
- Author
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Zhong-Yin Zhou, Dong Jae Baek, Zheng Liu, Wen-Mei Sun, Pan-Pan Ji, Jun Guo, Guang-Fu Yang, Xiao-Shan Geng, Xiang-Zhao Chen, Jian Wang, Xu-Guang Yin, and Xiao-Kang Zhang
- Subjects
medicine.medical_treatment ,Cell ,010402 general chemistry ,01 natural sciences ,Biochemistry ,medicine ,Physical and Theoretical Chemistry ,biology ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Carbohydrate ,Ligand (biochemistry) ,Molecular biology ,Combinatorial chemistry ,nervous system diseases ,0104 chemical sciences ,surgical procedures, operative ,Antibody response ,medicine.anatomical_structure ,nervous system ,Immunoglobulin class switching ,biology.protein ,Cancer vaccine ,Antibody ,therapeutics ,Adjuvant - Abstract
A fully synthetic self-adjuvanting cancer vaccine candidate was constructed through covalent conjugation of invariant natural killer T (iNKT) cell ligand α-galactosylceramide (αGalCer) with sialyl Tn (STn), a representative tumor-associated carbohydrate antigen (TACA). This two-component vaccine STn-αGalCer is devoid of antigenic peptide, featuring the well-defined structure with high simplicity. STn-αGalCer showed remarkable efficacy in inducing antibody class switching from IgM to STn-specific IgG. Subtypes of IgG antibody were primarily IgG1 and IgG3. more...
- Published
- 2017
26. Stereochemically Reliable Syntheses of Pachastrissamine and Its 2-epi-Congener via Oxazolidinone Precursors from an Established Starting Material N-tert-Butoxycarbonyl-Protected Phytosphingosine
- Author
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Hoon Bae, Sanghee Kim, Hongjun Jeon, Dongjoo Lee, and Dong Jae Baek
- Subjects
Congener ,Stereochemistry ,Chemistry ,Organic Chemistry ,Catalysis ,Pachastrissamine - Abstract
Efficient, stereochemically unambiguous, total syntheses of pachastrissamine and its 2- epi -congener from the readily available common precursor (1 R )-1-{(4 S ,5 S )-2-oxo-4-[(trityloxy)methyl]-1,3-oxazolidin-5-yl}pentadecyl methanesulfonate are reported. Syntheses of (3a S ,6 R ,6a R )- and (3a S ,6 S ,6a R )-6-tetradecylhexahydro-2 H -cyclopenta[ d ][1,3]oxazol-2-one by this route have unambiguously resolved a dispute over the structures of these products. more...
- Published
- 2012
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27. A Practical and Cost-Effective Synthesis of d-erythro-Sphingosine from d-ribo-Phytosphingosine via a Cyclic Sulfate Intermediate
- Author
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Sanghee Kim, Jae Hong Seo, Dong Jae Baek, Seokwoo Lee, Hongjun Jeon, Deukjoon Kim, and Yun Mi Lee
- Subjects
Cyclic compound ,animal structures ,Sphingosine ,Stereochemistry ,organic chemicals ,Organic Chemistry ,Reactive intermediate ,Diol ,Reaction intermediate ,Chemical synthesis ,Sphingolipid ,Catalysis ,chemistry.chemical_compound ,chemistry ,Protecting group - Abstract
The practical and efficient synthesis of D-erythro-sphingosine from commercially available D-ribo-phytosphingosine is described. An important feature of this synthesis is the selective transformation of the 3,4-vicinal diol of phytosphingosine into the characteristic E-allylic alcohol of sphingosine via a cyclic sulfate intermediate that contains a non-nucleophilic trifluoroacetamide protecting group. more...
- Published
- 2011
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28. Regioselective Inversion of the Hydroxyl Group in <scp>d</scp>-ribo-Phytosphingosine via a Cyclic Sulfate and Bis-Sulfonate Intermediate
- Author
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Sanghee Kim, Seokwoo Lee, Deukjoon Kim, Yun Mi Lee, and Dong Jae Baek
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Alkanesulfonates ,Magnetic Resonance Spectroscopy ,animal structures ,Molecular Structure ,Sulfates ,Stereochemistry ,Organic Chemistry ,Thermal decomposition ,Regioselectivity ,Stereoisomerism ,chemistry.chemical_compound ,Sulfonate ,chemistry ,Sphingosine ,Group (periodic table) ,Sulfate ,D-ribo-phytosphingosine - Abstract
The selective synthesis of D-xylo- and D-lyxo-phytosphingosines from commercially available D-ribo-phytosphingosine is described. Thermolysis of the N-carbonyl protected cyclic sulfate led to an inversion of configuration of the proximal hydroxyl group to give the xylo-isomer, whereas the corresponding bis-sulfonate resulted in an inversion of configuration of the distal hydroxyl group to give the lyxo-isomer. This study allowed the comparison between a cyclic sulfate and a bis-sulfonate in an intramolecular substitution reaction involving a carbonyl oxygen nucleophile. more...
- Published
- 2010
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29. Rational Design and Evaluation of a Branched-Chain-Containing Glycolipid Antigen That Binds to CD1d
- Author
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Chaemin Lim, Jae-Young Lee, Kyoo-A Lee, Sanghee Kim, Dong Jae Baek, Won-Jea Cho, Yoon-Sook Lee, Tae-Ho Lee, Chang-Yuil Kang, and Doohyun Lee
- Subjects
Binding Sites ,biology ,Chemistry ,Organic Chemistry ,Rational design ,General Chemistry ,Biochemistry ,Glycolipid ,Antigen ,Chain (algebraic topology) ,Drug Design ,CD1D ,biology.protein ,Humans ,Interleukin-2 ,Computer Simulation ,Antigens ,Antigens, CD1d ,Glycolipids ,Protein Binding - Published
- 2010
- Full Text
- View/download PDF
30. Cholesterol's Aliphatic Side Chain Structure Modulates Membrane Properties
- Author
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Ivan Haralampiev, Daniel Huster, Jörg Nikolaus, Robert Bittman, Thomas Meyer, Holger A. Scheidt, Peter Müller, Andreas Herrmann, and Dong Jae Baek
- Subjects
Membrane permeability ,Chemistry ,Bilayer ,Phospholipid ,Biophysics ,Raft ,Sterol ,chemistry.chemical_compound ,Membrane ,Membrane protein ,Side chain ,Organic chemistry ,lipids (amino acids, peptides, and proteins) - Abstract
The influence of the length of the cholesterol alkyl chain on essential membrane properties such as lipid ordering (condensation), lateral diffusion, membrane permeability, and membrane domain formation was studied using a series of synthetic cholesterol derivatives without a side chain or with an iso-branched chain bearing 5 to 14 carbons in length. We found that cholesterol's aliphatic side chain is crucial for all of the membrane properties investigated. First, we detected that the side chain is responsible for more than half of the phospholipid condensation in bilayers. Second, the length of the sterol side chain strongly determines membrane permeation, since a slightly longer or shorter side chain renders the bilayer significantly more permeable. Third, lateral lipid and sterol diffusion highly depends on the side chain length. Fourth, the length of the cholesterol side chain also determines the lateral organization of lipids in raft mixtures. While all tested sterols induce domain formation, the lipid distribution between the liquid disordered or raft phase is strongly dependent on side chain length. Fifth, the sterol side chain also influences the partitioning of a transmembrane peptide domain into liquid-ordered or liquid-disordered domains. Therefore, in addition to the flat tetracyclic ring system of cholesterol, the iso-branched side chain of cholesterol plays a key role in producing the relevant membrane properties of eukaryotic cells that result in an optimal interaction with phospholipids and presumably with membrane proteins. Sterols bearing an unbranched alkyl side chain of varying length also influence important properties of lipid membranes. However, the extent of this impact is lower compared with that measured for the respective branched iso-side chain sterols. Obviously, sterols having a branched iso-chains with two terminal methyl groups exhibit altered cholesterol-phospholipid-interactions compared to molecules with a straight unbranched chain. more...
- Published
- 2016
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31. Structure and dynamics of the aliphatic cholesterol side chain in membranes as studied by (2)H NMR spectroscopy and molecular dynamics simulation
- Author
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Daniel Huster, Dong Jae Baek, Holger A. Scheidt, Alexander Vogel, and Robert Bittman
- Subjects
0301 basic medicine ,Steric effects ,Magnetic Resonance Spectroscopy ,Molecular Structure ,Stereochemistry ,Molecular Conformation ,General Physics and Astronomy ,Molecular Dynamics Simulation ,Deuterium ,NMR spectra database ,03 medical and health sciences ,chemistry.chemical_compound ,Crystallography ,Molecular dynamics ,030104 developmental biology ,Membrane ,Cholesterol ,chemistry ,Side chain ,Proton NMR ,lipids (amino acids, peptides, and proteins) ,Physical and Theoretical Chemistry ,POPC ,Phospholipids ,Methyl group - Abstract
Cholesterol is an evolutionarily highly optimized molecule particularly known for its ability to condense the phospholipids in cellular membranes. Until recently, the accompanying increase in the chain order of the surrounding phospholipids was attributed to the planar and rigid tetracyclic ring structure of cholesterol. However, detailed investigations of cholesterol's aliphatic side chain demonstrated that this side chain is responsible for approximately half of the condensation effect. Therefore, we investigated the structure and dynamics of the aliphatic side chain of cholesterol using (2)H solid-state nuclear magnetic resonance (NMR) spectroscopy and microsecond timescale all-atom molecular dynamics (MD) simulations in four different model membranes: POPC, DPPC, PSM, and POPC/PSM (1 : 1 mol/mol) and at three different temperatures: 5 °C, 37 °C, and 50 °C. A cholesterol variant, in which 11 hydrogens of the aliphatic side chain were exchanged for deuterium, was used and the respective (2)H NMR spectra confirmed the axially asymmetric rotational diffusion of cholesterol in DPPC and PSM. Furthermore, NMR spectra indicated that some hydrogens showed an unexpected magnetic inequivalency. This finding was confirmed by all-atom molecular dynamics simulations and detailed analysis revealed that the hydrogens of the methylene groups at C22, C23, and C24 are magnetically inequivalent. This inequivalency is caused by steric clashes of the aliphatic side chain with the ring structure of cholesterol as well as the branched C21 methyl group. These excluded volume effects result in reduced conformational flexibility of the aliphatic side chain of cholesterol and explain its high order (order parameter of 0.78 for chain motions) and large contribution to the condensation effect. Additionally, the motional pattern of the side chain becomes highly anisotropic such that it shows larger fluctuations perpendicular to the ring plane of cholesterol with a biaxiality of the distribution of 0.046. Overall, our results shed light on the mechanism how the aliphatic side chain is able to contribute about half of the condensation effect of cholesterol. more...
- Published
- 2016
32. Synthesis and Evaluation of 1,2,3-Triazole Containing Analogues of the Immunostimulant α-GalCer
- Author
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Chang-Yuil Kang, Dong Jae Baek, Sung-Youl Ko, Sanghee Kim, Hyun-Jun Youn, Won-Jea Cho, Tae-Ho Lee, and Minjae Cho
- Subjects
Models, Molecular ,medicine.drug_class ,Stereochemistry ,medicine.medical_treatment ,Receptors, Antigen, T-Cell ,Triazole ,Galactosylceramides ,chemical and pharmacologic phenomena ,Immunostimulant ,Chemical synthesis ,Antigens, CD1 ,Interferon-gamma ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,Th2 Cells ,Adjuvants, Immunologic ,Cell Line, Tumor ,Drug Discovery ,medicine ,Animals ,Humans ,Moiety ,Interferon gamma ,Interleukin 4 ,Hybridomas ,Triazoles ,Natural killer T cell ,Coculture Techniques ,Rats ,Mice, Inbred C57BL ,carbohydrates (lipids) ,Cytokine ,chemistry ,Biochemistry ,Interleukin-2 ,Molecular Medicine ,lipids (amino acids, peptides, and proteins) ,Interleukin-4 ,Antigens, CD1d ,Spleen ,medicine.drug - Abstract
alpha-GalCer is the first defined and most potent agonistic antigen of the T cell receptor of natural killer T cells. We have prepared a series of 1,2,3-triazole-containing alpha-GalCer analogues in which the lipid chain lengths have been incrementally varied. We found that this isosteric replacement of alpha-GalCer's amide moiety with triazole increases the IL-4 versus IFN-gamma bias of released cytokines. The stimulatory effect was influenced by the length of the attached chain. In particular, the long-chained triazole analogues have a comparable stimulatory effect on cytokine production as alpha-GalCer and exhibit a stronger Th2 cytokine response. more...
- Published
- 2007
- Full Text
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33. Solid-Phase Synthesis of 1,3,7,8-Tetrasubstituted Xanthine Derivatives on Traceless Solid Support
- Author
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Seungyeon Lee, Jong-Sup Bae, Tae-Ho Lee, Doohyun Lee, Dong Jae Baek, and Kwang-Hyeon Liu
- Subjects
Pyrimidine ,Alkylation ,010405 organic chemistry ,Imidazoles ,Thiourea ,General Chemistry ,General Medicine ,010402 general chemistry ,Xanthine ,01 natural sciences ,Catalysis ,0104 chemical sciences ,Merrifield resin ,chemistry.chemical_compound ,Solid-phase synthesis ,chemistry ,Nucleophile ,Cyclization ,Xanthines ,Organic chemistry ,Imidazole ,Cyanamide ,Amine gas treating ,Solid-Phase Synthesis Techniques ,Lewis Acids - Abstract
Traceless solid-phase synthesis of 1,3,7,8-tetrasubstituted xanthine (1,3,7,8-tetrasubstituted 1H-purine-2,6(3H,7H)-dione) derivatives has been developed. The solid-phase synthetic route began on a solid supported N'-cyano-N-substituted carbamimidothioate, which was prepared from cyanamide, isothiocyanate, and Merrifield resin. After N-alkylation of carbamimidothioate resin with ethyl 2-bromoacetate, an imidazole ring is introduced by Thorpe-Ziegler-type cyclization. The resulting imidazole resin is converted to 1,3,7-trisubstituted xanthine resin using sequential reactions, such as Lewis acid-catalyzed urea formation, pyrimidine ring cyclization, and N-alkylation. After oxidation of sulfides to sulfones, traceless cleavage with amine or thiol nucleophiles afforded the desired 1,3,7,8-tetrasubstituted xanthines in good purities and overall yields (eight-steps; 36 examples). This efficient solid-phase synthesis enables the incorporation of four diversity points into the preparation of the 1,3,7,8-tetrasubstituted xanthines. more...
- Published
- 2015
34. Photoreactions of 1-(3-acetoxy or methoxycarbonylmethoxy-2-pyridyl)-2-(pentamethyldisilanyl)ethynes
- Author
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Seung Ki Park and Dong Jae Baek
- Subjects
chemistry.chemical_compound ,Chemistry ,Computational chemistry ,General Chemical Engineering ,Intramolecular force ,Product (mathematics) ,Photodissociation ,General Physics and Astronomy ,General Chemistry ,Benzene ,Medicinal chemistry ,Cycloaddition - Abstract
Photolysis of 1-(3-methoxycarbonylmethoxy-2-pyridyl)-2-(pentamethyldisilanyl)ethyne 2b in benzene provides a novel intramolecular cycloaddition product 15 via silacyclopropene intermediate 13 but the photoreaction of 1-(3-acetoxy-2-pyridyl)-2-(pentamethyldisilanyl)ethyne 2a in benzene affords 1-(3-acetoxy or 3-hydroxy-2-pyridyl)-2-(trimethylsilanyl)ethyne 5 or 6 , respectively, via silacyclopropene intermediate 3 instead of a intramolecular cycloaddition product. more...
- Published
- 2004
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- View/download PDF
35. Photoreactions of 1-(3-hydroxy-2-pyridyl)-2-(pentamethyldisilanyl)ethyne, aza analogue of 1-o-hydroxyphenyl-2-(pentamethyldisilanyl)ethyne
- Author
-
Dong Jae Baek and Seung Ki Park
- Subjects
Reaction mechanism ,Intramolecular reaction ,Stereochemistry ,General Chemical Engineering ,Photodissociation ,Carbon-13 ,General Physics and Astronomy ,General Chemistry ,Medicinal chemistry ,Cycloaddition ,chemistry.chemical_compound ,chemistry ,Intramolecular force ,Methylene ,Benzene - Abstract
Photolysis of 1-(3-hydroxy-2-pyridyl)-2-(pentamethyldisilanyl)ethyne 1, aza analogue of 1-o-hydroxyphenyl-2-(pentamethyldisilanyl)ethyne, in benzene provides novel intramolecular cycloaddition products 6 and 8 via silacyclopropene intermediate 3 but affords a novel intramolecular cycloaddition product 10 via 1-silaallene intermediate 9 in addition to 6 and 8 in methylene chloride. more...
- Published
- 2003
- Full Text
- View/download PDF
36. Solvent effects on the photochemical behavior of 1-(n-pyridyl)-2-(pentamethyldisilanyl)ethynes (n=2,3, or 4), aza analogs of 1-phenyl-2-(pentamethyldisilanyl)ethyne
- Author
-
Dong Jae Baek and Seung Ki Park
- Subjects
chemistry.chemical_compound ,chemistry ,General Chemical Engineering ,Organic solvent ,Photodissociation ,General Physics and Astronomy ,Flash photolysis ,General Chemistry ,Reaction intermediate ,Methanol ,Solvent effects ,Benzene ,Photochemistry - Abstract
Photolysis of 1-(n-pyridyl)-2-(pentamethyldisilanyl)ethynes (n=2,3, or 4) 1, 9, or 20, respectively, aza analogs of 1-phenyl-2-(pentamethyldisilanyl)ethyne, was performed in both non-polar and polar solvents. In benzene, they provide silacyclopropene and 1-sila-1,2-propadiene intermediates but afford only silacyclopropene intermediate in methanol. more...
- Published
- 2003
- Full Text
- View/download PDF
37. Photoreactions of 1-o-substituted-aminophenyl-2-(pentamethyldisilanyl)ethynes
- Author
-
Seung Ki Park and Dong Jae Baek
- Subjects
Addition reaction ,Intramolecular reaction ,General Chemical Engineering ,Organic solvent ,Photodissociation ,General Physics and Astronomy ,General Chemistry ,Reaction intermediate ,Photochemistry ,Cycloaddition ,chemistry.chemical_compound ,chemistry ,Intramolecular force ,Benzene - Abstract
Photolysis of 1-o-acetylaminophenyl-2-(pentamethyldisilanyl)ethyne 2a in benzene provides a novel intramolecular cycloaddition product 4 via 1-sila-1,2-propadiene intermediate 3. Photolysis of 1-o-amino-, allylamino-, or methoxycarbonylmethylaminophenyl-2-(pentamethyldisilanyl)ethynes 2b, 2c, or 2d in benzene only provides the reduction product 8. more...
- Published
- 2002
- Full Text
- View/download PDF
38. ChemInform Abstract: Synthesis of Selective Inhibitors of Sphingosine Kinase 1
- Author
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Neil MacRitchie, Robert Bittman, Dong Jae Baek, Susan Pyne, and Nigel J. Pyne
- Subjects
Inhibitory potency ,chemistry.chemical_compound ,chemistry ,Sphingosine kinase 1 ,biology ,Stereochemistry ,biology.protein ,General Medicine ,Derivative (chemistry) - Abstract
Among the novel compounds screened for their inhibitory potency against sphingosine kinase 1, derivative (IIIb) exhibits the highest activity.
- Published
- 2013
- Full Text
- View/download PDF
39. An α-GalCer analogue with branched acyl chain enhances protective immune responses in a nasal influenza vaccine
- Author
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Yoon-Sook Lee, Chang-Yuil Kang, Jae-Young Lee, You Chan Song, Kyoo-A Lee, Sanghee Kim, Min-Hee Kang, and Dong Jae Baek
- Subjects
Influenza vaccine ,medicine.medical_treatment ,chemical and pharmacologic phenomena ,Galactosylceramides ,Antibodies, Viral ,Virus ,Microbiology ,Mice ,Immune system ,Th2 Cells ,Adjuvants, Immunologic ,Orthomyxoviridae Infections ,medicine ,Cytotoxic T cell ,Animals ,Humans ,Immunity, Mucosal ,Administration, Intranasal ,Mice, Inbred BALB C ,General Veterinary ,General Immunology and Microbiology ,biology ,Public Health, Environmental and Occupational Health ,Th1 Cells ,Lymphocyte Subsets ,Immunoglobulin A ,carbohydrates (lipids) ,Mice, Inbred C57BL ,Infectious Diseases ,Cytokine ,Immunization ,Influenza A virus ,Influenza Vaccines ,CD1D ,Immunoglobulin G ,Immunology ,biology.protein ,Molecular Medicine ,Cytokines ,lipids (amino acids, peptides, and proteins) ,Female ,Adjuvant - Abstract
α-Galactosylceramide (α-GalCer) is a safe and effective adjuvant for nasal vaccines and induces protective immune responses against tumors and viral infections. In our previous study, the fatty acyl chains of α-GalCer were modified based on the CD1d/glycolipid structure to generate α-GalCer analogues with branched acyl chains. In this study, two α-GalCer analogues, KBC-007 and KBC-009, that have different branched chain lengths were prepared and evaluated for their efficacy as nasal influenza vaccine adjuvants. These analogues displayed improved solubility over α-GalCer and potently stimulated NKT cells in both murine and in vitro human systems. Examination of serum cytokines in vivo revealed that these analogues elicited different cytokine release profiles compared to α-GalCer. KBC-009 induced both Th1/Th2 cytokines, whereas KBC-007 induced a more Th2-polarized cytokine response with diminished IFN-γ production. We found that a single immunization of inactivated influenza virus A/PR/8/34 (PR8) combined with α-GalCer analogues enhanced PR8-specific humoral and cellular immune responses in both systemic and mucosal compartments. Notably, KBC-009 exhibited potent adjuvant effects, inducing significantly higher systemic IgG and mucosal IgA antibody titers and enhancing cytotoxic T lymphocyte generation when compared to immunization with inactivated PR8 alone. In contrast, addition of KBC-007 to inactivated PR8 only marginally increased PR8-specific immune responses. The protective effect of KBC-009 against challenge infection was comparable to the effect produced by α-GalCer. These results suggest that an α-GalCer analogue with a branched acyl chain could be used as an effective mucosal adjuvant for the induction of protective immune responses against influenza virus infection. more...
- Published
- 2010
40. Efficient synthesis of (+)-MK7607 and its C-1 epimer via the stereoselective transposition of a tertiary allylic alcohol
- Author
-
Sanghee Kim, Deukjoon Kim, Chaemin Lim, Dong Jae Baek, and So Won Youn
- Subjects
Allylic rearrangement ,Molecular Structure ,Stereochemistry ,Propanols ,organic chemicals ,Organic Chemistry ,Transposition (telecommunications) ,food and beverages ,Halogenation ,Galactose ,Alcohol ,Stereoisomerism ,Allylic alcohol ,Biochemistry ,Catalysis ,chemistry.chemical_compound ,Stereospecificity ,chemistry ,Phenols ,Stereoselectivity ,Epimer ,Physical and Theoretical Chemistry ,Palladium - Abstract
These studies provide an efficient and stereoselective synthetic route to (+)-MK7607 and its C-1 epimer from a common intermediate in high overall yields. The synthetic methodologies mainly rely on the stereospecific 1,3-allylic transposition of the hindered tertiary alcohol group through a palladium-catalyzed allylic rearrangement as well as a PBr(3)-mediated allylic-transposed bromination. more...
- Published
- 2009
41. Syntheses of sulfur and selenium analogues of pachastrissamine via double displacements of cyclic sulfate
- Author
-
Sanghee Kim, Deukjoon Kim, Hongjun Jeon, Dong Jae Baek, Young-Shin Kwak, and Hoon Bae
- Subjects
inorganic chemicals ,Cell Survival ,Stereochemistry ,chemistry.chemical_element ,Ring (chemistry) ,Biochemistry ,Oxygen ,Selenium ,chemistry.chemical_compound ,Sphingosine ,Cell Line, Tumor ,Humans ,Physical and Theoretical Chemistry ,Sulfate ,Molecular Structure ,Sulfates ,Organic Chemistry ,Intermolecular force ,Sulfur ,chemistry ,Cyclization ,Intramolecular force ,SN2 reaction - Abstract
Bioisosteric analogues of pachastrissamine that contain sulfur and selenium atoms replacing the oxygen in the ring system, were efficiently prepared from a cyclic sulfate intermediate by sequential intermolecular and intramolecular S(N)2 displacement reactions of the dianions. The analogues exhibited cytotoxicities comparable to that of pachastrissamine. more...
- Published
- 2011
- Full Text
- View/download PDF
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